•

KATEDRA ZA
ONKOLOGIJO
• SEKCIJA ZA
INTERNISTIČNO
ONKOLOGIJO

#2
INTERNATIONAL
SUMMER SCHOOL
IN
MEDICAL ONCOLOGY

ONKOLOŠKI INŠTITUT LJUBLJANA
7.-10. SEPTEMBER 2021

Strokovni odbor:
prof. dr. Janja Ocvirk, dr.med.
prof. dr. Davorin Radosavljević, dr.med.
doc. dr. Tanja Mesti, dr.med.

Organizacijski odbor:
prof. dr. Janja Ocvirk, dr.med.
doc. dr. Tanja Mesti, dr.med.

Uredniki zbornika:
Marko Boc, dr.med.
prof. dr. Janja Ocvirk, dr.med.
doc. dr. Tanja Mesti, dr.med.

Recezenti:
doc. dr. Tanja Mesti, dr.med.
doc. dr. Erika Matos, dr.med.

Organizator in izdajatelj (založnik):
Onkološki inštitut Ljubljana
Sekcija za internistično onkologijo
Katedra za onkologijo

Zborniki šol o melanoma in ostale publikacije s strokovnih dogodkov so dosegljivi na spletnih straneh
Onkološkega inštituta:
www.onko-i.si/publikacije-strokovnih-dogodkov-oi

Ljubljana, september 2021

Tuesday, September 7
08.50-09.10
09.10-09.30

09.30-10.00
10.00-10.30
10.30-10.45
10.45-11.15
11.15-11.45
11.45-12.15
12.15-12.45
12.45-13.15
13.15-13.30
13.30-13.50

13.50-14.20
14.20-15.00
15.00-15.40
15.40-16.10
16.10-17.00

Registration of participants
Satellite Symposium Abbott
The importance of the palliativist and nutritionist
(Moderators Mesti, Ocvirk)
The palliative care – is early too early? (Ebert)
The nutritional support – is fat bad? (Dobrila)
Discussion
Break
Systemic treatment – the other side of the coin
Side effects of immunotherapy and the management (Hribernik)
Our experience – interesting cases (Žižek, Hribernik)
Side effects of chemotherapy (including extravasation) and
management (Ovčariček)
Side effects of TKI and Management (Bokal)
Car-T Neurological complications (Carpentier)
Discussion
Break
Future perspectives – are we there yet
Systemic treatment of the skin cancer – where we stand
(Moderators Ocvirk, Mesti)
Adjuvant and neoadjuvant systemic treatment of melanoma
(Schadendorf)
Systemic treatment for metastatic melanoma (Kandolf Sekulović)
Our experience – interesting cases (Vid Čeplak Mencin, Mesti)
Systemic treatment of non melanoma (Ocvirk)
Our experience – interesting cases (Sever, Ocvirk)
NGS - the new Superhero in Oncology (Mesti)
Systemic treatment of the skin cancer – where we stand
Interesting interactive cases and discussion

Wednesday, September 8
08.40-9.00
09.00-09.30
09.30-10.00
10.00-10.30
10.30-11.00
11.00-11.30
11.30-12.00
12.00-12.15

Satellite Symposium Servier
Future perspectives – are we there yet (Moderators Ocvirk, Mesti)
Systemic treatment of the gastric cancer – where we stand (Boc)
Our experience – interesting cases (Erman, Mesti)
Systemic treatment of the biliary cancer – where we stand (Reberšek)
Systemic treatment for the pancreatic cancer – are we going forward
(Pašič)
How to approach NET/NEC (Ignjatovič)
Our experience – interesting cases (Leskovšek, Ocvirk)
HCC – lots has been going on (Ocvirk)
Our experience – interesting cases (Stefanovski, Ocvirk)
Precision systemic treatment of colorectal cancer – can we understand
the complexity (Pleština)
Discussion

12.15-12.40 Break
Future perspectives – are we there yet (Moderator Matos)
12.40-13.00 Enrichment of treatment at metastatic NSCLC with PD-L1
overexpression (PD-L1≥50) (Radisavljević)
13.00-13.20 Clinical choices at metastatic NSCLC without actionable oncogenic driver
regardless of PD-L1 status (Jakopović)
13.20-14.00 Systemic treatment of head and neck cancer – what's new in the old
(Grašič)
Our experience – interesting cases (Plavc, Zupančič, Grašič)
14.00-14.40 Management of cancer of unknown primary in the molecular era (Matos)
Our experience – interesting cases (Cankar, Matos)
14.40-15.10 Systemic treatment of Ewing sarcoma – where do we stand (Unk)
Our experience – interesting cases (Sokolova, Unk)
15.10-15.30 Discussion and conclusion
15.30-15.50 Satellite Symposium Amgen

Thursday, September 9
Future perspectives – are we there yet (Moderator Škrbinc)
08.40-09.00 Satellite Symposium BMS
09.00-09.30 Systemic treatment of prostate cancer – standards and prespectives
(Belev)
09.30-10.00 Systemic treatment of RCC - standards and prespectives (Šeruga)
10.00-10.30 An approach to patient with cancer and kidney disease (Milanez)
10.30-11.00 The systemic treatment of the bladder cancer – is something new
going on (Gnjidić)
11.00-11.30 Systemic treatment of germinal tumors – could it get better (Škrbinc)
11.30-12.00 Systemic treatment of gynecological tumors – standards and
perspectives (Mandič)
12.00-12.15 Discussion
12.15-12.45 Break
Future perspectives – are we there yet (Moderator Borštnar)
12.45-13.15 Early and locally advanced hormone dependant Breast cancer – where
do we stand (Bešlija)
13.15-13.45 Metastatic breast cancer – standards and perspectives (Borštnar)
13.45-14.00 Discussion and conclusion
14.00-14.20 Satellite Symposium Pfizer
14.20.14.40 Satellite Symposium Eli Lilly

Friday, September 10
Future perspectives – are we there yet (Moderators Jezeršek, Pahole, Rugelj)
09.00-09.20 Satellite Symposium Roche
(09.20-13.00) Standards and perspectives in the systemic treatment of Lymphomas
09.20-09.40 Diffuse Large B cell Lymphoma (Jezeršek)
09.40-10.00 Marginal Zone Lymphoma (Miljković)
10.00-10.20 Follicular Lymphoma (Južnič Šetina)
10.20-11.00 Break
11.00-11:20 Mantle Cell Lymphoma (Jagodic)

11.20-11.40
11.40-12.00
12.00-12.30
12.30-13.00
13.00-13.30

T Cell Lymphomas (Pahole)
Hodgkin lymphoma (Rugelj)
Break
Principles of Radiotherapy in Lymphomas (Zadravec Zaletel)
Discussion and Conclusion

KAZALO
Ebert M.:
The palliative care – is early too early?...................................................................................... 8
Dobrila-Dintijana R.:
The nutritional support – is fat bad?......................................................................................... 17
Hribernik N.:
Side effects of immunotherapy and the management………………………………………... 18
Žižek A., Hribernik N.:
Our experience – interesting cases…………………………………………………………… 22
Ovčariček T.:
Side effects of chemotherapy (including extravasation) and management…………………... 25
Bokal U.:
Side effects of TKI and Management………………………………………………………... 42
Carpentier A.:
Car-T Neurological complications…………………………………………………………… 49
Kandolf-Sekulović L.:
Systemic treatment for metastatic melanoma………………………………………………... 60
Čeplak-Mencin V., Mesti T.:
Our experience – interesting cases……………………………………………………………89
Simetić L., Blazičević K., Herceg D.:
Patient with BRAF mutated metastatic melanoma …………………………………………...90
Ocvirk J.:
Systemic treatment of non melanoma ………………………………………………………...92
Sever M., Ocvirk J.:
Our experience – interesting cases ………………………………………………………….121
Mesti T.:
NGS - the new Superhero in Oncology ……………………………………………………..134
Boc M.:
Systemic treatment of the gastric cancer – where we stand …………………………………136
Erman A., Mesti T.:
Our experience – interesting cases …………………………………………………………..139
Reberšek M.:
Systemic treatment of the biliary cancer – where we stand …………………………………141
Ignjatović M.:
How to approach NET/NEC ………………………………………………………………...142
Leskovšek K., Ocvirk J.:
Our experience – interesting cases …………………………………………………………..148
Ocvirk J.:
HCC – lots has been going on ……………………………………………………………….150
Stefanovski D., Ocvirk J.:
Our experience – interesting cases …………………………………………………………..174
Radosavljević D.:
Enrichment of treatment at metastatic NSCLC with PD-L1 overexpression (PD-L1≥50) … 180
Jakopović M.:
Clinical choices at metastatic NSCLC without actionable oncogenic driver regardless of PDL1 status ……………………………………………………………………………………..191
Grašič-Kuhar C.:
Systemic treatment of head and neck cancer – what's new in the old ………………………207
Zupančič T., Zakotnik B., Grašič-Kuhar C.:

Our experience – interesting cases …………………………………………………………..209
Matos E.:
Management of cancer of unknown primary in the molecular era ………………………….211
Unk M.:
Systemic treatment of Ewing sarcoma – where do we stand ………………………………..223
Sokolova A, Unk M.:
Our experience – interesting cases …………………………………………………………..231
Belev B.:
Systemic treatment of prostate cancer – standards and prespectives ………………………..236
Šeruga B.:
Systemic treatment of RCC - standards and prespectives …………………………………...243
Gnjidić M.:
The systemic treatment of the bladder cancer – is something new going on ……………….256
Škrbinc B.:
Systemic treatment of germinal tumors – could it get better (Škrbinc) ……………………. 271
Mandić A.:
Systemic treatment of gynecological tumors – standards and perspectives (Mandič)……... 295
Bešlija S.:
Early and locally advanced hormone dependant Breast cancer – where do we stand ………302
Borštnar S.:
Metastatic breast cancer – standards and perspectives (Borštnar) …………………………. 324
Jezeršek-Novaković B.:
Diffuse Large B cell Lymphoma ……………………………………………………………327
Miljković M.:
Marginal Zone Lymphoma ………………………………………………………………….331
Južnič-Šetina T.:
Follicular Lymphoma ………………………………………………………………………..335
Jagodic M.:
Mantle Cell Lymphoma ……………………………………………………………………..346
Pahole J.:
T Cell Lymphomas ………………………………………………………………………….347
Rugelj U.:
Hodgkin lymphoma………………………………………………………………………….349
Zadravec-Zaletel L.:
Principles of Radiotherapy in lymphomas …………………………………………………..350

2nd SUMMER SCHOOL IN MEDICAL ONCOLOGY

PALLIATIVE CARE
Is early too early?
Maja Ebert Moltara, MD
mebert@onko-i.si
Head of a Department for Acute Palliative Care
Department of Medical Oncology

7 - 10 September 2021, Ljubljana, Slovenia

PALLIATIVE CARE
Is early too early?

EARLY PALLIATIVE CARE

2

8

6 BASIC QUESTIONS:
WHAT?
For WHO?
WHO provides?
WHERE?
WHEN?
WHY?

3

WHAT?

WHO definition of palliative care
Palliative care is an approach that improves
the quality of life
of patients and their families
facing the problem associated with life-threatening illness, through the
prevention and relief of suffering
by means of early identification and impeccable assessment and treatment of
pain and other problems, physical, psychosocial and spiritual.

9

COMPREHENSIVE PALLIATIVE CARE

COMPREHENSIVE PALLIATIVE CARE
• pain
• dyspnea
• nausea
• vomiting
• fatigue

• fear
• anger
• anxiaty
• depression

PHYSICAL
SYMPTOMs

PSYCOLOGY

SOCIAL
SUPPORT

SPIRITUAL

SYMPTOMs

SUPPORT

• isolation
• family dynamic
• financial support

• question about
life/death
• religion
• hope

6

10

WHO provides and WHERE?
All medical and non-medical members of
teams in institutions where incurable
patients are treated.
Basic palliative care (80% patient):
All levels of health system
(hospitals, community health centre, at home, senior homes, hospicih...)
All.

Specialied palliative care (20%):
Does not substitute basic palliative care, but it upgrade it for the patients with the most
difficult and complex problems
Specialized teams (acute palliative care departent, mobile PC team)
EAPC: White Paper on standards and norms for hospice and palliative care in Europe

7

CONTINOUS PALLIATIVE CARE
SENIOR HOMES

REGIONAL HOSPITALS

FAMILY DOCTOR AND
DISTRIC NURSE

PATIENT WITH A FAMILY

EMERGANCY TEAM

UNIVERSITY HOSPITALS

PC MOBILE TEAM

HOSPIC MOVEMENT

8

11

For WHO?

CANCER

CHRONIC HEART
FAILURE
COPB

ELDERLY

Murray, S. A et al. BMJ 2008;336:958-959

months, weeks

SPECIFIC THERAPY
+
EARLY
PALLIATIVE CARE

LATE
PALLIATIVE CARE

days months

CARE OF THE GRIEVING

Months, years

CARE OF THE DYING

Performans status

WHEN?

DEATH
10

12

Conceptual framework
newer term
less stigma
more hospital based
wider range of services
lower definitional clarity
less volunteer involment

SUPPORTIVE CARE
PALLIATIVE CARE
HOSPICE CARE
SPECIFIC THERAPY
no
evidence
of disease

early stage disease
(curable)

advanced disease
(incurable)

older term
more stigma
more home based
more focused services
higher definitional clarity
more volunteer involment

bereavement

Hui, D. et al. Concepts and definitions for “supportive care,” “best supportive care, ” “palliative care, ” and
“hospice care” in the published literature, dictionaries, and textbooks. Support. Care Cancer 21, 659–685 (2013).

WHEN?

12

13

EARLY PALLIATIVE CARE

Temel, NEJM 2010

Ferell, J Pain Manag, 2015

Bakitas, JCO 2015

Higginson 2015

Murakami BMC Pall 2015

Bakitas, JCO 2013

14

14

PALLIATIVE CARE
Is early too early?

PALLIATIVE CARE
CAN NOT BE TOO EARLY

15

1. DENIAL

2. PALLIPHOBIA

PHASES OF DEVELOPMENT:

3. PALLILALIA

4. PALLIACTIVE

15

Hope is like the sun, which, as we journey toward it,
casts the shadow of our burden behind us.

THANK YOU!!!

2013 Mayo Foundation for Medical education an Research, Mayo Clin Proc. 2013; 88 (8):859865

16

The nutritional supportis fat bad?

Prof. Renata Dobrila-Dintinjana, MD. PhD.
Damir Vučinić, MD.
Clinical Hospital Center Rijeka
School of Medicine, University of Rijeka, Croatia

• Monounsaturated fat, n-3 PUFA, and fat soluble vitamins may have a profound
influence on the prevention and/or suppression of cancer, whereas saturated fat and
n-6 PUFA may increase the risk of carcinogenesis
• Monounsaturated fat and n-3 fatty acids should be preferred over animal fats and
other vegetable fats in the diet
• Malnutrition is an important issue in cancer patients, which should be appropriately
managed by structured collaboration of MDT
• Pharmacological approach (EPA/MA) to the treatment of anorexia cachexia syndrome
in cancer patients significantly improves QoL and probably prolongs OS

17

IMMUNE-RELATED ADVERSE EVENTS OF
IMMUNE CHECKPOINT INHIBITORS
Nežka Hribernik, MD
Institute of Oncology Ljubljana
2nd Summer School in Medical Oncology
September 2021

Possible mechanisms underlying irAE

Postow MA, et al. NEJM 2018

18

Martins F, et al. Nature Clinical Oncology Reviews, 2019

Fatal irAE (cont`d)
•

Risk of fatality:
– Myocarditis 40%
– Hypophysitis, adrenal insufficiency, colitis 2 - 5%
– 10 – 17% for other irAEs
– Older patients at higher risk (impared functional reserve,
comorbidities)

Wang el al. JAMA ONCO 2018

19

Management of irAEs

Champiat S et al. Ann Oncol 2016

20

Special populations that are not presented
in RCT

Rzeniewicz el al. Ann Oncol 2021

TAKE-HOME MESSAGES!
• MULTIDISCIPLINARY APPROACH
– Baseline assessment
– Ongoing assessment
– PATIENT & PHYSICIAN EDUCATION
– Management protocols
– Collaboration with emergency departments, GPs,
specialists, visiting nurses!!

21

Melanoma patient with multiple irAE
- clinical case

Side effects of immunotherapy and the management
2nd International Summer school
Ana Žižek, dr.med
Nežka Hribernik, dr.med.

1/

Female, 1960
●

Family history: mother had skin cancer

●

Comorbidities: arterial hypertension

●

Year 2012: presented with skin lesion on her left thigh, changing in colour
–

June 2012 – excision: melanoma, Clark IV, Breslow 2,4 mm, no ulceration

–

September 2012 – reexcision of tumor bed + SLNB (Institute of Oncology LJ)

–

pT3a N0 (0/1), R0, stage IIA

–

FU

2/

22

January 2021 progression of disease (DFI: 9 years)
January 2021: palpable resistance in her left thigh, loss of 6 kg in 1 month, nausea,
back pain, night sweats
●

●

Diagnostic procedure:
– Lab: LDH 2.66 ukat/L, S-100 1.250 ug/L, CRP 160 mg/L
–

Bx of resistance: melanoma metastasis → BRAF V600E mutation

– PET/CT: high metabolic uptake in the liver, subcutaneous tissue of left thigh, bones (Th
4,5,8,11, L1,5, sacrum, pubis, scapula, 10th and 5th rib)
– CT of the head: solitary metastasis in basal ganglia (1 cm) without edema; no neurological
symptoms

3/

Systemic treatment
●

February 2021: started with comboIT ipilimumab 3 mg/kg + nivolumab 1 mg/kg
- Supportive treatment: Zoledronic acid, vitamin D, CaCO3
- No radiotherapy (1 week after 1st infusion her back pain was gone)

March 2021: increased appetite, no back pain, reduction in size of subcutaneous resistance
in left thigh --> continues with 2nd infusion of nivo1/ipi3

●

–Side

effects: pruritus grade II (Th: antihistamine)

●April 2021 – early time-point PET/CT (study QTA): PMR in most localisations, S100
normalized

●

April 2021: 3rd infusion of nivo1/ipi3

4/

23

Multiple irAE
End od April 2021 - Regional hospital admission: hepatitis gr. III, diarrhoea gr. I, arthralgia gr.

●

•
●
●
●

Treatment: steroids i.v. (2mg/kg/d)+Pneumocystis prophylaxis, PPI
In one week no more liquid stools and no more pain in her joints
regular lab controls - liver transaminases decreased to gr. I
Tapering of dexamethasone

End of May 2021: worsening of sympthoms - skin rash around waist, fatigue, transaminitis gr.
III, diarrhoea gr. I → again higher dose of steroids p.o. (2mg/kg/d)
●

After improvement of lab and sympthoms, SLOW tapering of dexametasone over 5 weeks

●

ACTH test!

●

Permanently completed IT due to irAE

●

5/

●

June 2021: PET/CT: complete metabolic response of all metastatic localisations

●

July 2021: normal AST/ALT, bili, S100, LDH, CRP

●

August 2021: regular check-up, no signs of progression

6/

24

Side effects of chemotherapy and the
management

Tanja Ovčariček
Oncology institute Ljubljana, 2021

Knowing side effects of certain treatment is basic
knowledge every oncologist should have!

 a number of potential side effects
 Side effects and long term sequelae of
chemotherapy major source of concern for
patients
 Education of patients is important for
adherence to cht treatment

25

Topoisomeras
e inhibitors
antimetabolites
Alkylating
agents

taxanes
Vinca alkaloids

 Gastrointestinal epithelial cells
 Bone marrow cells
 Hair follicles

Nurgali K, et al. Front.Pharmacol.2018

Timing of chemotherapy side effects
Acute (minutes to
hours/first days)

Subacute
During cht application:
- allergic/infusion
reaction
- cardiac arrythmia
- exstravasation
Early (in hours after cht
application):
- nausea/vomiting
- malaise
- tumor lysis syndrome
- phlebitis
- cystitis

After couple of
days/week:
- stomatisis,
gastroenteritis
- renal insufficiency
- myelosuppression
- peripheral neurotoxicity
- Fatigue
- alopecia

26

Late
After weeks, months, years
- nail changes
- organ failure (heart failure)
- infertility
- teratogeneticy and
cancerogeneticy

GASTROINTESTINAL SIDE EFFECTS OF CHEMOTHERAPY

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)
 the most common and feared side-effects among the patients
 compromise treatment outcomes

What should oncologist know about CINV?
 Timing of nausea
 Emetogenic potential of chemotherapy/individual risk
 Patophysiology of CINV and drugs used

Roila F et al, Ann Oncol 2016

27

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)

 in two phases, the acute and the delayed phase:

Acute CINV: up to 24 h
Delayed CINV: more than 24 h after chemotherapy administration
Anticipatory CINV: before next cycle

Cht administration

Next cht cycle

Roila F et al, Ann Oncol 2016

Emetic classification of chemotherapy agents
High risk

Moderate risk

Low risk

Minimal risk

(>90 % patients)

(30-90 % patients)

(10-30% patients)

(<10 % patients)

Anthracycline/cyclophosphamide
combinationb
Carmustine
Cisplatin
Cyclophosphamide ≥1500 mg/m2
Dacarbazine
Mechlorethamine
Streptozocin

Azacitidine
Bendamustine
Carboplatin
Clofarabine
Cyclophosphamide <1500
mg/m2
Cytarabine >1000 mg/m2
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Ifosfamide
Irinotecan
Oxaliplatin
Romidepsin
Temozolomidec
Thiotepad
Trabectedin

28

Cabazitaxel
Cytarabine ≤1000
mg/m2
Docetaxel
Eribulin
Etoposide
5-Fluorouracil
Gemcitabine
Ixabepilone
Methotrexate
Mitomycin
Mitoxantrone
Nab-paclitaxel
Paclitaxel
Pemetrexed
Pegylated liposomal
doxorubicin
Topotecan
Trastuzumabemtansine
Vinflunine

Bleomycin
Busulfan
2Chlorodeoxyadenosi
ne
Cladribine
Fludarabine
Pixantrone
Pralatrexate
Vinblastine
Vincristine
Vinorelbine

Roila et. Al. Ann Oncol 2016

Mechanism of antiemetic
drugs:
1.
2.
3.
4.
5.
6.

5HT3 RA acute CINV
NK1 RA delayed CINV
D2 RA
Multiple R
CB1
Other

Navari RM, et al. NEJM 2016

Antiemetic arsenal:







5HT3 RA: granisetron, palonosetron, ondasetron
NK1 RA: aprepitant, fosaprepitant, netupitant
D2 RA: metoklopramid
Multiple R: deksamethasone, olanzepin
CB1: canabinoids
Other: benzodiazepines

Navari RM, et al. NEJM 2016

29

Roila et. Al. Ann Oncol 2016

CLINICAL CASE
 50 years old women with T3N0M0 urothelial bladder cancer, hematuria, no comorbidities
 Treatment plan: neoadjuvant cisplatin-based chemotherapy
 Worried about nausea and vomiting

High risk
(>90 % patients)

 Acute CINV: NK1 RA (aprepitant 125 mg)+5HT3 RA (granisetron 1 mg)+deksamethason
12 mg
 Delayed CINV: aprepitant 80 mg 2.3 D+deksamethason 8 mg 2.-4. d
 Persisting N/V: breakthrough CINV:
antiemetics with different mechanism of
action: metoclopramide/olanzapine

30

MUCOSITIS
 inflammatory and/or ulcerative lesions of the oral and/or
gastrointestinal tract
 anatomical
distribution:
oral
mucositis
(OM),
gastrointestinal mucositis (GIM, diarrhea), and proctitis
 the incidence of clinically significant mucositis has been
reported to range from 40% (standard dose cht), 60–100%
(high-dose cht)
 Predisposing factors:
 various mucotoxicity for different cht agents: 5-FU,methotrexate,
irinotecan, cyclophosphamide, cisplatin, anthracyclines and taxanes
 bolus infusion tends to be more toxic
 in general, if a patient develops mucositis in the first cycle of treatment, the
probability of the condition recurring in a subsequent cycle is high

Stein et al, 2010, Kwon et al. 2016

ORAL MUCOSITIS

.

 erythema of the movable mucosa which progress to form painful
ulcerations often covered by a pseudomembrane
 may be associated with microbial colonization that may remain
localized or become disseminated, especially in patients with
severe neutropenia-SEPSIS!!
 first signs appear shortly after administration and usually peak at
about days 7–14, is usually self-limiting

Stein et al, 2010, Kwon et al. 2016, Peterson DE et al, Ann Oncol 2015

31

MASCC and ESMO have developed guidelines whith strategies for managing oral mucositis

 effective preventative and treatment strategies are lacking
 Preventative meassurements: Oral health at the start of and during chemotherapy: general hygiene
standards, dental care, normal saline and baking soda-non-alcochol mouthwashes, regular tooth brush,
dietary and behavioral measures

Peterson DE et al, Ann Oncol 2015

CHEMOTHERAPY INDUCED DIARRHEA (CID)
 CID is potentially fatal (5%) due dehidration and electrolyte imbalances
 CHT regimens CID: 5-fluorouracil and irinotecan are associated with rates of CID of up to 80% with one
third of patients experiencing severe (grade 3 or 4) diarrhea, taxanes
 CID:-uncomplicated (grade 1–2 with no complications) or complicated (grade 3–4 with one or more
complicating signs or symptoms),
-early onset (<24 h after administration, irinotecan) or late onset (>24 h after administration)
-persistent (present for >4 weeks) or non-persistent (present for <4 weeks)

 Treatment CID:
1.
2.
3.
4.

Modification of diet and re-hydration
Loperamide
Ocreotide: loperamide refractory diarrhea (48 h), severe diarrhea
Tincture of opium: may be considered as a second-line therapy for persistent and uncomplicated diarrhea

Peterson DE et al, Ann Oncol 2015, Stein et al. Ther Adv Med Oncol 2010

32

CLINICAL CASE

 54 years old patient on adjuvant chemotherapy for T3N1M0 BC
 4. cycle of adjuvant chemotherapy, 1. application of docetaxel 100 mg/m2, prior cht
applications without meaningful AE
 Docetaxel was administreted with deksamethasone premedication according to standard
scheme without acute toxic reaction
 D7: confusion, sleepiness, unable to answer questions; afebrile, RR 100/70, p: 100/min,
normal ECG, without major neurologic deficit on examination, physical examination
otherwise unrenarkabe
 Heteroanamnesis: profound diarrhea (6-10 stools per day 5 days, last 2 days vomiting)
without fever
 Lab. Test: profound hyponatremia (Na: 115, K:2.1 mmol/l) elevated creatinin value and urea,
CRP, PCT normal, no signs of myelosuppression
 X-ray abdomen and stool cultures: negative
 DIAGNOSIS: acute dehydration and hypovolemic hyponatriemia as a consequence of
diarrhea, nausea and vomiting
 Treated with parenteral saline infusion, loperamide
 Adjuvant chemotherapy: weekly paclitaxel administration

CHEMOTHERAPY INDUCED MYELOSUPPRESSION

MYELOSUPPRESSION

Leucopenia/
Neutropenia

Thrombocytopenia
Anemia

33

FEBRILE NEUTROPENIA
DEFINITION:an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an
absolute neutrophil count (ANC) of <0.5 × 109/l
 FN remains one of the most frequent and serious complications of cancer chemotherapy
 20-30 % pts require hospitalisation, mortality 10%
 Predisposing factors: certain chemotherapeutics regimen-FN risk, age, advanced disease, prior FN,
mucositis, low PS, CVS disease

TREATMENT:
1. Urgent recognition
2. Immediate treatment

PREVENTION:
Chemoprpphylaxis
according to risk for FN
(individual, cht scheme)

Klastersky J et al, Ann Oncol 2016

Klastersky J et al, Ann Oncol 2016

34

FEVER AND SUSPECTED NEUTROPENIA

History, previous
microbiology reports,
physical examinationsource of infection?

Lab test: blood
counts, CRP, liver,
kidney
Blood cultures:
i.v.cathethers,
peripheral vein
Urinanalysis
X-ray
Urin/sputum/other
culture in case of
suspicion

≥21
Low
risk

MONITORING!!!

No pneumonia, stable, no i.v.
cathethers:
Po/iv antibiotics: amoksicillin
plus clavulanic acid and
quinolones

Early discharge?

• extravasation
• alopecia
• nail changes
• hand-foot syndrome
(capecitabin, taxanes, 5-FU)
• dermatitis

35

<21
High
risk

i.v. broad spectrum
antibiotics

Klastersky J, eta al. Ann Oncol 2016

 HFS:palmar-plantar erythrodysaesthesia syndrome: redness, marked discomfort, swelling and tingling in the
palms of the hands or the soles of the feet (5-fluorouracil (5-FU), (6%-34%), capecitabine (50%-60%),
doxorubicin (22%-29%), PEGylated liposomal doxorubicin (40%-50%), docetaxel [6%-58%; preventative
mesures are important-10% urea cream significantly reduces the incidence of HFS
 Treatment of HFS: , skin inflammation: high-potency topical corticosteroids], while erosions and ulcerations:
with antiseptic solutions (silver sulfadiazine 1%), analgesia on painful areas: lidocaine 5% patches
 Skin cooling (e.g. cold gloves or socks) significantly reduce of HFS for ChT given as an infusion( paclitaxel,
docetaxel and liposomal doxorubicin)

Lacouture ME, et al, Ann Oncol 2020

EXTRAVASATION:inadvertent infiltration of chemotherapy into the tissues surrounding the intravenous
site
 Extravasated drugs are classified according to their potential for causing damage as ‘vesicant’, ‘irritant’ and
‘nonvesicant’
VESICANT: blisters/tissue destruction !!!!!
IRRITANTS: pain along the vein and inflammatory reaction
.

DNA-binding vesicant drugs

Mechloretamine
Doxorubicin, Daunorubicin,
Epirubicin, Idarubicin
Mitomycin, Dactinomycin,
Mitoxantrone*

Alkylating agents
Anthracyclines
Antitumor antibiotics
Non-DNA binding vesicant
drugs

Vinca alkaloids Taxane

Vinblastine, Vincristine,
Vinorelbine, Vindesine
Paclitaxel, Docetaxel

Irritant drugs

Alkylating agents
Platinum analogs
Topoisomerase II inhibitors
Anthracyclines
Topoisomerase I inhibitors

Carmustine, Dacarbazine,
Ifosfamide, Melphalan,
Thiotepa, Carboplatin,°
Cisplatin,# Oxaliplatin
Teniposide, Etoposide
Liposomal Doxorubicin,
Liposomal Daunorubicin
Irinotecan, Topotecan

36

Fidalgo JA, et al, Ann
Oncol 2012

Extravasated vesicant
Anthracyclines

Antidote

Treatment

DMSO Dexrazoxane

Topical cooling

Docetaxel

Hyaluronidase

Topical cooling

Mytomicin

DMSO

Topical cooling

Mitoxantrone

DMSO

Topical cooling

Vinca alkaloids

Hyaluronidase

Topical warming

 DMSO (topical application): is a solvent capable of penetrating tissue, it neutralizes free-radical
accumulation and encances systemic absorption of the extravasated drug.
 Dexrazosane (intravenously): is approved for anthracycline extravasation treatment, it binds to iron
and prevents the formation of free radicals which induce extravasation-induced tissue necrosis.
 Hyaluronidase (subcutaneously) degrades hyaluronic acid, breaks down subcutaneous tissue bonds
promoting drug diffusion and enhances the absorption of injected substances.

Signs and symptoms of vesicant extravasation:
swelling, redness and/or discomfort, resistance during
drug administration, a slow and sluggish infusion, and
lack or loss of a blood return from the i.v. cannula,
implanted port or other central venous access device.
Fidalgo JA, et al, Ann Oncol 2012

It is essential to recognize that an extravasation has taken place as quickly as possible!!!

 40 years BC patients develops sweeling
and redness in the arm where the canula
during doksorubicin infusion is inserted
WHAT WOULD YOU DO?

Fidalgo JA, et al, Ann Oncol 2012

37

CENTRAL AND PERIPHERAL CHEMOTHERAPY INDUCED NEUROTOXICITY (CIPN)

 chemotherapy-induced cognitive dysfunctions=„chemo-brain“, other: other types of acute encephalopathy:
ifosfamide-induced acute encephalopathy, increased risk of trombemolic stroke
 incidence of CIPN approximately 38% (up to 90% with oxaliplatin)
 reduce functional capacity and quality of life, the long-term reversibility questionable, symptoms may last
years after chemotherapy discontinuation
 CIPN: platinum-based agents (cisplatin, oxaliplatin), vinca alkaloids (vincristine, vinorelbine), taxanes
(docetaxel, paklitaksel)
 Oxaliplatin-Induced Peripheral Neuropathy:
 more than 90% of patients developed acute neuropathy (paresthesia, dysesthesia of the hands, feet and
perioral area induced by cold stimuli in the hours and days ) and 30–50% of patients developed chronic
neuropathy (paresthesia, numbness, sensory ataxia )
 Taxane, vinca alkaloids neuropathy: sensory neuropathy with a stocking-and-glove distribution over the
hands and feet

Kerckhove N, et al. F Phar 2017

Kerckhove N, et al. F Phar 2017

38

 no effective agent exists to prevent CIPN
 prevention of CIPN with cryotherapy can be considered according to ESMO, similar recommendation for
medical exercise for cancer patients (low LoeE/GoR-IIC)
 Management of CIPN:- reducing or discontinuing chemotherapy when CIPN develops
- treatment of the symptoms of neuropathic pain- only duloxetine was shown to help
neuropathic pain in established CIPN; any other medications (gabapentin, topical preparations, etc.) are used in
an off-label fashion

Jordan B, et al. Ann Oncol 2020

True allergic responses vs non-allergic responses

Rosello S, et al, Ann Oncol 2016

39

Rosello S, et al, Ann Oncol 2016

CARDIOTOXICITY

Arrythmias: taxanes
Coronary artery spasem:5-FU, capecitabin,
cisplatin
Heart failure: anthracyclines

40

 Use all the knowledge for preventative meassures!
 Educate the patient!

THANK YOU FOR YOUR ATTENTION!

41

Toxicity of tyrosine kinase inhibitors (TKI)
and the management
Urška Bokal

2nd Summer School of Medical Oncology, 7/ 9/2021

Tyrosine kinase
inhibitors

Tyrosine kinases:
• activate proteins/autoactivate by
phosphorylation of tyrosine moiety important for signal transduction and cell
cycle regulation
Tyrosine kinase inhibitors:
• Small molecules, oral application
• act mostly by blocking ATP binding site,
therefore inhibit phosphorylation
• bind reversibly or irreversibly
ATC classification system

Other protein kinases:
B Raf (serine threonine kinase)

https://www.whocc.no/atc_ddd_index/?code=L01XE&showdescription=no

42

On- and off- target toxicity
On-target:
• due to inhibition of the desired target (mechanism based)
• class effect: shared with all agents that inhibit specific target
• VEGFR TKI: hypertension
• EGFR TKI: rash
Off-target:
• due to inhibiton of other unintended targets
• „off targets“ share structures or residues with
the intended targets
• sunitib: hematologic toxicity (FLT3 inhibition)
• toxicities can ovelap due to cross interaction of
multiple pathways

CA Cancer J Clin. 2013;63:249-79
https://www.targetedonc.com/publications/targeted-therapies-cancer/2013/december-2013/Toxicities-of-Targeted-Therapies-and-Their-Management

The good news: toxicity may correlate with
response/better survival
• rash due to EGFR TKI in lung cancer
• hypertension and hypothyroidism due to VEGFR TKI in renal cell carcinoma

Liu S et al. Cancer Treat Rev. 2014; 40: 883-91

43

ErbB tyrosine kinase inhibitors

Shah R et al. Drug Safety. 2019; 42:181-98

all agents: hepatotoxicity

spc of selected drugs

ErbB TKI toxicity: management

• drug interruption,
lowering of the dose
• life threatening:
discontinuation of
treatment

Up to Date
Shah R et al. Drug Safety. 2019; 42:181-98
Lacouture M et al. Am J Clin Dermatol. 2018; 19: S31-9

44

VEGFR tyrosine kinase inhibitors

VEGFR TKI – management of cardiovascular toxicity

CA Cancer J Clin. 2013;63:249-79

TE: thromboembolic events

Up to Date

45

VEGFR TKI – management of toxicity

CA Cancer J Clin. 2013;63:249-79
Rimassa L et al. Can Treat Rev 2019; 77: 20-8

ALK tyrosine kinase inhibitors

CPK – creatine
phosphokinase
AP – alkaine
phosphatase

ALL: interstital lung disease
Kassem L et al. Crit Rev Oncol Hematol 2019; 134:56-64
smpc

46

ALK TKI – management of toxicity

Kassem L et al. Crit Rev Oncol Hematol 2019; 134:56-64
smpc
http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Crizotinib_monograph_1Sep2014.pdf

MEK 1,2 inhibitors (+ B-RAF inhibitors)

CK – creatine phosphokinase

MEK1,2 inhibitors:
• ↓ LVEF, hypertension,
• retinal pigment epithelial
detachment/retinal vein occlusion,
• interstitial lung disease,

B-RAF inhibitors:
• QT prolongation (vemurafenib,
encorafenib),
• uveitis,
• cutaneus squamous cell carcinoma,
keratoacantomas, hyperkeratosis,
• pyrexia

Kdaud A et al. The Oncologist 2017;22:823-33
smpc

47

Ocular toxicity
Possible mechanism of MET TKI ocular toxicity:
• ERK activation is important for photoreceptor survival
• MEK inhibition results in apoptosis and loss of differentiation during photoreceptor
development

EGFR TKI: keratoconjunctivitis
crizotinib: poor light-dark adaptation

Kdaud A et al. The Oncologist 2017;22:823-33
smpc

Take home messages
• Toxicity varies between patients.
• Beware of interactions with food and drugs!
• Multidisciplinary management: referral to doctors of other
specialities.
• Chronic low grade toxicity influence the quality of life of patients.

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

SURVIVAL ANALYSIS IN SLOVENIAN
PATIENTS WITH METASTATIC MELANOMA
AND IMMUNE RELATED ADVERSE EVENTS
Vid Čeplak Mencin
assist. prof. Tanja Mesti, MD, PhD
Summer School 2021
Institute of Oncology Ljubljana, sept. 2021

CONCLUSION

• irAE cohort: better treatment outcome, longer time to disease progression, better ORR
• ORR: irAE 57%, NirAE 37%
• PFS: irAE 301,6 days, NirAE 247,3 days
• SP: irAE 80%, NirAE 60%
• Better SP in patients with elevated LDH and irAE M1a/b (TNM classification)
• Worse SP for M1c/d – new type of melanoma?

89

Patient with BRAF mutated metastatic melanoma
Sequencing, rechallenge, new therapies...

L.Simetic, K.Blazicevic and D. Herceg
On behalf of MDT for melanoma and skin
cancers
UHC Zagreb, Croatia

QUESTIONS
• Should we continue with BRAF MEK therapy or not? Patient was treated
with 2 lines in metastatic setting so no other option, except Cht, is
available in Croatia ( by National regulatory agency for health insurance)
• Do we have „ a joker card” with previous response to ICI ( lung mets
regression) ? Rechallenge with mono PD-1 inhibitors or combo ICI?
• Clinical study/ compassionate use programe:: ICI+ lenvatinib or?
• Something new like Fecal Transplant therapy + ICI?
• Your comments are precious 

90

Multidisciplinary team for melanoma treatment
University hospital centre Zagreb; core members
 dermatologist, dermatooncologist: D. Štulhofer (chair), R.Čeović
 plastic surgeon: D. Mijatović, S. Smuđ Orehovec
 head and neck surgeon: M.Jurlina, J.Biloš, D. Leović
 ophthalmologist: N.Vukojević, M. Štanfel
 medical oncologist: D.Herceg, K.Blažičević, L.Simetić
 radiooncologist: F.Šantek
 pathologist: S.Dotlić, I.Ilić
 nuclear medicine specialist: G.Horvatić Herceg, S. Kusačić Kuna,
M.Ciglar
 radiologist: M.Lušić, M.Kralik

lsimetic@kbc-zagreb.hr

91

Systemic treatment of
nemelanomskih skin cancer
Prof. Janja Ocvirk

Ljubljana, 7.9.2021

Systemic treatment of non-melanoma
skin cancers - immunotherapy?

92

Squamous cell carcinoma of the skin
The second most common NMSC (20%)
The incidence has been growing over the last 30 years(50-200%)
Head and neck 80-90%
90% has a good prognosis

What about the rest 10%?

SCC in transplant patients
36 times higher incidence than usual(BCC: SCC 4: 1)
Aggressive course - poor prognosis

93

Tumor Mutational Burden in CSCC
Formation of
Neoantigens

Somatic Mutation Frequency (/Mb)

1,000

100

61.2

8.2

10

Potential Sensitivity
to Immunotherapy

Frequently

13.2

3.2
Regularly

1

0.1
Occasionally
0.01
SCCHN
(178)

LUSC
(178)

Melanoma
(121)

CSCC
(39)

Tumor Type
Red horizontal line and associated number in figurer = median mutations per MB.
CSCC, cutaneous squamous cell carcinoma; LUSC, lung squamous cell carcinoma; Mb, megabase of DNA; SCCHN, Squamous cell carcinoma of the head and neck.
Pickering CR, et al. Clin Cancer Res. 2014;20:6582–6592.

Tumour mutational burden & objective response rate
Anti–PD-1 and anti–PD-L1 therapy across 27 tumour types1

1. Yarchoan M, et al. N Engl J Med. 2017; 377: 2500–01; 2. Papadopoulos K, et al. Presentation at 2017 American Society of Clinical Oncology, Chicago,
IL. J Clin Oncol. 2017;35(15_suppl):9503; Adapted from Yarchoan et al, 2017

94

Reasons for immunotherapy in CSCC
High tumor mutation load (TMB) and immunogenic cancer
High TMB may contribute to increased neoantigen production, which may
increase tumor antigenicity 1
Immunosuppression is a well-described risk factor for CSCC (especially in
organ transplant patients)2
PD-L1 expression was detected in advanced CSCC3

1. Pickering CR, et al. Clin Cancer Res. 2014;20:6582-92; 2. Euvrard E, et al. N Engl J Med. 2003;348:1681-1691.
3. Slater NA, et al. J Cutan Pathol. 2016;43:663-70.

Candidates for immunotherapy in
advanced CSCC
Patients with advanced CSCC

Locally advanced / metastatic disease
Patients with recurrences after previous surgeries
Patients who are not candidates for surgery due to morbidity / potential
exhaustion or a low level of confidence within clear boundaries
Patients who are not candidates for radiotherapy

95

Migden MR, et al. N Engl J Med. 2018;379:341-351.

96

EMPOWER-CSCC-1 study design
1

Metastatic CSCC
(nodal and/or distant)

2

Locally advanced CSCC

Key inclusion criteria

Cemiplimab
3 mg/kg Q2W IV*
for up to 96 weeks

•
•
•

Tumour imaging
every 8 weeks
for the assessment of
efficacy

(retreatment optional for
patients with progression
during follow-up†)

•

ECOG performance status of 0 or 1
Adequate organ function
At least one lesion measurable by RECIST
1.1 criteria (for scans) or modified WHO
criteria (for photos)
CSCC lesion that is not amenable to surgery
or radiation therapy per investigator
assessment

Key exclusion criteria
Metastatic CSCC
(nodal and/or distant)

3

Tumour imaging
every 9 weeks
for the assessment of
efficacy

Cemiplimab
350 mg Q3W IV
for up to 54 weeks

•

•
•

Tumour response assessment by ICR
(RECIST 1.1 for scans: modified
WHO criteria for photographs)

Ongoing or recent (within 5 years)
autoimmune disease requiring systemic
immunosuppression
Prior anti–PD-1 or anti–PD-L1 therapy
History of solid organ transplant, concurrent
malignancies (unless indolent or not
considered life threatening; for example, basal
cell carcinoma), or haematologic malignancies

†To account for possible pseudoprogression, treatment

could be continued beyond initial RECIST 1.1-defined
progression informed by ir-related response criteria

*Cemiplimab is not licensed at this dose for the treatment of CSCC

CSCC, cutaneous squamous-cell carcinoma; ECOG, Eastern Cooperative Oncology Group; ICR, independent central review; IV, intravenous; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1;
Q2W,every 2 weeks; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumours; WHO, World Health Organisation.
Migden MR, et al. Presentation at 2019 American Society of Clinical Oncology, Chicago, IL. J Clin Oncol. 2019;37(15_suppl):6015

CSCC, cutaneous squamous cell carcinoma

1
1

EMPOWER-CSCC-1 treatment arms
Phase II data supporting cemiplimab license (n=193)

Group 1

Group 2

Group 3

Metastatic

Locally advanced

Metastatic

Number of patients

59

78

56

Cemiplimab dosing

3 mg/kg Q2W

3 mg/kg Q2W

350 mg Q2W

Sept 20 2018

Oct 10 2018

Sept 20 2018

16.5

9.3

8.1

CSCC

Data cut-off
Median follow-up (months)

Cemiplimab SmPC, available at https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_hr.pdf; accessed January 2020

97

EMPOWER-CSCC-1
Response rates in three treatment groups
Group 1

Group 2

Group 3

Metastatic CSCC
Cemiplimab 3 mg/kg
Q2W*
N=59

Locally advanced CSCC
Cemiplimab 3 mg/kg
Q2W*
N=78

Metastatic CSCC
Cemiplimab 350 mg Q3W
N=56

49.2%
35.9, 62.5

43.6%
32.4, 55.3

39.3%
26.5, 53.2

16.9%

12.8%

3.6%

Objective response rate
95% Confidence interval
Confirmed objective response
Complete response†
Partial response

32.2%

30.8%

35.7%

Stable disease

15.3%

35.9%

14.3%

Progressive disease

16.9%

11.5% is not licensed at this dose for
26.8%
*Cemiplimab
the treatment of CSCC

†Only patients with complete healing of

prior cutaneous involvement; for
locally advanced CSCC, biopsy required to confirm complete response
CSCC, cutaneous squamous-cell carcinoma; Q2W, every 2 weeks
Cemiplimab SmPC, available at https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_hr.pdf; accessed January 2020

Kaplan–Meier Estimation Overall Survival, Progression-Free Survival,
and Duration of Response in Advanced CSCC Patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Median PFS by ICR was
18.4 months (95% CI: 7.3–
not evaluable)

0

2

4

6

Probability of survival

Probability of PFS

Metastatic CSCC (Group 1)1

8 10 12 14 16 18 20 22 24 26 28

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Median OS has not been reached;
Kaplan-Meier estimation of OS at
24 months was 70.6% (95% CI:
57.0–80.6;)

0 2

4

6

Number
59 43 39 36 32 26 26 26 25 18 15 10
at risk

8 10 12 14 16 18 20 22 24 26 28
Months

Months

1

0

0

Number
59 56 52 49 47 47 46 41 39 32 24 14 6
at risk

Median DOR not reached

Locally Advanced CSCC (Group 2)2
Median PFS
K-M Estimated PFS at 12 months
Median OS
K-M Estimated OS at 12 months
Median DOR

NR
58.1% (95% CI: 43.7–70.0)
NR
93.2% (95% CI: 84.4–97.1)
NR

Group 1: Median duration of follow-up = 16.5 mos (range 1.1 – 26.6); Group 2: Median duration of follow-up = 9.3 mos (range 0.8 – 27.9)
Data cut-off date: Sept 20, 2018 (Group 1); Oct 10, 2018 (Group 2)
CI, confidence interval; CSCC, cutaneous squamous cell carcinoma; ICR, independent central review; OS, overall survival; PFS, progression-free survival;
NR, not reached
1. Guminski et al. J Clin Oncol. 2019:37 (suppl; abstr 9526) [poster presentation]. 2. Migden MR, et al. J Clin Oncol. 2019:37 (suppl; abstr 6015) [poster presentation].

98

1

0

Probability of no
progression or death

EMPOWER-CSCC-1:Duration of response K-M estimated
event-free probability by ICR in responding patients
Data cut-off date: 20 Sep 2018 (Group 1); 10 Oct 2018 (Group 2).

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

88.9%
87.8%

96.4%
96.2%

82.5%
87.8%

Metastatic CSCC
Locally advanced
CSCC

0
Number of patients at risk
Metastatic CSCC
29
Locally advanced CSCC

2

4

6

8

10

12
14
Month

16

18

20

22

24

26

29
34

28
30

27
27

22
23

22
17

22
14

15
9

11
6

7
6

0
4

0
1

0
1

22
12

0

Median duration of response has not been reached.
CSCC, cutaneous squamous cell carcinoma; ICR, independent central review.

Cemiplimab adverse reaction profile
Safety population
N=591

Permanent discontinuation

Serious adverse events

8.6%

5.8%

Immune-related adverse reactions

20.1%

4.4%

≥Grade 3 irARs
Grade 3

6.1%

Grade 4

1.2%

Grade 5

0.7%

Most common irARs
Hypothyroidism

7.1%

0

Pneumonitis

3.7%

1.9%

Immune-related skin ARs

2.0%

0.3%

Hyperthyroidism

1.9%

0

Hepatitis

1.9%

0.8%

9.1%

0.3%

Infusion-related reactions

Cemiplimab SmPC, available at https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_hr.pdf; accessed January 2020
irARs, immune-related adverse reactions

99

Pembrolizumab for Recurrent/Metastatic Cutaneous Squamous Cell
Carcinoma: Efficacy and Safety Results From Phase 2 KEYNOTE-629
Study
Studiendesign

CR, complete response; cSCC, cutaneous squamous cell carcinoma; DCR, disease control rate;
DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status
LA, locally advanced; ORR, objective response rate; OS, overall survival; PFS, progression-free survival
Q3W, every 3 weeks; R/M recurrent and/or metastatic.
aPatients

who discontinue treatment after achieving CR may be eligible to receive an additional
17 cycles of pembrolizumab if disease progression occurs.

J.-J. Grob et al., KEYNOTE-629 Efficacy and Safety of pembrolizumab in patients with R/M cSCC, Poster presented at ESMO 2019

Pembrolizumab for Recurrent/Metastatic Cutaneous Squamous Cell
Carcinoma: Efficacy and Safety Results From Phase 2 KEYNOTE-629
Study
PFSa in the R/M Cohort

OSa in the R/M Cohort

NR, not reached; OS, overall survival; PFS, progression-free survival; R/M, recurrent and/or metastatic.
aFrom product-limit (Kaplan-Meier) method for censored data.

J.-J. Grob et al., KEYNOTE-629 Efficacy and Safety of pembrolizumab in patients with R/M cSCC, Poster presented at ESMO 2019

100

Cemiplimab is indicated as monotherapy in adult patients with metastatic
or locally advanced squamous cell carcinoma of the skin who are not
candidates for curative surgery or curative first-line radiation.

101

Basal cell carcinoma of the skin

A major cause of BCC is exposure to
UV radiation
A major cause of BCC is exposure to
UV radiation, leading to cumulative
DNA damage and gene mutations1–5

Most sporadic cases of BCC arise
from chronic sun-exposure1,2

Epidemiological data suggest the
overall incidence of BCC is increasing
significantly and show marked
geographical variation1,6–8
Australia has the highest incidence
rate of BCC in the world, reporting a
rate of 1–2% per year1,6

80% occur on the head and neck
15% occur on the trunk
5% occur on the arms, legs or other sites

1. Rubin AI et al. N Engl J Med 2005;353:2262–9
2. Wong CSM et al. Br Med J 2003;327:794–8
3. Roewert-Huber J et al. Br J Dermatol 2007;157:47–51
4. Lear JT et al. J R Soc Med 1998;91:585–8

102

5. Caro I, Low JA. Clin Cancer Res 2010;16:3335–9
6. Diepgen TL, Mahler V. Br J Dermatol 2002;146(suppl):1–6
7. Ting PT et al. J Cutan Med Surg 2005;9:10–15
8. Rogers HW et al. Arch Dermatol 2010;146:283–7

Advanced basal cell carcinoma
Locally advanced basal cell carcinoma (lnBCC)

Aggressive disease with local tissue damage
Frequent recurrences after surgery
The operation would cause deformation

BCC

Metastatc BCC (mBCC)
Locally advanced BCC
Metastatski BCK

nBCC (1-2%)

Rare but serious form of BCK
It involves the presence of metastases (e.g., lymph
nodes, bones, lungs, liver 1
Weak outcome (median survival: 8-14 months2-3
5-year survival rate: 10% 3,4
1. Ting PT et al. J Cutan Med Surg 2005;9:10–15
2. von Domarus H, Stevens PJ. J Am Acad Dermatol 1984;10:1043–60
3. Lo JS et al. J Am Acad Dermatol 1991;24:715–19
4. Wong CSM et al. Br Med J 2003;327:794–8

23

Treatment of basal cell carcinoma
Curettage and cavertisation, cryosurgery
Cream imiquimod
Surgical excision
Electrochemotherapy

nBCC

Radiotherapy
Targeted therapy – HHI:Vismodegib, Sonidegib,
Immunotherapy

24

103

BCC and Hedgehog signal pathway
26
The pathway of cell growth and
differentiation that controls the
formation of organs in embryonic
development

•

•

The Hedgehog signaling
pathway is inactive in most of
the tissue of the adult
Abnormal activation
(mutation) of the Hedgehog
signal pathway plays an
important role in pathogenesis
BCC1
Hedgehog signaling pathway
inhibitors provide a new
treatment option for
advanced patients BCC
(vismodegib, sonidegib)

104

105

RR in 1st line treatment - HHI

106

Phase 2 Study of Cemiplimab in Advanced BCC
31
(Study
1620) ‒ NCT031326361-3
An open-label, non-randomized Phase 2 study of cemiplimab in patients with advanced BCC who experienced
progression on or intolerance to hedgehog pathway inhibitor therapy1-4

Group 1
Adult patients with metastatic
(nodal and distant) BCC
N=54

350 mg IV Q3W for up to 93 weeks (or until
disease progression, unacceptable toxicity, or
withdrawal of consent)

Group 2
Adult patients with laBCC
N=84

Primary endpoint
• ORR by ICR
Select secondary endpoint

Cemiplimab
Tumor response assessments:
Q9W for treatment cycles 1-5,
Q12W for treatment cycles 6-9*

• DOR, PFS, OS, complete
response by ICR, ORR
per investigator, and
safety and tolerability

*Tumor response assessment by ICR (RECIST 1.1 and/or modified WHO criteria).

BCC=basal cell carcinoma; DOR=duration of response; ICR=independent central review; IV=intravenous; laBCC=locally advanced BCC; N=number of patients; ORR=overall response rate;
OS=overall survival; PFS=progression-free survival; Q3W=every 3 weeks; Q9W=every 9 weeks; Q12W=every 12 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; WHO=World Health
Organization.
1. ClinicalTrials.gov/NCT03132636. https://clinicaltrials.gov/ct2/show/NCT03132636. Accessed October 2020. 2. Stratigos AJ, et al. Poster presented at: European Society for Medical Oncology
(ESMO) Virtual Congress; September 19–21, 2020:LBA47. 3. Lewis KD, et al. Poster presented at: Society for Immunotherapy of Cancer (SITC) Virtual Congress; November 9–14, 2020:Poster 428.

Patient Eligibility
Select Exclusion Criteria1-3

Select Inclusion Criteria1-3

Ongoing or recent (within 5 years) autoimmune
disease requiring systemic immunosuppression

•

Adults (≥18 years) with histologically
confirmed diagnosis of invasive BCC

•

•

Prior disease progression on HHI therapy,
or intolerance to prior HHI therapy,* or no
better than stable disease after 9 months
on HHI therapy

•

Prior anti–PD-1 or anti–PD-L1 therapy

•

Active brain metastases

•

Immunosuppressive doses of steroids
(>10 mg prednisone daily or equivalent)

•

Concurrent malignancy other than BCC and/or
history of malignancy other than BCC within 3 years
of date of first planned dose of cemiplimab, except
for tumors with negligible risk of metastasis

•

≥1 measurable baseline lesion

•

ECOG performance status ≤1

•

Adequate organ function

•

Must not be a candidate for radiation
therapy or surgery

*Defined as any Grade 3/4 HHI-related AEs, or any of the following Grade 2 HHI-related AEs following ≥3 months of exposure: muscle spasms or myalgias, dysgeusia or anorexia (if
accompanied by Grade ≥1 weight loss), nausea, or diarrhea (despite medical management).
BCC=basal cell carcinoma; ECOG=Eastern Cooperative Oncology Group; HHI=hedgehog inhibitor; PD-1=programmed cell death protein-1; PD-L1=programmed death-ligand 1.
1. ClinicalTrials.gov/NCT03132636. https://clinicaltrials.gov/ct2/show/NCT03132636. Accessed October 2020. 2. Stratigos AJ, et al. Poster presented at: European Society for Medical Oncology
(ESMO) Virtual Congress; September 19–21, 2020:LBA47; 3. Lewis KD, et al. Poster presented at: Society for Immunotherapy of Cancer (SITC) Virtual Congress; November 9–14, 2020:Poster 428.

107

Kaplan-Meier
Curve for PFS by ICR in Patients with
33
Progression-free Survival
laBCC
1.0
0.9

Probability of PFS

0.8
0.7
0.6
0.5
0.4
0.3
0.2

Estimated median PFS, months: 19.3[95% CI, 8.6–NE]
0.1 Estimated 12-month event-free probability: 56.5% [95% CI, 44.3–67.0]
0
0

2

4

6

8

10 12

14 16

18 20

22 24

26 28

15

6

0

Month
Data cut-off date: 17 February 2020.

No. at
risk

84

76 64

56 48

40 35

27 15

9

2

0

CI=confidence interval; ICR=independent central review; laBCC=locally advanced basal cell carcinoma; NE=not evaluable; PFS=progression-free survival.
Stratigos AJ, et al. Poster presented at: European Society for Medical Oncology (ESMO) Virtual Congress; September 19–21, 2020:LBA47.

Kaplan-Meier
Curve for OS by ICR in Patients with laBCC
34
Overall Survival
1.0
0.9

Probability of OS

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1

Estimated median OS, months: not reached [95% CI, NE–NE]
Estimated 12-month probability of survival: 92.3% [95% CI, 83.6–96.5]

0
0
No. at
risk

2

4

6

8

10

12

14

16

18

20

22

24

26

28

51

35

25

15

3

0

0

Month
84

83

80

78

73

72

66

61

Data cut-off date: 17 February 2020.
CI=confidence interval; ICR=independent central review; laBCC=locally advanced basal cell carcinoma; NE=not evaluable; OS=overall survival
.
Stratigos AJ, et al. Poster presented at: European Society for Medical Oncology (ESMO) Virtual Congress; September 19–21, 2020:LBA47.

108

Cemiplimab is the first systemic treatment to show clinical benefit in
patients with laBCC and mBCC after HHI therapy.
31% and 21% ORR The safety profile is acceptable for the patient
population. Consistent with other PD-1 antibodies and previous reports of
cemiplimab in other tumor types

Merkel cell carcinoma (MCC)

109

Merkel cell carcinoma (MCC) - Epidemiology
Each year ~ 2,500 new cases diagnosed in the EU1 and 1,500 in USA
Increasing incidence over the past few decades2
Unclear whether this trend is due to an aging population or increased awareness and diagnosis

The highest rates of MCC have been observed in Australia, with an incidence rate of 1.6 per
100,000 persons reported in Queensland3,4
~80% of MCCs are caused by MCV (Merkel cell polyomavirus)

Each year approximately 1 in 3 patients with Merkel Cell Carcinoma will die from their disease
1. IMMOMEC (European Commission). Merkel cell carcinoma. Available at: www.immomec.eu/project/objectives/background/merkel-cell-carcinoma (accessed July 2017); 2. Saini
AT, Miles BA. Onco Targets Ther 2015;8:2157–67; 3. Schadendorf D, et al. Eur J Cancer. 2017;71:53–69; 4. Youlden DR, et al. JAMA Dermatol 2014;150:864–72.
37

MCC – Signs, Symptoms and Risk Factors
Clinical Presentation
Typical presentation
–single painless lump on
sun-exposed skin1
MCC on the lip

FEATURES OF MCC4,5
• Firm, red to purple
papule/nodule
• Asymptomatic/lack of
tenderness
• Rapidly Expanding
• Mets at an early stage

COMMONLY AFFECTED
AREAS6
• Head and neck (~50%)
• Upper extremities
(~16%)
• Lower extremities
(~30%)
• Trunk (<5%)

MCC on a cheek

RISK FACTORS5
• Immune suppression
• Median age ~76
years – Older age
• UV exposure
• Fair skin

.

1. Merkel Cell Carcinoma. National Cancer Institute. Available at: www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq (accessed December 20163. Image
credit: Klaus D. Peter, Gummersbach, Germany. Available at: commons.wikimedia.org/wiki/File:Merkel_cell_cancer.jpg – attribution required for re-use; 4. Nutan FNU et al.
Cutis 2014;94:E18–20; 5. Heath M et al. J Am Acad Dermatol 2008;58:375–81; 6. Hitchcock CL et al. Ann Surg 1988;207:201–7.

110

38

Merkel cell carcinoma
Where does MCC occur on the body?

• MCC primarily occurs on
highly sun-exposed skin, but
it can occur anywhere on
the body, including sunprotected areas such as the
buttock or the scalp under
hair.
Solid circles depict MCC tumors that arose on the
skin:
86% of these cases.

O Open circles indicate MCCs that presented in
lymph nodes
without an associated “primary lesion” : 14% of
cases
39

Treatment
Treatment is generally based on stage of the disease and many issues that
are highly variable between patients.
It is best to obtain care from a multi-disciplinary team of physicians with
significant MCC experience who take into consideration many clinical
factors.
Major treatments
1) surgical excision of the primary lesion or lymph node,
2) radiation therapy, and
3) systemic therapy including immunotherapy and chemotherapy.

111

Reason for use of immunotherapy in
mMCC
PD-L1 is expressed in MCC tumor cells and infiltrates of adjacent immune cells1
Dysfunction of MCPyV-specific T cells2

-Levels of CD8 T cells increase with a higher tumor load
-Exhausted phenotype (PD-1 +, Tim-3 +)
MCPyV-negative tumors have a higher burden on mutations and neoanthigens3

1. Lipson EJ, et al. Cancer Immunol Res. 2013;1(1):54-63; 2. Afanasiev O, et al. Clin Cancer Res. 2014;19(19):5351-60; 3. Goh G, et al. Oncotarget.
2016;7(3):3403-15.

JAVELIN MERKEL 200
N=200
(estimated
)

A phase II, open-label, multicenter trial to investigate the clinical activity and
safety of avelumab (MSB0010718C) in subjects with Merkel cell carcinoma

Patients with
• Histologicallyproven mMCC
• ECOG PS 0–1
Part A: patients have
received at least one line of
chemotherapy (n=88)2

Part B: patients have not
received any prior systemic
treatment for mMCC
(n=112)1,2

Tumor assessments every 6 weeks
(RECIST v1.1; IERC)

Part A:
PRIMARY ENDPOINT:
• Best Overall Response

Avelumab 10 mg/kg IV
(1-h infusion) every 2
weeks
until disease progression,
clinical deterioration,
unacceptable toxicity or
other criterion for
withdrawal

SECONDARY ENDPOINTS:
• DoR, PFS, OS, safety,
anti-drug antibodies, PK

Part B:
PRIMARY ENDPOINT:
• Durable response
SECONDARY ENDPOINTS:
• BOR, DoR, PFS, OS, safety,
anti-drug antibodies, PK

42
1. NCT02155647. Available at ClinicalTrials.gov (accessed Oct 2017). 2. Kaufman HL et al. Lancet Oncol 2016;17:1374–85.

112

Part A cohort, mMCC 2L+: design1
n=88
(estimated
)

A phase II, open-label, multicenter trial to investigate the clinical activity and
safety of avelumab (MSB0010718C) in subjects with Merkel cell carcinoma

PRIMARY
Part A:ENDPOINT:

Avelumab 10 mg/kg IV
(1-h infusion) every 2 weeks
until disease progression,
clinical deterioration,
unacceptable toxicity or
other criterion for withdrawal

Key Inclusion Criteria
• Histologically-proven
Stage IV MCC
• ECOG PS 0–1
• Patients received at
least one line of
chemotherapy

• Durable response*

PRIMARY ENDPOINT:

KEY SECONDARY ENDPOINTS:

• Best Overall Response

• BOR**, DoR, PFS, OS, safety,
SECONDARY
anti-drug antibodies, PK

ENDPOINTS:
• DoR, PFS, OS, safety,
anti-drug antibodies,
PK

Tumor assessments every 6 weeks
(RECIST v1.1; IERC)

**Best Overall Response is defined as complete response, partial response, stable
disease, or progressive disease, according to RECIST version 1.1 and assessed by
an independent review committee.

43
1. NCT02155647. Available at ClinicalTrials.gov (accessed Oct 2017

).

In previously treated patients who received avelumab 52% are still
1
alive at 1 year
100
OS

90
80

OS (%)

n=88

Events, n (%)

48 (54.5)

70

Median, months (95%
CI)

12.9 (7.5, –)

60

1-year rate, % (95% CI)

52 (41–62)

50
40

Avelumab

30
20
10
0
0

2

4

6

8

10

12

14

16

18

20

22

24

26

3

1

0

Months since initiating treatment
Number 88
at risk

81

68

59

50

46

41

27

19

9

6

1. Kaufman HL et al. AACR 2017. Abstract CT079 (presentation). – ≥ 12 month follow-up44

113

Part B cohort, mMCC –Treatment naïve - 1L: design1
n=1121,2
(estimated
)

A phase II, open-label, multicenter trial to investigate the clinical activity and
safety of avelumab (MSB0010718C) in subjects with Merkel cell carcinoma

Key Inclusion Criteria
• Histologically-proven
Stage IV MCC
• ECOG PS 0–1
• Not received any
prior systemic
treatment for
mMCC

Avelumab 10 mg/kg IV
(1-h infusion) every 2 weeks
until disease progression,
clinical deterioration,
unacceptable toxicity or
other criterion for withdrawal
Tumor assessments every 6 weeks
(RECIST v1.1; IERC)

PRIMARY ENDPOINT:
• Durable response*
KEY SECONDARY
ENDPOINTS:
• BOR, DoR, PFS, OS,
safety, anti-drug
antibodies, PK
Estimated primary completion date:
September 2019
* By Kaplan Meier Method

*Durable response is defined as proportion of patients of the total ITT population
with objective response (CR or PR) according to RECIST v1.1, with a duration of at
least 6 months.*

*
45
1. NCT02155647. Available at ClinicalTrials.gov (accessed Oct 2017). 2. Kaufman HL et al. Lancet Oncol 2016;17:1374–85.

Avelumab in 1L mMCC:
High ORR 62.1% and >80% on-going for at least 6 months CR in 4 patients
Preliminary Efficacy Data – Treatment naïve – 1L1

1. D'Angelo SP, et al. Efficacy and Safety of First-lineAvelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned
Interim Analysisof a Clinical Trial. JAMA Oncol 2018 Sep 1;4(9):e180077;

114

46

In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote- 017), 50
adults na¨ıve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3
weeks) for up to 2 years. Radiographic responses were assessed centrally per Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1.

J Clin Oncol 37:693-702. 2019

ORR to pembrolizumab was 56% (complete response [24%] plus partial response [32%];
95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors.
Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months).
Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+
months).
The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6
months to not estimable).
The 24-month OS rate was 68.7%, and median OS time was not reached.
Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend
toward improved PFS and OS in patients with programmed death ligand-1–positive
tumors.
Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients
and led to treatment discontinuation in seven (14%) of 50 patients, including one
treatment-related death.

J Clin Oncol 37:693-702. 2019

115

J Clin Oncol 37:693-702. 2019

In patients with aMCC receiving first-line anti– programmed cell death-1
therapy - Pembrolizumab demonstrated durable tumor control, a generally
manageable safety profile, and favorable OS compared with historical data
from patients treated with first-line chemotherapy.

J Clin Oncol 37:693-702. 2019

116

Nivolumab trial:
CheckMate358 (NCT02488759)
Non-comparative, two-cohort, single-arm, open-label,
Phase I/II study of nivolumab (BMS-936558) in subjects with
virus-positive and virus-negative solid tumors

N=500

Tumor types: MCC, gastric or GEJ carcinoma,
nasopharyngeal carcinoma, SCC of cervix, vagina or vulva, SCCHN

NEOADJUVANT COHORT
Nivolumab

METASTATIC COHORT
Nivolumab

PRIMARY ENDPOINT
Safety and tolerability, ORR in metastatic patients,
surgery delay rate

SECONDARY ENDPOINTS
Change in immune cells of viral-specific T-cells;
change in immune activation/inhibitory molecules
of viral-specific T-cells; PFS; OS

•

NCT02488759. Available at: ClinicalTrials.gov (accessed December 2016). 51

Nivolumab in 1L advanced MCC - Efficacy
RESPONSE*

(n=15)

ORR, %
(95% CI)

73
(45–92)

CR, n (%)
PR, n (%)

7 (47)
4 (27)

*By RECIST v1.1, investigator assessed

1. Topalian SL et al. AACR 2017. Abstract CT074
(presentation).

117

52

Nivolumab* in 2L+ - Efficacy
RESPONSE*

(n=10)

ORR, %
(95% CI)

50
(19–81)

CR, n (%)
PR, n (%)

10 (1)
40 (4)

*By RECIST v1.1, investigator assessed

1. Topalian SL et al. AACR 2017. Abstract CT074
(presentation).

53

Immunotherapy
Phase II of the JAVELIN Merkel 200 trial studied Avelumab in patients with metastatic MCC
either as 1st line therapy1 or in chemotherapy-refractory MCC2-3. In patients with no prior
systemic therapy, after a median follow-up of 5.1 months (range 0.3-11.3 months), the overall
response rate was 62.1%, and 83% of patients had a duration of response of at least 6
months1. In patients treated with avelumab after progression on chemotherapy, the overall
response rate was 33.0% after a minimum follow up of 12 months. At the time of data cut-off,
72.4% of responses were ongoing3
A different phase II trial studied patients with advanced MCC treated with pembrolizumab4;
- after a median follow up of 33 weeks (range 7-53 weeks) the overall response rate was 56%,
with a response duration ranging from 2.2-9.7 months.
The ongoing CHECKMATE 358 phase I/II trial is studying nivolumab in patients with resectable
MCC5. In pts treated with nivolumab prior to surgery, 80% had tumour regression and 65% had
a major pathologic response including 8 CR.
1.D'Angelo SP, et al. Efficacy and Safety of First-lineAvelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim
Analysisof a Clinical Trial. JAMA Oncol 2018 Sep 1;4(9):e180077; 2.Kaufman HL, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell
carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol 2016 Oct;17(10):1374-1385; 3. Kaufman HL, et al. Updated efficacy of avelumab in
patients with previously treated metastatic Merkel cell carcinoma after >/=1 year of follow-up: JAVELIN Merkel200, a phase 2 clinical trial. J Immunother Cancer
2018 Jan 19;6(1):x. 4.Nghiem PT, et al. PD-1 Blockade withPembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016 Jun 30;374(26):2542-2552.
5.Topalian SL, Bhatia S, Kudchadkar RR, Amin A, Sharfman WH, Lebbe C, et al. Nivolumab (Nivo) as neoadjuvanttherapy in patients with resectable Merkel cell
carcinoma (MCC) in CheckMate 358. JCO 2018;36(15):9505.

118

Anti PD-1/PD-L1 in advanced MCC
ORR

1st line 56-73%

2nd line 33-50%
PFS

1st line 17 mo (median)

2nd line 3 mo (median)

OS

1st line median not reached

2nd line 13 mo (median)

119

Summary MCC
NMSC - the most common cancer
Incidence is rising
Numerous mutations in UV-induced cancer
Surgery is a standard therapy for non-complicated cases
Limited role of radiotherapy despite radiosensitivity in MCC
anti-PD-1/PD-L1 should be applied as first-line treatment
ChT should be postponed to 2nd line
Previous ChT impairs outcome of anti-PD-1/PD-L1

Summary NMSC
There is no clear benefit of chemotherapy

Targeted therapy in BCC patched / SMOi is effective (RR 58%, CR 20-30%)

Imunoterapies (PD-1 and PD-L1 antibodies) are effective in MCC and SCC,
they also promise a great deal of potential for BCC

120

Our experience &
interesting cases
Maša Sever, Janja Ocvirk

Vismodegib in Routine Clinical Practice in Slovenia

121

Although basal cell carcinoma (BCC) is the most common malignancy
among Caucasians, the incidence of advanced forms is relatively rare
and therefore there is little data in the literature on treatment of locally
advanced BCC (laBCC) or metastatic BCC (mBCC) by systemic therapy.
Vismodegib is a Hh signaling pathway inhibitor and was approved by
the European Medicines Agency for the treatment of adults with mBCC,
or with laBCC inappropriate for surgery or radiotherapy.
A retrospective analysis was conducted to provide vismodegib longterm efficacy and safety data in a real-world setting in Slovenia.

Methods

Evaluation of efficacy and safety of vismodegib (V) was done in a
retrospective analysis of patients (pts) with laBCC or multiple BCC
and pts with Goltz-Gorlin Syndrom (G-G Syn) in routine clinical
practice.
Baseline characteristics, efficacy data and treatment-related
adverse events (AEs) were collected from pts who were treated
with V from November 2012 to January 2021.
Efficacy was assessed by objective response rate - ORR (CR + PR),
disease control rate - DCR (CR + PR + SD) and duration of
vismodegib treatment – DoT. Reasons for treatment
discontinuation were analyzed.

122

Baseline characteristics
During the 100-month period, 46 pts were diagnosed with laBCC (26 pts),
multiple BCC (13 pts) or G-G Syn (7 pts), all inappropriate for surgery or
radiotherapy. Baseline characteristics: median age was 72.8 years in laBCC
+ multiple BCC pts group and 47.4 years in the G-G Syn pts group (Fig.1).
Fifty-six percent of pts in laBCC +multiple BCC group were females; the
majority (67%) of pts were previously treated by surgery and/or
radiotherapy; 51% of pts had one lesion with predominant localization in
the central face area (eyes, nose, lips, or ears in 76% of pts), 18% had 2-3
lesions, and 31% more than 3 lesions. Fifty-seven percent of pts in G-G Syn
group were males; 86% of pts were previously treated with surgery and/or
radiotherapy.

Results

Figure 1. Age distribution at vismodegib treatment initiation
Patients with Goltz-Gorlin Syndrom
(N=7)

16
14
12
10
8
6
4
2
0

4
Number of patients

Number of patients

Patients with laBCC and multiple BCC
(N=39)
3
2
1
0
30-39

40-49

50-59

60-69

70-79

80-89

90-

20-29

30-39

Age distribution

Efficacy results

40-49

50-59

60-69

Age distribution

• At the time of analysis in laBCC or multiple BCC group treatment has
been interrupted during the treatment course in 23% of pts [in 8 out of 9
pts due to adverse events (AEs)], 31% of pts are still on treatment. In G-G
Syn group treatment has been interrupted in 57% of pts (in most cases
due to adverse events), 43% of pts are still on treatment. Efficacy data
are presented in Table 1.

Table 1. Response to vismodegib treatment
laBCC +
multiple BCC
group (N=39)

Efficacy variable
Investigator-assessed objective response rate
(CR+PR); n, %
Investigator-assessed disease control rate
(CR+PR+SD); n, %
Duration of treatment (months); median
(range)

123

G-G Syn group
(N=7)

31 (80%)

6 (86%)

37 (95%)

7 (100%)

9.9 (1.5-43.1)

19.5 (3.6-94.1)

Safety results

Serious adverse events were reported in 6 out of 46 patients (13.0%):
two cases of squamous cell cancer, one case of angiosarcoma,
melanoma, cholangiocarcinoma and intracerebral hemorrhage each,
while one patient died due to other reasons than cancer. AEs of any
grade were reported in 82% of pts in laBCC or multiple BCC group
and 71% in G-G Syn group.
The majority of AEs in laBCC or multiple BCC group were grade 1 or 2
(96%) and only 4% of AEs were grade 3: muscle cramps in 3 pts,
respiratory infection, vomiting and anemia in 1 patient each. The
majority of AEs in G-G Syn group were also grade 1 or 2 (87%), while
13% of AEs were grade 3: muscle cramps in 2 pts, weight loss and
diarrhea in 1 patient each. No grade 4 or 5 vismodegib related AEs
were reported.

Conclusion
Vismodegib has shown meaningful long-term efficacy with
manageable safety profile in pts with laBCC or multiple BCC
as well as in pts with G-G Syn in real-world setting.

124

Clinical cases

BCC

125

19. 12. 2013

Case from OIL

31. 7. 2014

23. 9. 2013

Quick response to high-dose treatment
Side effects: alopecia gr. 2 after one year of treatment, increased CPK gr.1,
muscle cramps gr.1

11. 2012
Case8.from
OIL

11

16. 10. 2014

Patient with Gorlin syndrome
(multiple BCC)

Side effects: alopecia gr.1
weight loss gr.2 increased CPK
gr.1-3

12

126

Side effects: alopecia gr. 2, muscle spasms gr.2, change in taste gr.1

Case from OIL
21.11.2013

25.9.2014

13

Man, 87 years old
History:
2001 – Multipl epiteliomas left leg
2001 – Malignant melanoma left leg/excision
2011 – BCC/SCC left leg/
excision, RT → ulcus
BCC right leg →
Not suitable for RT or excision
Others:
2003 – Nefrectomy
2006 – Deep vein thrombosis
2012 – Deep vein thrombosis
2012 – hypertension
therapy: varfarin and trandolapril since 2012

14

127

January 2018

July 2019

March 2019

128

August 2020

October 2020

January 2020

129

May 2020

La BCC

After 3 m
vismodegib

BCC – 2 lines
of treatment
After 6 w of
immunotherapy

Progres on
vismodegib,
Start of
immunotherapy

After 3 m of
immunotherapy

October 2018

MCC Case
October 2018

Male 68-year-old, presented with bleeding tumor on right thigh,
invasions in inguinal lymph nodes, obturator lymph nodes, right
iliac lymph nodes
Biopsy - MCC
TMB decision: immunotherapy- avelumab

130

before starting immunotherapy
marked pain occurred
bleeding from the tumor
the surgeons decided for resection of a bleeding tumor on the
thigh
complication of treatment for sepsis, wound dehiscence
he was recovering from complications of surgical treatment in
January 2019

referred to medical oncologist
the patient also has rheumatoid arthritis on methotrexate therapy
highly motivated for immunotherapy treatment
he began with immunotherapy (Avalumab) in January 2019
CT scan in April 2019 - PRCT

January 2019

scan in July 2019 – further response
CT scan in october 2019 - borderline enlarged lymph node left
inguinal, no other evident residum of the disease
Stop immunotherapy due to AE in March 2020

131

16.10.2018

27.8.2019

SCC

132

11.10.2020

Start treatment
with cemiplimab

2.11.2020

After 1
application

22.2.2021

After 2 appl and
post COVID
pneumonia

Thank you for your attention

133

7.6.2021

CR confirmed with
biopsy

NEXT-GENERATION
SEQUENCING
Assist. Prof. Tanja Mesti, MD., PhD
2nd Summer school
7 September 2021

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from
the ESMO Precision Medicine Working Group

◦ ESMO Scale for Clinical Actionability of
molecular Targets (ESCAT)
◦ Advanced lung carcinoma
◦ Metastatic prostate cancer
◦ Metastatic ovarian cancer
◦ Metastatic cholangiocarcinoma
*cancer types without clear standard-of-care
options, such as carcinoma of unknown primary
and other rare tumors

Annals of Oncology 2020 311491-1505DOI: (10.1016/j.annonc.2020.07.014)

134

CONCLUSION
◦ ESMO Guidelines
◦ NGS consilium - subgroup of patients with advanced cancer and no standard
therapeutic options.

135

Systemic treatment of gastric
carcinoma
Marko Boc, MD
Department for Medical Oncology
Institute of Oncology Ljubljana

Ljubljana, 08.09.2021

NEOADJUVANT AND PERI-OPERATIVE CHEMOTHERAPY

◆

◆

◆

◆

Downstage the tumour
Increase R0 resection rate
Treat micrometastatic disease
Improve overall survival

Neoadjuvant and perioperative chemotherapy is more commonly used in non-Asian countries
where tumours are frequently locally advanced and require downstaging prior to successful
resection

136

NEOADJUVANT AND PERI-OPERATIVE CHEMOTHERAPY

5 year OS 45%*
5 year OS 38%*
5 year OS 36%*
5 year OS 23%*
2002
2 cycles
neoadjuvant CF
(OE02)

2011
3+3 cycles CF
(ACCORD)

2006
3+3 cycles ECF
(MAGIC)

*chemotherapy patients; CF, cisplatin + 5-fluourouracil; ECF epirubicin + CF; FLOT. 5-fluororuraci, leucovorin, oxaliplatin, docetaxel

ADJUVANT CHEMOTHERAPY FOR NON-ASIAN PATIENTS

2017
4+4 cycles FLOT
(FLOT4)

1. OE02 Trial Group, Lancet 2002.
2. Cunningham D, et al. N Engl J Med 2006.
3. Ychou M, et al. J Clin Oncol. 2011.
4. Al-Batran S, et al. Lancet 2019.

ADJUVANT CHEMOTHERAPY

Although non-Asian adjuvant gastric cancer trials have not shown a survival benefit, this metanalysis can be used to justify use of
adjuvant chemotherapy in non-Asian patients
Paolettiet al, JAMA. 2010 May 5;303(17):1729-37.

137

mOS: 8-11m
mPFS: 4.8-6.2m

138

2nd Summer School in medical oncology – Precision oncology – Are we there yet

CLINICAL CASE
GASTRIC CANCER

Ana Erman, dr. med.
Mentor: doc. dr. Tanja Mesti, dr. med.

Ljubljana, 8.9.2021

SUMMARY
November
2015

March
2016

May 2016

July 2017

October
2018

April
2018

January
2021

Peritoneal carcinomatosis

Gastric and esophageal
adenocarcinoma T4NxM0
Neoadjuvant CRT

Capecitabine and Trasuzumab
Reinduction of paclitaxel
PFS 14 months
PFS 6 months
st
1 line systemic
therapy: Capecitabine,
Paclitaxel and ramucirumab
oxaliplatin and
PFS 16 months
Immunotherapy - Pembrolizumab
trastuzumab
PFS 14 months

139

SUMMARY
• HER2, MSI and NTRK testing
• If sufficient tissue: NGS
• Pembrolizumab for MSI-H/dMMR tumors or TMB-high (>10 mutations/megabase)
tumors

140

Systemic treatment of the Biliary
tract cancer (BTC)– where we
stand
Summer School, 8th September 2021
assist.prof. Martina Reberšek, MD, PhD

Current recommendations for systemic treatment of metastatic
disease
Systemic chemotherapy:
- 1st line: gemcitabine + cisplatin (PS ECOG 0-1), gemcitabine mono (PS ECOG 2)
- 2nd line: mFOLFOX or new standard option Nal-IRI+5FU/LV
Immunotherapy:
- 1st line: MSI-H/dMMR → pembrolizumab
- 2nd line: nivolumab, MSI-H/dMMR/TMB-H → pembrolizumab
Targeted therapy
- 1st line: positive NTRK fusion gene →larotrectinib, entrectinib
- 2nd line:
→posi:ve NTRK fusion gene → larotrectinib, entrectinib
→ mt BRAF V600 → dabrafenib+trametinib
→ mt IDH1 → ivosidenib
→FGFR2 fusions or rearrangements → pemigatinib

141

How to approach GEP NET & NEC
MARIJA IGNJATOVIĆ.
2ND SUM M ER SCHO O L IN M EDICA L O NCO LO G Y
08.09.2021

NEUROENDOCRINE
NEOPLASMS
(NENs)

 Heterogeneous group of malignancies ► arise from
neuroendocrine cells ► release of catecholamines and
hormones
 Rare malignancies
 Less then 0.5% of all malignancies, only 1%-2% of gastrointestinal
malignancies
 Growing incidence, especially of localized and regional NENs
 EUR 1.33 – 2.33/100.000; USA: 3.56/100.00
 men > women, men have adverse outcome

 Sporadic/hereditary
 Younger then < 40 with gastrinoma
 Multiple neuroendocrine neoplasia (MEN)
 Family history of NENs

142

CLASSIFICATION OF
GASTROENTEROPANCREATIC
NEOPLASMS
(GEP-NENs)

FIRST
MORPHOLOGY
Well-differentiated &
poorly-differentiated

THEN

KI67

Grade1/2/3

WHO 2019
MORPHOLOGY

WELL
DIFFERENTIATED
POORLY
DIFFERENTIATED

GRADE

MITOTIC
INDEX
(2 mm²)

KI 67
(%)

G1

<2

<3

G2

2-20

3-30

G3

>20

>20

G3

>20

>20

Neuroendocrine tumors
(NET)
Neuroendocrine carcinomas
(NEC)

MiNEN

GASTROENTEROPANCREATIC
NEOPLASMS
(GEP-NENs)

143

GEP-NET ► 80% - 90%
GEP-NEC ► 10% - 20%

YOUR PATIENTS MIGHT BE
(A)SYMPTOMATIC

HYSTOPATHOLOGY
• Morphology
• Grade
• IHC

DIAGNOSIS

144

STAGING

PET CT with GALLIUM 68/SRS
FDE-PETCT
MRI
CT

MANAGEMENT OF PATIENTS WITH
LOCAL & LOCOREGIONAL
GEP NETs

145

SURGERY

MANAGEMENT OF PATIENTS WITH
LOCAL & LOCOREGIONAL
GEP NECs

MANAGEMENT OF
PATIENTS WITH
METASTATIC GEP NET

146

SURGERY
SYSTEMIC TREATMENT

CONTROL OF HORMONAL
OVERPRODUCTION

Systemic
treatment and
mGEP-NETs

CONTROL OF TUMOUR GROWTH

MENAGMENT OF
PATIENTS WITH mGEP
NEC

147

SYSTEMIC TREATMENT

How to approach NET/NEC

Our experience –
clinical case
Katja Leskovšek, dr. med.
prof. dr. Janja Ocvirk, dr. med.
Institute of Oncology Ljubljana,
08.09.2021

D.N., female, 54y


On presentation, Nov 2005
 6 months of diarrhoea, loss of weight (10 kg).


Family history: positive.



Past medical history: asthma (2003), discus hernia L4-5 op. (1999).



PS ECOG 1.



Therapy: Symbicort.



Alergies: ketoprofen.

 US: 3 liver metastases

Core needle biopsy: NEC metastases;

origo ignota.
 Laparotomy (Sept 2005): tumor of distal pancreas, invading spleen


Distal pancreatectomy and splenectomy, resection of IV. and V. liver segment,
cholecystectomy.

148

D.N., female, 54y


Histopathology report: NEC of pancreas, invading
retroperitoneal fat, hilum of spleen, vascular, peri- and
intraneural invasion, lymphangiosis carcinomatosa; lymph node
status 3/5.



R1 resection.



Somatostatin: 10 %.



Partial liver resection: metastasis of endocrine carcinoma.

Discussion


NEC of pancreas, liver metastasis, R1.



On treatment for 15 years.



Systemic therapy:





I. line ChT: etoposide + cisplatin;



II. line ChT: 5-FU + dacarbazine + epidoxorubicin;



3 x partial liver resection/metastasectomy (12‘, 13‘, 13‘);



III. line: lanreotide;



IV. line: lanreotide + everolimus;



V. line: octreotide + sunitinib;



6 x TACE (19‘, 20‘, 21‘);

PRRT ?

149

HCC – LOTS HAS
BEEN GOING ON
Janja Ocvirk

INCIDENCA

150

HCC
The fourth most common cause of cancer-related death worldwide1
HCC accounts for >80% of primary liver cancers worldwide1
Chronic HBV and HCV infection are the most important causes of HCC and account for 80%
of HCC cases globally1
It is estimated that 72% of cases occur in Asia (more than 50% in China)2
Staging of HCC is important to determine outcome and planning of optimal therapy. While
there are a number staging systems used, the BCLC is currently commonly used to
compare clinical outcomes:3

◦
1.
2.
3.

BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; TACE, transarterial chemoembolisation
Yang JD, et al. Nat Rev Gastroenterol Hepatol. 2019;16:589-604
Singal AG, et al. J Hepatol. 2020;72:250-61
Bruix J, et al. Nat Rev Gastroenterol Hepatol. 2019;16:617-30

BCLC Staging System

151

3

HCC

Early and intermediate
HCC

BCLC staging

Survival rate
with current therapy

Standard of care treatment

Stage 0-A

>5 years

Ablation, resection, transplantation

Stage B

>2.5 years

Chemoembolisation (TACE)

Stage C

>1 year

Systemic therapy

Stage D

3 months

Best supportive care

Advanced HCC

◦
1.
2.
3.

BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; TACE, transarterial chemoembolisation
Yang JD, et al. Nat Rev Gastroenterol Hepatol. 2019;16:589-604
Singal AG, et al. J Hepatol. 2020;72:250-61
Bruix J, et al. Nat Rev Gastroenterol Hepatol. 2019;16:617-30

1L FOR ADVANCED
HCC PATIENTS

152

5

Phase 3 SHARP trial of sorafenib vs
placebo: study design1
Eligibility
•Advanced HCC*
•Child–Pugh A
•ECOG PS 0–2
•No prior systemic
therapy
Stratification
•Geographic region
•ECOG PS (0 vs 1-2)
•MVI/EHS
(present/absent)

N=602

R
A
N
D
O
M
I
Z
E

Sorafenib
400 mg BID
(n=299)

Placebo
(n=303)

1:1

Primary endpoints
•OS
•TTSP†
Secondary endpoints
•TTP
•DCR
•Safety‡

Note: same study design
was used for SHARP-AP2

*Not eligible for, or had disease progression after surgical or locoregional therapies.
†Assessed by the Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index-8 (FSHI-8).
‡Assessed using version 3.0 of the USA National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).
BID, twice daily; DCR, disease control rate; EHS, extrahepatic spread; MVI , macroscopic vascular invasion; OS, overall survival; TTP, time to treatment progression;
TTSP, time to symptomatic progression.
1. Llovet JM et al. N Engl J Med. 2008;359(4):378-390; 2. Cheng A et al. Lancet Oncol 2009;10:25–34.

SHARP: Baseline Patient
Characteristics

BCLC stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs.
0%) in sorafenib and placebo respective
Llovet JM, et al. N Engl J Med. 2008;359:378-390.

153

SHARP - efficacy data
Efficacy parameter

Median OS, months
(95% CI)
Median TTP, months
(95% CI)

Sorafenib
(n=299)

Placebo
(n=303)

P-value

10.7
(9.4-13.3)

7.9
(6.8-9.1)

0.00058

0.69
(0.55-0.87)

5.5
(4.1-6.9)

2.8
(2.7-3.9)

0.000007

0.58
(0.45-0.74)

1. Llovet JM et al. N Engl J Med. 2008;359(4):378-390; 2.

HR
(95% CI)

9

SHARP: sorafenib is generally well
tolerated in advanced HCC
Incidence by grade (%)
(N=297)

Adverse event*

Any grade

Grade 3/4

Diarrhoea

39

8†

Fatigue

22

4

HFSR

21

8†

Rash/desquamation

16

1†

Anorexia

14

<1†

Abdominal pain

8

2†

Liver dysfunction

<1

<1†

Nausea

11

<1†

Vomiting

5

1†

Weight loss

9

2†

Hypertension

5

2†

*Defined by NCI CTC (version 3.0) that occurred in at least 5% of patients; †No grade 4 events reported.
HFSR, hand–foot skin reaction.
Llovet JM et al. N Engl J Med 2008;359:378–90; EASL–EORTC Clinical Practice: Management of hepatocellular carcinoma. J Hepatol 2012;56:908–43; Verslype C et al. ESMO guidelines. Ann
Oncol 2012;23(Suppl 7):vii41–8.

154

Data from SHARP and real-world practice
support use of sorafenib in intermediate HCC
SHARP1
BCLC-B subgroup

•Increased OS and TTP with sorafenib (n=54) vs placebo (n=51)
– Median OS: 14.5 vs 11.4 months (HR: 0.72; 95% CI: 0.38–1.38)
– Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: 0.23–0.96)

SHARP1
previous TACE subgroup

•Increased OS and TTP with sorafenib (n=86) vs placebo (n=90)
– Median OS: 11.9 vs 9.9 months (HR: 0.75; 95% CI: 0.49–1.14)
– Median TTP: 5.8 vs 4.0 months (HR: 0.57; 95% CI: 0.36–0.91)

SOFIA2

•Good efficacy demonstrated in BCLC-B HCC
– Longer survival in BCLC-B vs BCLC-C patients:
20.6 vs 8.4 months

INSIGHT3

•Good efficacy demonstrated in BCLC-B HCC
– Longer survival in BCLC-B vs BCLC-C patients:
19.6 vs 14.5 months

GIDEON interim
analysis4

•Similar safety profile for sorafenib across BCLC stages

BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; HR, hazard ratio; OS, overall survival; TTP, time to
progression
1. Bruix J et al. J Hepatol. 2012;57:821–9; 2. Iavarone M et al. Hepatology 2011;54:2055–63; 3. Ganten TM et al. EMSO
2012;poster 77;
4. Lencioni R et al. Eur J Cancer 2011;47 (Suppl 1):abstract 6500

155

Lenvatinib - REFLECT
REFLECT (NCT01761266): phase 3, international,
multicentre, open-label, randomised study in 954 patients
with hepatocellular carcinoma
Non inferiority assessment of lenvatinib vs. sorafenib for OS
Primary endpoint: OS
Secondary endpoints: PFS, ORR (mRECIST and RECIST v1.1)
Population enrolled: BCLC stage B: 20%; stage C: 80%

BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; mRECIST, modified RECIST;
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours
Sources: lenvatinib summary of product characteristics dated June 2020; lenvatinib US prescribing information dated February 2020

Efficacy parameters
Overall survival
Number of deaths (%)
Median OS in months (95% CI)
Hazard ratio (95% CI)
Progression-free survival (mRECIST)
Number of events (%)
Median PFS in months (95% CI)
Hazard ratio (95% CI) and P-value
Objective response rate (mRECIST)
Objective response rate
Complete responses, n (%)
Partial responses, n (%)
95% CI
P-value
Progression-free survival (RECIST 1.1)
Number of events (%)
Median PFS in months (95% CI)
Hazard ratio (95% CI)
Objective response rate (RECIST 1.1)
Objective response rate
Complete responses, n (%)
Partial responses, n (%)
95% CI

Lenvatinib

Sorafenib

N=478

N=476

13

351 (73)
350 (74)
13.6 (12.1-14.9)
12.3 (10.4-13.9)
0.92 (0.79-1.06)
311 (65)
323 (68)
7.3 (5.6-7.5)
3.6 (3.6-3.7)
0.64 (0.55-0.75); <0.001
41%
10 (2.1)
184 (38.5)
(36-45)

12%
4 (0.8)
55 (11.6)
(10-16)
<0.001

307 (64)
7.3 (5.6-7.5)

320 (67)
3.6 (3.6-3.9)
0.65 (0.56-0.77)

19%
2 (0.4)
88 (18.4)
(15-22)

7%
1 (0.2)
30 (6.3)
(4-9)

◦ BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; mRECIST, modified RECIST;
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours
◦ Sources: lenvatinib summary of product characteristics dated June 2020; lenvatinib US prescribing information dated February 2020
14

156

Sorafenib and lenvatinib safety data in
HCC patients
Most common adverse reactions (≥20%)
sorafenib-treated patients in
SHARP trial

Diarrhoea – fatigue – hand-foot skin reaction – weight loss –
anorexia – nausea – abdominal pain

lenvatinib-treated patients in
REFLECT trial

Hypertension – fatigue – diarrhoea – decreased appetite –
arthralgia/myalgia – decreased weight – abdominal pain –
palmar-plantar erythrodysesthesia syndrome – proteinuria –
dysphonia – haemorrhagic events – hypothyroidism – nausea

◦ Sources: sorafenib SmPC; lenvatinib SmPC

15

IMbrave150 clinical trial
Key eligibility criteria
• Locally advanced
metastatic
or unresectable HCC
• ECOG PS 0-1
• No prior systemic therapy
• No bleeding or high risk
of bleeding
(n=501)

Stratification criteria
• Region: Asia (excluding Japan) or
rest of world
• ECOG PS 0 or 1
• Presence or absence of
macrovascular invasion or
extrahepatic spread

atezolizumab
1200 mg IV
q3w
+ bevacizumab
15 mg/kg IV
q3w
R
(Open label)
2:1

sorafenib

Until loss of
clinical
benefit
or
unacceptab
le toxicity

Survival
followup

400 mg BID

• Baseline AFP <400 or ≥400 ng/mL

Co-primary endpoints
• OS
• IRF-assessed PFS per RECIST 1.1

Secondary endpoints include
• IRF-assessed ORR per RECIST 1.1 and HCC mRECIST
• PROs

AFP, alpha-fetoprotein; BID, twice a day; ECOG PS; Eastern Cooperative Oncology Group performance status; HCC; hepatocellular carcinoma;
IRF, independent review facility; IV, intravenous; mRECIST, modified RECIST; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1;
PFS, progression-free survival; PRO, patient-reported outcome; q3w, every 3 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumours;
VEGF, vascular endothelial growth factor
Finn RS, et al. N Engl J Med. 2020;382:1894-905

157

16

IMbrave150 clinical trial
Efficacy results: primary endpoints
atezolizumab +
bevacizumab (n=336)

sorafenib
(n=165)

NE

13.2
(10.4–NE)

Median OS (95% CI), months

0.58
(0.42–0.79)

OS, HR (95% CI)

<0.001

P-value
6.8
(5.7–8.3)

Median PFS (95% CI) per
IRF RECIST v1.1, months

4.3
(4.0–5.6)
0.59
(0.47–0.76)

PFS, HR (95% CI)

<0.001

P-value
◦ Finn RS, et al. N Engl J Med. 2020;382:1894-905

17

IMbrave150 clinical trial
Efficacy results: secondary endpoints
Confirmed ORR per IRF RECIST v1.1,
% (95% CI)

atezolizumab +
bevacizumab (n=326)

sorafenib
(n=159)

27.3
(22.5–32.5)

11.9
(7.4–18.0)
<0.001

P-value

Confirmed ORR per HCC specific
mRECIST, % (95% CI)

atezolizumab +
bevacizumab (n=325)

sorafenib
(n=158)

33.2
(28.1–38.6)

13.3
(8.4–19.6)

P-value

<0.001

◦ Finn RS, et al. N Engl J Med. 2020;382:1894-905
18

158

IMbrave150 clinical trial - safety results
atezolizumab + bevacizumab
(n=329)

sorafenib
(n=156)

Patients with an AE from any cause

323 (98.2)

154 (98.7)

Grade 3-4 AEs (numbers represents the highest
grades assigned)

186 (56.5)

86 (55.1)

15* (4.6)

9** (5.8)

Serious adverse event

125 (38.0)

48 (30.8)

AEs leading to withdrawal from any trial drug

51 (15.5)

16 (10.3)

AEs leading to dose modification or interruption of
any trial drug

163 (49.5)

95 (60.9)

163 (49.5)

64 (41.0)

–

58 (37.2)

Variables, n (%)

Grade 5 AEs

Dose interruption of any trial treatment
Dose modification of sorafenib
*Grade 5 events in the atezolizumab–bevacizumab group:
gastrointestinal haemorrhage (in 3 patients), pneumonia (in 2 patients),
empyema, gastric ulcer perforation, abnormal hepatic function, liver
injury, multiple-organ dysfunction syndrome, oesophageal varices
haemorrhage, subarachnoid haemorrhage, respiratory distress, sepsis,
and cardiac arrest (in 1 patient each)
◦
◦

**Grade 5 events in the sorafenib group:
death (in 2 patients), hepatic cirrhosis (in 2 patients), cardiac arrest,
cardiac failure, general physical health deterioration, hepatitis E,
and peritoneal haemorrhage (in 1 patient each)

AEs, adverse events
Finn RS, et al. N Engl J Med. 2020;382:1894-905

19

IMbrave150 clinical trial - conclusion
◦ IMbrave150 demonstrated a statistically significant improvement in OS and PFS with
atezolizumab + bevacizumab versus sorafenib in the first-line setting in patients with
advanced HCC
◦ Times to response were similar in the combination and sorafenib arms
◦ Response rates were significantly higher in the combination arm
◦ The trial was conducted in a patient population that had preserved liver function
(Child–Pugh class A) and a decreased risk of variceal bleeding. The safety of the
combination in a broader population warrants further study

Finn RS, et al. N Engl J Med. 2020;382:1894-905

20

159

Atezolizumab + bevacizumab vs sorafenib for unresectable hepatocellular carcinoma
(HCC): Results from older adults enrolled in IMbrave150
Overall survival
Key results

Age <65 years
Median OS, mo
HR (95%CI)

Sorafenib
(n=74)

NE

11.4

Median OS, mo

0.59 (0.38, 0.91)

80

80

60

60

40

20

0

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time, months
No. at
Atezo
risk 175172169163156147140127107 81 55 42 30 16 8 4 2 NE
+ bev
2

1 NE NE

Atezo + bev
(n=161)

Sorafenib
(n=91)

NE

14.9

0.58 (0.36, 0.92)

40

20

SOR 74 69 62 56 54 51 44 36 33 25 20 16 11 7

HR (95%CI)

100

OS, %

OS, %

100

Age ≥65 years

Atezo + bev
(n=175)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time, months
161157151149146141135128115 84 63 45 34 24 12 7

1 NE

91 88 81 76 73 67 61 58 53 35 25 17 13 9

1 NE

5

2

Li D, et al. Ann Oncol 2020;31(suppl):abstr O-8

Atezolizumab + bevacizumab vs sorafenib for unresectable hepatocellular carcinoma
(HCC): Results from older adults enrolled in IMbrave150
AEs occurring in ≥15% of patients treated
with atezolizumab + bevacizumab, n (%)

<65 years
(n=171)

≥65 years
(n=158)

Hypertension

47 (27)

51 (32)

Fatigue

24 (14)

43 (27)

Diarrhoea

28 (16)

34 (22)

Appetite decreased

26 (15)

32 (20)

Pyrexia

29 (17)

30 (19)

Pruritus

35 (20)

29 (18)

Proteinuria

39 (23)

27 (17)

AST increased

39 (23)

25 (16)

Conclusions
◦ In older patients (≥65 years) with unresectable HCC, atezolizumab + bevacizumab demonstrated
clinically meaningful benefits with no significant additional toxicities

Li D, et al. Ann Oncol 2020;31(suppl):abstr O-8

160

CheckMate 459: long-term efficacy outcomes with nivolumab versus sorafenib as firstline treatment in patients with advanced hepatocellular carcinoma – Sangro B, et al
Study objective
◦ To evaluate the long-term efficacy and safety of nivolumab as a 1L treatment for patients with
advanced HCC
Key patient inclusion criteria

Nivolumab 240 mg iv q2w
(n=371)

• Advanced HCC
• Ineligible for surgery and/or
for loco-regional therapy or
PD after surgery and/or
loco-regional therapy

PD/
toxicity

Stratification
• Aetiology (HCV vs. non-HCV)
• Vascular invasion and/or extrahepatic spread (present vs. absent)
• Geography (Asia vs. non-Asia)

R
1:1

• Child-Pugh class A
• Systemic therapy naïve

Sorafenib 400 mg po bid
(n=372)

• ECOG PS 0–1

PD/
toxicity

(n=743)
SECONDARY ENDPOINTS
• ORR, PFS, efficacy by PD-L1 status, safety

PRIMARY ENDPOINT
• OS

Sangro B, et al. Ann Oncol 2020;31(suppl):abstr LBA-3
This talk was presented at the 22nd ESMO WCGC on 1 July 2020 at 18:20

CheckMate 459: long-term efficacy outcomes with nivolumab versus sorafenib as firstline treatment in patients with advanced hepatocellular carcinoma – Sangro B, et al
Overall survival
Nivolumab
(n=371)

Key results

Primary analysis: June 2019 database lock

100

Median OS, months (95%CI)

16.4 (13.9, 18.4)

HR (95%CI); p-value

80

12-mo rate

60

Median OS, months (95%CI)

37%

16.4 (14.0, 18.5)

HR (95%CI); p-value

24-mo rate
55%

14.7 (11.9, 17.2)

0.85 (0.72, 1.02); 0.0752

Long-term follow-up analysis: April 2020 database lock

60%

OS, %

Sorafenib
(n=372)

33-mo rate

40

29%
33%

20

21%

0
0
3
6
9 12 15 18 21
No. at risk
NIVO 371 326 273 237 213 189 167 148
SOR 372 330 276 234 198 175 156 133

24 27 30 33
Time, months

36

39

42

45

48

51

130 120 112 102 86
116 98 82 72 59

63
37

42
22

23
10

2
1

0
0

Sangro B, et al. Ann Oncol 2020;31(suppl):abstr LBA-3

161

14.8 (12.1, 17.3)

0.85 (0.72, 1.00); 0.0522

CheckMate 459: long-term efficacy outcomes with nivolumab versus sorafenib as firstline treatment in patients with advanced hepatocellular carcinoma – Sangro B, et al
Overall survival by PD-L1 expression
Key results (cont.) Tumour-cell PD-L1 expression ≥1%
Median OS, mo (95%CI)

Nivolumab
(n=71)

Sorafenib
(n=64)

16.1 (8.4, 22.3)

8.6 (5.7, 16.3)

HR (95%CI)

Tumour-cell PD-L1 expression <1%

Median OS, mo (95%CI)

0.80 (0.54, 1.17)

Sorafenib
(n=300)
15.2 (12.7, 18.1)

HR (95%CI)

100

80

80
OS, %

100

60

OS, %

Nivolumab
(n=295)
16.7 (13.9, 19.4)

40
20

0.84 (0.70, 1.01)

60
40
20

0

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time, months

Time, months

No. at risk
NIVO 71 64 53 43 41 38 32 29 25 24 23 20 16 12 8
SOR 64 53 37 29 28 25 23 22 20 17 15 14 13 12 7

0
0

295 257 216 190 169 148 133 117 104 95 88 81 69 50 34 23 2
300 271 233 199 165 145 128 106 93 78 65 56 45 25 15 10 1

0
0

Sangro B, et al. Ann Oncol 2020;31(suppl):abstr LBA-3

CheckMate 459: long-term efficacy outcomes with nivolumab versus sorafenib as firstline treatment in patients with advanced hepatocellular carcinoma – Sangro B, et al
Overall survival by aetiology
HCVa

Key results (cont.) Nivolumab
Median OS,
mo (95%CI)
HR (95%CI)

HBVa

(n=87)

Sorafenib
(n=86)

17.5 (13.9, 21.9)

12.7 (9.9, 16.2)

Median OS,
mo (95%CI)

0.72 (0.51, 1.02)

Uninfected

Nivolumab
(n=116)

Sorafenib
(n=117)

16.1 (12.5, 21.3)

10.4 (8.5, 17.3)

HR (95%CI)

Median OS,
mo (95%CI)

0.79 (0.59, 1.07)

HR (95%CI)

80

80

80

60

60

60

OS, %

100

OS, %

100

OS, %

100

40

40

40

20

20

20

0

0
0

No. at risk

3

6

9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Nivolumab
(n=168)

Sorafenib
(n=168)

16.0 (10.8, 20.2)

17.4 (13.7, 21.3)

0.91 (0.72, 1.16)

0
0

3

6

9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time, months

Time, months

0

3

6

9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time, months

NIVO 87 77 67 58 53 48 40 34 29 27 26 25 20 13 8

4

1

0

116 106 86 72 68 56 51 46 42 37 36 33 31 21 14 9

0

168 143 120 107 92 85 76 68 59 56 50 44 35 29 20 10 1

0

SOR 87 74 61 54 43 34 30 25 22 18 17 17 14 7

2

0

0

117 101 77 63 53 50 45 37 33 29 27 24 21 17 8

0

168 154 137 116 101 90 80 70 60 50 37 30 23 13 9

0

5

4

4

1

aPatients

could have had active or resolved HBV or HCV infection as a
risk factor for HCC

Sangro B, et al. Ann Oncol 2020;31(suppl):abstr LBA-3

162

CheckMate 459: long-term efficacy outcomes with nivolumab versus sorafenib as firstline treatment in patients with advanced hepatocellular carcinoma – Sangro B, et al
TRAEs

Key results (cont.)

Fatigue
Pruritus
Rash
AST increased
Diarrhoea
Appetite decreased
Nausea
Palmar-plantar erythrodysesthesia syndrome
Weight decreased
Alopecia
Hypertension
Dysphonia

NIVO grade 3/4

25

15
13
11
11

9
14
9
47

9
26

6
5

11
49

1
1
1
1
1
20

10

11
18
21
12

0
TRAEs, %

NIVO grade 1/2

10

20

SOR grade 3/4

30

40

50

SOR grade 1/2

Conclusions
◦ In patients with advanced HCC, 1L nivolumab continued to demonstrate improvements
in OS regardless of PD-L1 status or viral aetiology and had a manageable safety profile
Sangro B, et al. Ann Oncol 2020;31(suppl):abstr LBA-3

SECOND-LINE
SYSTEMIC THERAPY

163

Second-Line Systemic Therapy
Regorafenib

Nivolumab

Cabozantinib

Pembrolizumab

Nivolumab
+ ipilimumab

Ramucirumab

KEYNOTE-240: Pembrolizumab for
Patients With Previously Treated HCC
◦

Randomized, double-blind phase III trial of pembrolizumab vs placebo (both with BSC) for pts with advanced HCC with intolerance to or PD on or after sorafenib; Child-Pugh A (N = 413)

◦

Failed to reach prespecified level of statistical significance for OS, PFS in primary analysis (prespecified P = .0174 [OS] and P = .002 [PFS] required) (median f/u 10.6-13.8 mos); updated analysis
with additional 18 mos f/u

100
OS (%)

80
60

24-mo rate
28.8%
20.4%

40
20

36-mo rate
17.7%
11.7%

Median PFS, Mos (95% CI)
Pembrolizumab
3.3 (2.8-4.1)
Placebo
2.8 (1.6-3.0)
HR (95% CI)
0.70 (0.56-0.89)
Nominal P = .0011

100
80
OS (%)

Median OS, Mos (95% CI)
Pembrolizumab 13.9 (11.6-16.0)
Placebo
10.6 (8.3-13.5)
HR (95% CI)
0.77 (0.62-0.96)
Nominal P = .0112

60
40

24-mo rate
11.8%
4.8%

20

36-mo rate
9.0%
0

0

0
0


0

4

8 12 16 20 24 28 32 36 40 44 48
Mos
ORR: pembrolizumab, 18.3%; placebo 4.4%

Finn. JCO. 2020;38:193. Merle. ASCO GI 2021. Abstr 268.

164

4

8 12 16 20 24 28 32 36 40 44
Mos

CheckMate 040: Nivolumab + Ipilimumab
for Advanced HCC
◦ Open-label phase I/II trial of 3 different dosing schemes of nivolumab + ipilimumab for patients
with advanced HCC and prior sorafenib treatment; Child-Pugh score A5-A6; ECOG PS 0/1
OS

◦ Dosing:
◦ NIVO1/IPI3 Q3W: nivolumab 1 mg/kg +
ipilimumab 3 mg/kg Q3W (4 doses)

100

◦ NIVO3 Q2W/IPI1 Q6W: nivolumab 3 mg/kg
Q2W + ipilimumab 1 mg/kg Q6W
NIVO1/IPI3
Q3W
(n = 50)

NIVO3/IPI1
Q3W
(n = 49)

NIVO3 Q2W/
IPI1 Q6W
(n = 49)

32 (20-47)

31 (18-45)

31 (18-45)

ORR, % (95% CI)

80
OS (%)

◦ NIVO3/IPI1 Q3W: nivolumab 3 mg/kg +
ipilimumab 1 mg/kg Q3W (4 doses),
each followed by nivolumab 240 mg Q2W

Median OS, mos (95% CI)
NIVO1/IPI3 Q3W 22.2 (9.4-NA)
NIVO3/IPI1 Q3W 12.5 (7.6-16.4)
NIVO3 Q2W/IPI1 Q6W 12.7 (7.4-30.5)

60
40
20
Median follow-up: 46.5 mos

LTFU period

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

Mos

Yau. JAMA Oncol. 2020;6:e204564. El-Khoueiry. ASCO GI 2021. Abstr 269.

Efficacy and safety of nivolumab + ipilimumab in Asian patients with advanced
hepatocellular carcinoma: subanalysis of the CheckMate 040 study

Key patient inclusion criteria
• Advanced HCC
• Sorafenib naïve or
progression after or
intolerant to sorafenib
• Child-Pugh A5 or A6
• HBV, HCV or non-viral HCC
• ECOG PS 0–1
(n=71)

R
1:1:1

Nivolumab 1 mg +
ipilimumab 3 mg q3w x4
(n=50; 34 Asian)
Arm B
Nivolumab 3 mg +
ipilimumab 1 mg q3w x4
(n=49; 27 Asian)
Arm C
Nivolumab 3 mg q2w +
ipilimumab 1 mg q6w
(n=49; 29 Asian)

PRIMARY ENDPOINTS
• Safety, ORR (RECIST v1.1, investigator
assessed), DoR

Nivolumab
240 mg iv
q2w
flat dose

PD/toxicity

Study objective
◦ To evaluate the efficacy and safety of nivolumab + ipilimumab in Asian patients with advanced
HCC
Arm A

SECONDARY ENDPOINTS
• DCR, TTR, TTP, PFS, OS

Yao T, et al. Ann Oncol 2020;31(suppl):abstr O-5

This talk was presented at the 22nd ESMO WCGC on 1 July 2020 at 18:29

165

Efficacy and safety of nivolumab + ipilimumab in Asian patients with advanced
hepatocellular carcinoma: subanalysis of the CheckMate 040 study
Asian patients
CR

SD
PD

Patients, n (%)

PR

60

0

9
(31)

7
(26)

7
6 (21)
(18)
2
(6)

24
(49)

20
(40)

40

20

All patients
15
(52)

15
(56)

16
(47)

2
(7)

4
(14)

2
(7)

3
(6)

Arm B
NIVO3 +
IPI1 q3w
(n=27)

9
(18)

5
(10)
0

0

Arm A
NIVO1 + IPI3
q3w
(n=34)

15
(31)

12
(24)

12
(24) 9
(18)
4
(8)

21
(43)

Arm C
NIVO3 q2w
+ IPI1 q6w
(n=29)

Arm A
NIVO1 +
IPI3 q3w
(n=50)

Arm B
NIVO3 +
IPI1 q3w
(n=49)

Arm C
NIVO3 q2w
+ IPI1 q6w
(n=49)

ORR, n (%)

8 (24)

9 (33)

9 (31)

16 (32)

15 (31)

15 (31)

DCR, n (%)

17 (50)

11 (41)

13 (45)

27 (54)

21 (43)

24 (49)

Median DoR, mo
(95%CI)

9.8
(7.0, NR)

15.2
(4.2, NR)

11.1
(4.2, NR)

17.5
(8.3, NR)

22.2
(4.4, NR)

16.6
(4.3, NR)

Median OS, mo
(95%CI)

16.4
(8.6, NR)

11.8
(6.1, 16.4)

11.2
(6.1, NR)

22.8
(9.4, NE)

12.5
(7.6, 16.4)

12.7
(7.4, 33.0)

Yao T, et al. Ann Oncol 2020;31(suppl):abstr O-5

Efficacy and safety of nivolumab + ipilimumab in Asian patients with advanced
hepatocellular carcinoma: subanalysis of the CheckMate 040 study
Key results (cont.)

Asian patients
Grade 3/4 TRAEs,
n (%)

Any

All patients

Arm A
NIVO1 +
IPI3 q3w
(n=33)

Arm B
NIVO3 +
IPI1 q3w
(n=27)

Arm C
NIVO3 q2w
+ IPI1 q6w
(n=29)

Arm A
NIVO1 +
IPI3 q3w
(n=49)

Arm B
NIVO3 +
IPI1 q3w
(n=49)

Arm C
NIVO3 q2w
+ IPI1 q6w
(n=48)

17 (52)

7 (26)

8 (28)

26 (53)

14 (29)

15 (31)

Pruritus

1 (3)

0

0

2 (4)

0

0

Rash

1 (3)

1 (4)

0

2 (4)

2 (4)

0

Diarrhoea

1 (3)

0

0

2 (4)

1 (2)

1 (2)

AST increased

5 (15)

3 (11)

2 (7)

8 (16)

4 (8)

2 (4)

0

0

0

1 (2)

0

0

3 (9)

2 (7)

0

4 (8)

3 (6)

0

Fatigue
ALT increased

Conclusions
◦ In Asian patients with advanced HCC, nivolumab + ipilimumab demonstrated clinically meaningful responses,
particularly in the nivolumab 1 + ipilimumab 3 arm
◦ The safety profile was manageable with no new safety signals observed
Yao T, et al. Ann Oncol 2020;31(suppl):abstr O-5

166

167

Checkmate 040 : nivolumab in
advanced hepatocellular carcinoma
◦ Nivolumab 3 mg/kg lead to objective response in 16% of the patients using RECIST 1.1 (15% of
PR and 1% of CR)
◦ Disease control rate of 68%
◦ Median overall survival of 15 months
◦ Acceptable safety profile
◦ Randomized controlled trial phase 3 comparing sorafenib to ivolumab in advanced HCC
(Checkmate 459)

El Khoueiry AB, et al. Lancet 2017

168

169

Outcomes for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh
B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo
Study objective
◦ To evaluate the efficacy and safety of cabozantinib in the subgroup of patients with advanced HCC
whose liver function had deteriorated to Child-Pugh B by Week 8

Cabozantinib
60 mg/day
(n=470)

Key patient inclusion criteria
•

Advanced HCC

•

Child-Pugh score A

•

Received prior sorafenib

•

Progressed after ≥1 prior systemic
treatment for HCC

•

Received ≤2 prior systemic
regimens for advanced HCC

•

ECOG PS 0–1

Stratification
• Disease aetiology (HBV, HCV, other)
• Geographic region (Asia, other)
• Presence of extrahepatic spread and/or
macrovascular invasion (EHS/MVI)

R
2:1

Placebo
(n=237)

(n=707)
PRIMARY ENDPOINT
• OS

Loss of
clinical
benefit
/
toxicity

Loss of
clinical
benefit
/
toxicity

SECONDARY ENDPOINTS
• PFS, ORR, safety

El-Khoueiry A, et al. Ann Oncol 2020;31(suppl):abstr SO-9
This talk was presented at the 22nd ESMO WCGC on 1 July 2020 at 19:32

170

Outcomes for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh
B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo
Overall survival
Child-Pugh B subgroup

Key results
Cabozantinib
(n=51)

Overall

Median OS,
mo (95%CI)

No. of
deaths

8.5 (7.7, 12.2)

37

Cabozantinib (n=470)
Placebo (n=237)

Placebo (n=22)
3.8 (3.3, 4.8)
20
HR 0.32 (95%CI 0.18, 0.58)

No. of
deaths

10.2 (9.1, 12.0)

317

8.0 (6.8, 9.4)

167

HR 0.76 (95%CI 0.63, 0.92); p=0.005

1.0
Probability of OS

1.0
Probability of OS

Median OS,
mo (95%CI)

0.8
0.6
0.4
0.2
0

0.8
0.6
0.4
0.2
0

0

6

12

18
24
30
Time, months

36

42

0

6

12

18
24
30
Time, months

36

42

El-Khoueiry A, et al. Ann Oncol 2020;31(suppl):abstr SO-9

Outcomes for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh
B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo
Key results (cont.)
Grade 3/4 AEs, %
Any

Child-Pugh B
subgroup
(n=51)
71

Overall population
(n=467)
68

Fatigue

20

Ascites

14

10
4

AST increased

14

12

Thrombocytopenia

12

3

Palmar-plantar
erythrodysesthesia

8

17

Hypertension
8
16
Conclusions
◦ In patients with advanced HCC and Child-Pugh B liver function by Week 8, cabozantinib demonstrated
similar outcomes to those of the overall population and had a manageable safety profile

El-Khoueiry A, et al. Ann Oncol 2020;31(suppl):abstr SO-9

171

Multiple VEGF-Targeted Therapies Have
Activity After Sorafenib: Phase III Data
RESORCE

CELESTIAL

REACH-2

Regorafenib vs placebo

Cabozantinib vs placebo (N = 707)

Ramucirumab vs placebo

2L, sorafenib-tolerating pts only
(N = 573)

2L or 3L
(N = 707)

2L, AFP ≥ 400 ng/mL
(N = 292)

Median OS: 10.6 vs 8.0 mos

Median OS: 10.2 vs 8.0 mos

Median OS: 8.5 vs 7.3 mos

HR: 0.63 (P < .0001)

HR: 0.76
OS(P = .005)

HR: 0.71 (P = .0199)

Regorafenib: multitargeted TKI

Ramucirumab: anti-VEGFR2 Ab

Cabozantinib: multitargeted TKI

Bruix. Lancet. 2017;389:56. Abou-Alfa. NEJM. 2018;379:54. Zhu. Lancet Oncol. 2019;20:282.

Evolving Landscape of HCC
Nivolumab or lenvatinib
Not worse than sorafenib

Sorafenib
Better than placebo

Atezolizumab + bevacizumab
Better than sorafenib

Anti-VEGF

I-O

Regorafenib
OS vs placebo

Pembrolizumab,
nivolumab ± ipilimumab
Some durable responses

Cabozantinib
OS vs placebo
Ramucirumab
OS vs placebo for
AFP ≥ 400 ng/mL

172

Systemic treatment sequencing for BCLC
Stage C advanced HCC
◦ Targeted first-line therapies
◦ Combination: atezolizumab (PD-L1 inhibitor) + bevacizumab* (VEGF inhibitor) (US only)
◦ Oral multikinase inhibitors: sorafenib and lenvatinib

◦ Targeted second-line therapies
◦
◦
◦
◦
◦

Multikinase inhibitor: regorafenib
Multikinase inhibitor: cabozantinib
Anti-VEGFR (AFP ≥400 ng/mL) antibody: ramucirumab
PD-1 inhibitors: nivolumab, pembrolizumab
Immune therapy Combination: nivolumab + ipilimumab

First line
atezolizumab +
bevacizumab1

Second line

AFP ≥400 ng/mL

sorafenib
lenvatinib

regorafenib
cabozantinib
ramucirumab
nivolumab
pembrolizumab
nivolumab +
ipilimumab1

Bruix J, et al. Nat Rev Gastroenterol Hepatol. 2019;16:617-30

Third line

cabozantinib

47

173

ADVERSE EFFECTS OF
IMMUNOTHERAPY IN
HEPATOCELLULAR CARCINOMA
- case presentation Dimitar Stefanovski, dr.med.
Prof. dr. Janja Ocvirk, dr. med.
2nd International Summer school

OCTOBER 2019
• 83 years old female patient;
• former smoker, no history of alcohol consumption;
• y. 2010 - excision of the submandibular gland (adenoca.),
osteoporosis GERD, AMD;
• PS WHO 1
• pain under the right costal arch;
• abdominal US: tumour formation in the liver;
• moderately differentiated, pseudo glandular HCC.

174

• CT thorax + abdomen: hypervascular tumour in the right liver lobe
with A – V fistulas, invasion of the middle hepatic vein, without
cirrhosis, no signs of distant metastasis.

NOVEMBER 2019
• 1st line treatment with Sorafenib
• After 1st application: skin toxicity - erythematous skin with macular
rash
• Continuing the treatment with dose reduced Sorafenib
• pain in the palms and soles of the feet, macular rash.

DECEMBER 2019
• Sorafenib therapy was terminated prematurely due to side effects.

175

NEXT OPTION?
• EMBOLIZATION not possible due to the vascular shunt.

• IMbrave 150 tiral results:
Patients with unresectable
hepatocellular carcinoma have
better survival with the
combination of atezolizumab
and bevacizumab than with
sorafenib
as
first
line
treatment.

176

JANUARY 2020
• Systemic therapy with Atezolizumab + Bevacizumab.
• CT scans showing stable disease.

JUNE 2021
• oral mucositis (grade 2)
• petechiae, somewhere ulcerated skin with bleeding (grade 1)
• productive cough, non purulent sputum (grade 1)

• temporarily suspended bevacizumab, continuation with atezolizumab

177

JULY 2021 - HOSPITALIZATION
• feeling extremely unwell
• cough (grade 2)
• bloody diarrhea (grade 2)
• ecchymosis, somewhere superficially ulcerated skin with bleeding
(grade 1)
• negative microbiological analyses

• CT scan: PNEUMONITIS

178

TREATMENT
• i.v. corticosteroids in high doses 1 mg/kg BW
• i.v. Vit K
• after 1 week of hospitalization, discharged in stable condition
• continuation of corticosteroids therapy p.o. at home

THANK YOU FOR YOUR ATTENTION

179

Enrichment of treatment
at metastatic NSCLC with
PD-L1 overexpression
(PD-L1≥50%)
Davorin Radosavljevic
Institute for Oncology and Radiology
of Serbia Belgrade
2nd International Summer School of Oncology
Onkološki Inštitut Ljubljana, 08.09.2021.

Advent of immunotherapy
supstantially changed initial
treatment of advanced NSCLC
Factors in choosing initial therapy:
 Level of PD-L1(≥50%)
 Presence or absence of a driven mutation
(EGFR, ALK, ROS1, BRAF,etc)
 The extent of disease (number and sites of
metastases, symptoms)
 Squamous vs nonsquamous histology

180

Treatment algorithm for stage IV NSCC, molecular tests
negative (ALK/BRAF/EGFR/ROS1), ESMO 2020

Check-point inhibitors, specially targeting PD-1
or PD-L1 have became the cornerstone of 1st
line therapy
 Monotherapy
 Chemotherapy-immunotherapy combinations
 Immunotherapy-exclusive regimens
Decision-making in this space is complex:
 the absence of head-to-head prospective comparisons
Paramount for patient selection:
 tumor cell PD-L1 expression and histology

181

Immunotherapy today
MONOTHERAPY1–6
CheckMate 026
Nivolumab monotherapy

CHEMOTHERAPY COMBINATIONS7–13
KEYNOTE-189

IMpower150

Pembrolizumab + cisplatin/
carboplatin + pemetrexed

Atezolizumab + bevacizumab
+ carboplatin + paclitaxel

CIT + CIT COMBINATIONS4,14
CheckMate 227
Nivolumab
+ ipilimumab

KEYNOTE-024
Pembrolizumab monotherapy

CheckMate 9LA

KEYNOTE-407
KEYNOTE-042
Pembrolizumab monotherapy

MYSTIC
Durvalumab monotherapy

Nivolumab + ipilimumab
+ chemotherapy

Pembrolizumab + carboplatin
+ paclitaxel/nab-paclitaxel

IMpower131

CheckMate 227

Atezolizumab + carboplatin
+ paclitaxel/nab-paclitaxel

Nivolumab
+ chemotherapy

MYSTIC
Durvalumab
+ tremelimumab

IMpower110
Atezolizumab monotherapy

B-FAST*

IMpower130

POSEIDON*

Atezolizumab + carboplatin
+ nab-paclitaxel

Durvalumab + tremelimumab
+ chemotherapy

Atezolizumab monotherapy

IPSOS*
Atezolizumab monotherapy

IMpower132

EMPOWER-lung 3

Atezolizumab + cisplatin/
carboplatin + pemetrexed

Cemiplimab + platinum
doublet chemotherapy
1. Carbone, et al. N Engl J Med 2017; 2. Reck, et al. N Engl J Med 2016; 3. Mok, et al. Lancet 2019
4. Rizvi, et al. JAMA Oncol 2020; 5. Spigel, et al. ESMO 2019 (Abs LBA78)
6. Regeneron press release (5 November 2019); 7. Gandhi, et al. N Engl J Med 2018
8. Socinski, et al. N Engl J Med 2018; 9. West, et al. Lancet Oncol 2019
10. Papadimitrakopoulou, et al. WCLC 2018 (Abs OA05.07); 11. Paz-Ares, et al. ESMO IO 2019 (Abs LBA3)
12. Reck, et al. ASCO 2020 (Abs 9501; 13. AstraZeneca press release (28 October 2019)
14. Hellmann, et al. N Engl J Med 2018

EMPOWER-lung 1
Cemiplimab monotherapy
*Data not yet made public

5

Tumor PD-L1 expression ≥ 50%: Initial systemic treatment
(driven mutation absent or unknown) for patients with
squamous or non-squamous NSCLC
 Pembrolizumab superior in OS over platinum doublet (KN024)
 Atezolizumab superior in OS over platinum doublet (IMpower 110)
 Cemiplimab superior in OS over platinum doublet (EMPOWER-Lung1)
 An exception, combination doublet chemotherapy with concurrent
pembrolizumab : high tumor burden or rapidly progressive disease in which
early PD might preclude the option of chemotherapy in 2nd line setting, due
to functional decline
 Contraindication for immunotherapy (a histology-appropriate platinum
doublet): allograft recipiens, myastenia gravis, severe IBD or vasculitis

182

Cochrane Meta-analysis 2020: data from 7 clinical trials
comparing the efficacy of PD-L1/PD1 inhibitors to that of
chemotherapy in patients with advanced NCSLC (n=5893)
Ferrara et al. Cochrane Database Syst.Rev 12. CD13257 (2020)

 Anti PD1/PD-L1 antibodies improved OS in patients with tumor cell PDL1≥50% (n=2111) compred with chemotherapy (HR 0.68, 95%CI 0.60-0.76)
with a moderate level of certainty
 Among never-smokers with PD-L1 expression ≥50%, N=179, no
stat.significant difference in OS between PD1/PD-L1 Abs and
chemotherapy; current or former smokers had OS advantage with
immunotherapy over chemotherapy
 No statistically significant difference in OS in PD-L1˂1% or ≥1%

Response rate and Survival at Key Timepoints With
PD-L1 Blockade vs Chemotherapy in PD-L1 Subgroups:
Meta-analysis of Metastatic NSCLC trials
J.Man et al. JNCI Cancer Spectrum(2021)5(3):pkabo012
 9810 pts in 27 studies, retrospective analysis, systematic research of MEDLINE/EMBASE
 In treatment naive patients benefits with PD-L1 blockade over CT were seen in
ORR in pts having PD-L1 ≥50%,
2yrOS for PD-L1 ≥1%,
1-yrPFS, 2-yrPFS and 3-yrOS in unselected pts
 First-line PD-L1 blockade compared with CT:
Higher ORR, 2-yrPFS and 3-yrOS if PD-L1 was 50% or greater
Lower ORR, higher 2-yrPFS and similar 3-yrOS if PD-L1 was 1-49%
Lower ORR, similar 1-yrPFS and lower 2-yrOS if PD-L1 was less than 1%
 In previously treated patients, PD-L1 blockade demonstrated similar or superior
outcomes in all PD-L1 subgroups

183

Outcomes to first-line pembrolizumab
in patients with non-small-cell lung
cancer and very high PD-L1 expression
Aguilar EJ. Et al. Ann Oncol 2019.

Multicentric retrospective analysis 187 patients,
ORR 44.4%, mPFS 6.5mo, mOS NR
 PD-L1 50-89% N=107pts, ORR 32.7%, mPFS 4.1mo, OS 15.9mo
 PD-L1 90-100% N=80pts, ORR 60%, mPFS 14.5mo, OS NR
Implication: treatment selection, clinical trial intepretation and design

Does immuno-chemotherapy and imuno-immunotherapy
provide additional benefit beyond that of pembrolizumab
or atezolizumab monotherapy in PD-L1≥50% population?

24 months OS:
50% pembrolizumab mono in KEYNOTE 024 trial
52% pembrolizumab+chemotherapy in PD-L1≥50% subgroup of KEYNOTE189
48% with nivolumab+ipilimumab in CheckMate227 trial.
Immuno-chemo and immuno-immuno combination are associated with
predictable but higher risk of toxicities, while mono anti-PD1/PD-L1 provide
impressive levels of tolerability compared to chemotherapy
AntiPD1/PD-L1 antibodies as monotherapy for most patients

184

Whom we should offer combo immuno-chemotherapy in
PD-L1≥50% population?
Imminent need for cytoreduction:
 substantial tumor burden,
 rapidly progressive disease and/or
 severe disease related symptoms
Numerically higher ORR than PD-1/PD-L1 monotherapy
Rapid cytoreduction produced by combo might also attenuate the early
decrements in OS seen in patients receiving monotherapies
Only 51% of patients with PD on pembrolizumab in KN024 and 38% in
experimental arm of KN042 received subsequent therapy

Mono vs combo approach
ORR in patients with PD-L1 expression > 50%

Combo therapy

80%

80%

70%

70%

Objective Response Rate
(%)

Objective Response Rate (%)

Monotherapy

60%

46%
50%

39%

40%

40%
30%
20%
10%

69%
62%

60%

60%

50%
50%
40%
30%
20%
10%
0%

0%

KN 024

KN 042

IMP 150

IMP 110

KN 189

KN 407

Brahmer et al ESMO 2020 KEYNOTE-024 5 year OS update, Gray et al WCLC 2020 KEYNOTE-189 4 year OS update, Cho et al WCLC 2020 KEYNOTE-042 3 year OS update,
Herbst, et al. WCLC 2020 Abs FP13.03, Reck et al ASCO 2021 (Abs 9000), Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med
2018;379:2040-51. DOI: 10.1056/NEJMoa1810865

185

CM 9LA

Addition of chemo to immunotherapy does not add benefit in nonsquamous
mNSCLC with high expression of PD-L1 (except in patients with no smoking
history) S.Peters et al. ESMO Virtual Pnenary, April 8, 2020.

Observational study, Flatitron Health database, 520 pts, PS 0-2, PD-L1≥50%,
pembrolizumab mono (N=351) or plus paclitaxel-carboplatin (N=169)
Mono arm: higher proportion of poor prognostic baseline characteristics (age, extent
of disease)
Median OS 22.1mo vs 21.0mo p=0.63 HR 1.03, PFS 11.5 vs 10.8mo
No smoking population: combo reduced risk by 75%, P=0.02 and 60%,P=0.04
Liver and brain metastases: outcomes were similar

Invited discutant F.Cappuzzo, ESMO 2020.
About 30% of patients in phase III clinical trials have better survival outcome
with chemotherapy than with single-agent CPI.
In most relevant trials mOS with single-agent was less than two years, but more
than two years in combo approach, ORR were also higher
Cost: toxicity – grade 3-5 in appr. 60% with combo, compared to 20% treated with
single agents
Combo certainly in never-smokers
Not all patients with PD-L1 are equall (Pts with≥90% are extremly sensitive to
immunotherapy)

186

Mono imunotherapy options in 1L NSCLC
ORR,DoR, PFS, OS in PD-L1 >50% population

39%

40%

30%
20%

25
20
15
10

10%

5

0%

KN 042

IMP 110

7.7

8

6.5

7

26.3

6
5
4
3
2

25

20

20.2

KN 042

IMP 110

20

15

10

5

1
0

0

KN 024

30

8.1
Overall survival (months)

27.3

30

46%

40%

29.1

9

Progression free survival
(months)

35

60%

DoR (months)

Objective Response Rate (%)

38.9

40

70%

50%

10

45

80%

KN 024

KN 042

0

KN 024

IMP 110

KN 042

Brahmer et al ESMO 2020 KEYNOTE-024 5 year OS update, Cho et al WCLC 2020 KEYNOTE-042 3 year OS update, Herbst, et al. WCLC 2020 Abs FP13.03, Herbst, et al. N England J Med 2020

Combo and hyperprogression
A subset of patients have a paradoxical
acceleration in tumor growth and clinical
deterioration upon initiation of therapy
The incidence of hyperprogression in previously
treated NSCLC ranges from 8 to 21%
In treatment-naive NSCLC receiving anti-PD1/PDL1 as monotherapy the incidence was 16%
This effect can largely be avoided using first-line
chemo-immunotherapy combinations

187

IMP 110

KN 024

Therapy duration
Up to 2 years in KEYNOTE and CheckMate 227 trials
Indefinite maintenance in IMpower119, IMpower 130 and IMpower150
Results of KN158 randomized study favored longer duration than a 1 year
fixed dose (small sample, lack of alternative fixed dose, such as 2 years)
In KEYNOTE 024 39 of 154 pts (25%) completed 2 years
pembrolizumab, and 3-year landmark OS from completion was 81%

of

These data suggest that most patients completing 2 years of
treatment continue to derive long-term benefit, despite therapy
cessation
The decision to discontinue maintenance in the absence of
substantial toxicities or disease progression should be individualized:
whether therapy beyond 2 years improves outcome remains largely
unclear

Post-progression outcome of NSCLC patients with PD-L1
expression
≥50%
receiving
first-line
single-agent
pembrolizumab in a large multicentre
real-world study
Cortellini A. et al, Eur J Cancer 2021.
974 patients were included, median follow-up 22.7months
Median OS 15.8 months (95% CI:13.5-17.5; 548 events)
55.9% had not received any further treatment, 52.9% died
Patients who did not receive post-PD therapies were: older (p=0.0011),
with a worse PS (p˂0.0001) and were on corticosteroids prior to
pembrolizumab (p=0.0024);
At disease progression, 29.2% received a switched approach, 14.9%
received pembrolizumab beyond PD, either alone (9.4%) or in combo
with local ablative treatments (5.5%): OS 13.9 vs 7.8mo (p=0.0179)
35.5% received second-line systemic treatment (sign.higher proportion
of age under 70, poorer PS, having CNS and liver mets)

188

Real-world study (Cortellini 2021) and KN024:
Pts with PDL1≥50%
Median OS 15.8mo vs 26.3mo
Not unsuprising: higher proportion of patients with adverse prognostic
factors (PS ≥2, receiving corticosteroids, older than 70years)
Patients in clinical studies are highly selected for lower co-morbidity burden
Inferior outcome: patients with poor baseline PS, particulary if related to
disease burden; 55.9% did not receive any further treatment;

Real-world study (Cortellini 2021) and KN024:
Pts with PDL1≥50%

Older pts, PS ≥ 2, receiving systemic corticosteroids are at higher risk of lifethretening progressive disease – thus, treatment sequencing approach ICI-CT
doublet is unlikely to be completed
Oligoprogression and pembrolizumab beyond PD: the best post-PD outcome:
pembrolizuimab beyond PD + local ablative treatment
Among patients who reach a second-line treatment, PS still remains th major
determinent of clinical outcome

189

Take home messages –
mNSCLC with PD-L1≥50%
Decision-making in this space is complex: the absence of
head-to-head prospective comparisons
Paramount for patient selection: tumor cell PD-L1
expression and histology
AntiPD1/PD-L1
patients

antibodies as monotherapy for most

Not all patients with PD-L1 are equall: patients with ≥ 90%
are extremly sensitive to immunotherapy, non-smokers
are for combo approach or chemotherapy

Take home messages –
mNSCLC with PD-L1≥50%

The decision to discontinue maintenance in the absence of
substantial toxicities or disease progression should be
individualized: whether therapy beyond 2 years improves
outcome remains largely unclear
Hyperprogression can largely be avoided using first-line
chemo-immunotherapy combinations
Toxicity – grade 3-5 in appr. 60% with combo, compared to 20%
treated with single agents

190

Clinical choices in metastatic NSCLC without actionable oncogenic
driver mutations regardless of PD-L1 status

Marko Jakopović, MD, PhD
Associate Professor
Zagreb Medical School
Department of Respiratory Medicine
University Hospital Centre Zagreb

Disclosures

Speakers fees: AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Berlin Chemie,
Sandoz, Novartis, MSD, Novartis Oncology, Abbott
Advisory boards: AstraZeneca, Roche, BoehringerIngelheim, Eli Lilly, MSD, Novartis
Oncology

191

Overview

How to choose treatment options in metastatic NSCLC in patients without driver
mutation?
 Immunotherapy vs chemotherapy?

Nivolumab vs docetaxel in previously treated squamous NSCLC

Brahmer J et al. N Engl J Med 2015;373:123-135.

192

Pembrolizumab in treatment-naive highly positive PD-L1 NSCLC
patients

Reck M et al. N Engl J Med 2016; 375:1823-1833.

Atezolizumab was superior to docetaxel regardless of PD-L1
expression in NSCLC

Rittmeyer et al. Lancet 2016.

193

Overview

How to choose treatment options in metastatic NSCLC in patients without driver
mutations?
 Immunotherapy vs chemotherapy? The winner is immunotherapy!!!!!
 Line of treatment of immunotherapy?
 Monotherapy vs combination therapy (CT+IO, IO+IO)?
 Does histology matter?
 Open questions
 Conclusions

Line of treatment of immunotherapy?

194

Nivolumab in heavily preatreated patients

Brahmer JR et al. N Engl J Med 2012;366:2455-2465.

Second-line immunotherapy in NSCLC

195

KeyNote-024: First-line pembrolizumab
in PD-L1 highly positive patients

Overview

How to choose treatment option in metastatic NSCLC in patients without driver
mutations?
 Immunotherapy vs chemotherapy? The winner is immunotherapy!!!!!
 Line of treatment of immunotherapy? The winner is first – line immunotherapy!!!!
 Monotherapy vs combination therapy (CT+IO, IO+IO)?
 Does histology matter?
 Open questions
 Conclusions

196

Monotherapy vs combination therapy (CT+IO, IO+IO)?

Keynote-042: Pembrolizumab vs Chemotherapy in PD-L1 positive
NSCLC

197

Keynote-042: Overall survival in ITT population

Mok TS et al. Lancet 2019

Overview

How to choose treatment option in metastatic NSCLC in patients without driver
mutations?
 Immunotherapy vs chemotherapy? The winner is immunotherapy!!!!!
 Line of treatment of immunotherapy? The winner is first – line immunotherapy!!!!
 Monotherapy vs combination therapy (CT+IO, IO+IO)? In patients with PD-L1
expression <50% the winner is combination therapy!!!!
 Does histology matter?
 Open questions
 Conclusions

198

Does histology matter?

18

199

IMower131: Study Design
Maintenance therapy
(no crossover permitted)

Stratification factors:
• Sex
• PD-L1 IHC expression
• Liver metastases
N = 1021

R
1:1:1

Arm B
Atezolizumab +
Carboplatin + Nab-Paclitaxel

Until PD
per RECIST v1.1
or loss of clinical
benefit
Atezolizumab

4 or 6 cycles

Arm C (control)
Carboplatin + Nab-Paclitaxel
4 or 6 cycles

Co-primary endpoints

Best Supportive
Care

Until PD
per RECIST v1.1

Secondary endpoints

• Investigator-assessed PFS per RECIST v1.1 (ITT)
• OS (ITT)

a

Atezolizumab

4 or 6 cycles

Survival follow-up

Arm A
Atezolizumab +
Carboplatin + Paclitaxel

Stage IV squamous NSCLC
• Chemotherapy naivea
• ECOG PS 0 or 1
• Any PD-L1 IHC status

• PFS and OS in PD-L1 subgroups
• ORR, DOR; safety

Atezolizumab 1200 mg IV q3w; carboplatin AUC 6 IV q3w; nab-paclitaxel 100 mg/m2 IV qw; paclitaxel 200 mg/m2 IV q3w.
Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance to treatment with ≥ 1 approved targeted therapies. Testing for EGFR mutation or ALK translocation was not mandatory.
b PD-L1 expression was evaluated using the VENTANA SP142 IHC assay.

Jotte R, et al. IMpower131 PFS Analysis.

200

https://bit.ly/2snPEzb

Progression-Free Survival (%)

INV-Assessed PFS in the ITT Population (Arm B vs Arm C)

Median PFS
(95% CI), mo

Arm B:
Atezo + CnP

Arm C:
CnP

6.3
(5.7, 7.1)

5.6
(5.5, 5.7)

HRa (95% CI)
P value

0.71 (0.60, 0.85)
0.0001

12-month PFS
Minimum follow-up, 9.8 mo
Median follow-up, 17.1 mo

24.7%

12.0%
Time (months)

No. at risk

Data cutoff: January 22, 2018.
INV, investigator. a Stratified HR.

https://bit.ly/2snPEzb

Jotte R, et al. IMpower131 PFS Analysis.

CheckMate 9LA: NIVO + IPI + 2 cycles of chemo in 1L NSCLC

Overall survival by histology
NSQ NSCLCa

SQ NSCLCb

NIVO + IPI + chemo
(n = 246)

17.0
11.9
(14.0–NR)
(9.9–14.1)
0.69 (0.55–0.87)

Median OS, mo
(95% CI)
HR (95% CI)

100
83%

Chemo
(n = 246)

100

80

76%

80
63%

60
NIVO + IPI + chemo

50%

40

OS (%)

73%
OS (%)

NIVO + IPI + chemo
Chemo
(n = 115)
(n = 112)
14.5
9.1
Median OS, mo
(95% CI)
(13.1–19.4)
(7.2–11.6)
HR (95% CI)
0.62 (0.45–0.86)

64%

71%

60

NIVO + IPI + chemo

40

40%

Chemo

20

Chemo

20

0

0
0

3

6

9

12

204
180

170
152

154
122

No. at risk
224
223

15 18
Months
107
87

62
53

21

24

27

20
18

6
9

0
0

30
0
0

201

0
115
112

3

6

9

12

102
96

88
80

80
56

73
44

15 18
Months
46
29

24
14

21

24

13
8

4
2

27
1
0

30
0
0

Overview
How to choose treatment options in metastatic NSCLC in patients without driver
mutations?
 Immunotherapy vs chemotherapy? The winner is immunotherapy!!!!!
 Line of treatment of immunotherapy? The winner is first – line immunotherapy!!!!
 Monotherapy vs combination therapy (CT+IO, IO+IO)? In patients with PD-L1
expression <50% the winner is combination therapy!!!!
 Does histology matter? Combination treatment is superior to chemotherapy alone
regardless of histology subtype!!!!
 Open questions
 Conclusions

Sorry….
I still have to talk about patients wit metastatic NSCLC and driver mutations

202

Check-point inhibitors in EGFR mutated lung cancer

Lee CK et al. J Thorac Oncol 2016; in press

In EGFR/ALK+ NSCLC patients, OS benefit seen with
combination of bevacizumab + atezolizumab + chemotherapy
EGFR/ALK+

EGFR/ALK+

Bev + atezo + CP* vs Bev + CP

Atezo + CP vs Bev + CP
100

Bev + atezo + CP
Bev + CP

HR†=0.54
(95% CI: 0.29–1.03)

80

Overall survival (%)

Overall survival (%)

100

60
40
20
0

17.5 mo

NE

HR†=0.82
(95% CI: 0.49–1.37)

80
60
40
20
0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (months)

Atezo + CP
Bev + CP

17.5 mo

21.2 mo

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (months)

OS benefit in EGFR/ALK+ patients was observed despite lower PD-L1 expression in these patients
*One patient had EGFR exon 19 deletion and also tested ALK positive per central lab;
†Unstratified HR; Data cut-off: 22 January 2018

Socinski, et al. ASCO 2018 (Abstract 9002); Kowanetz, et al. AACR 2018 (Abstract CT076)

203

26

Mono-immunotherapy vs combination therapy?

Mono vs combination of IO plus chemotherapy – what to choose?

204

Overview
How to choose treatment options in metastatic NSCLC in patients without driver
mutations?
 Immunotherapy vs chemotherapy?
The winner is immunotherapy!!!!!
 Line of treatment of immunotherapy?
The winner is first – line immunotherapy!!!!
 Monotherapy vs combination therapy (CT+IO, IO+IO)?
In patients with PD-L1 expression <50% the winner is combination therapy!!!!
 Does histology matter?
Combination treatment is superior to chemotherapy alone regardless of histology
subtype!!!!
 Open questions? In patients with driver mutations combination of IO+bevacizumab+CT is an
option!!!!
In patients with PD-L1<50% combination therapy is better option!!!!
Some questions open in PD-L1≥50% about monoIO vs combination!!!!
 Conclusions

Instead of conclusions

205

Long-term survival with mono-immunotherapy

Long-term survival with combination therapy

206

Systemic treatment of head and neck
cancer – what's new in the old
Assist. Professor Cvetka Grašič Kuhar, MD, PhD
Institute of Oncology Ljubljana, Slovenia

Main question: comparing curative locoregional treatment (LRT) with LRT+Cht

Which treatment is the most effective?

207

Conclusions regarding systemic treatment in SCHNC
• Treatment of stage III/IV disease
• Cisplatin based CRT remained the standard of care in cisplatin-fit patients
• There is evidence from 2 phase III trials that weekly cisplatin could be delivered instead of
high dose cisplatin, efficacy is similar, treatment is less toxic
• Addition of cetuximab or ICI does not improve outcome
• Replacing cisplatin with cetuximab or ICI is less effective (less locoregional control)
• Xevinepant may further increase treatment efficacy

• Recurrent/metastatic disease
• Cisplatin sensitive:
• ICI (Immune checkpoint inhibitor pembrolizumab) in I. line of SCHNC
• with Chemotherapy (CPS≥1) or as monotherapy (CPS ≥ 1/, >20)

• Extreme regimen: CPS<1 or contraindication for ICI
• Cisplatin resistant : ICI monotherapy, mono-chemotherapy

208

Updated results of patients with recurrent or metastatic head and neck cancer treated with
nivolumab between January 2018 and March 2020 in Slovenia
In total, 27 patients with head and neck cancers were treated with nivolumab in this period. The
cohort consisted almost entirely of male patients (96%) and the median age was 59 years. Most of
these patients were smokers (89%), and their performance status was 0-1 in 88.9%.
The majority had pharyngeal cancer (63%) of which 3 were HPV positive. Almost a third of patients
were heavily pre-treated, having received three or more lines of systemic therapy. Cetuximab was a
part of this treatment in 44% of patients.
There were in total 14 immune-related adverse events occurring in 8 patients in total, of which there
was only one case of grade 2-3 event (bullous pemphigoid), while other 13 events were all grade 1.
Only one patient received concurrent radiotherapy (60Gy to parastomal recurrence).
At the end of the updated observation period there were 22 deaths in total. Median overall survival
from the first nivolumab application was 10.7 months (95% CI 1.7-19.7) which is comparable to the
CheckMate 141 results.1 One-year overall survival rate was 48.1% (95%CI 29.3-66.9).
Univariate analyses of possible predictive variables with log-rank test, namely the impact of
presence of distant metastases, immune-related adverse events, neutrophil to lymphocyte ratio, and
impact of concurrent antibiotics treatment on overall survival, found no statistically significant
correlation. Individual patients’ timelines from diagnosis to death or to last follow up are presented
in figure 1.
Overall, we can conclude that treatment with nivolumab has been shown to be safe also in Slovenian
patients with recurrent or metastatic head and neck cancer. Due to the small number of patients, it
is difficult to align the outcomes with the results of previous studies, but in general results are
comparable.
Figure 1. Individual patients’ timelines from diagnosis to death or to last follow up

References
1.

Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for
Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016;375(19):1856–
67.
209

Outcome of patients with recurrent/metastatic squamous cell head and neck
cancer treated with platinum-based chemotherapy with or without cetuximab in
real-world practice
Tina Zupančič, prof.dr. Branko Zakotnik, doc.dr. Cvetka Grašič Kuhar

• A retrospective analysis of patients with R/M SCHNC treated at the Institute of Oncology Ljubljana
between April 2008 and May 2018.
• A total of 67 patients: 34 patients received the PF (platinum, 5-FU), 33 the PFE (PF + cetuximab).
• Inclusion criteria for the PF and PFE protocols: First-line therapy for R/M SCHNC, PS 0-2,
adequate haematologic, renal and liver function, approved reimbursement for cetuximab (for PFE
only).
• Exclusion criteria for the PE and PFE protocols: Patients with nasopharyngeal carcinoma, PS >2.
• Exclusion criteria for PFE only: Infusion reaction to cetuximab grade >2, prior treatment with
cetuximab, known allergy to bee or wasp venom grade >2,bulky tumour in the oropharynx or
larynx.
• The primary aim: to compare the PSF and OS in the routine clinical setting with outcomes in a
randomized trial and to identify possible prognostic factors for PFS and OS.
• The secondary aim: to assess the tolerability.

Conclusions
• PFE regimen has improved OS (but not PFS) when compared to the PF regimen
(median PFS 7.1 vs 6.6; median OS 11.5 vs 9.6 months).
• Objective response to therapy, good nutritional status and possible further
treatment after progression have better prognosis (prognostic factors for OS).
• Our results regarding OS are comparable to the EXTREME study.
• Similar median PFS and OS with PFE were reported by other real-world studies.
• OS of our patients is better than real-world global OS.
• No differences in diarrhoea, hypomagnesaemia, infections and febrile neutropenia.
• High mortality (13.4%).
• PFE still represents the optimal 1st line therapy for fit patients with PD-L1 negative
R/M SCHNC (20-30%) or with contraindication for anti-PD-L1 inhibitors and as 2nd
line therapy.

210

Management of cancer of
unknown primary in the
molecular era
2nd Summer School in medical oncology, September 8th
Erika MATOS,MD, PhD
Kaja CANKAR, MD

Definition
• CUP is biopsy-proven malignancy for which the anatomic origin at the
time of presentation remains unidentified in spite of a detailed history,
physical examination and a thorough diagnostic work-up.
• CUP is a heterogeneous group of metastatic tumors, which share some
common features:
•
•
•
•
•

the ability of an early dissemination,
clinical absence of the primary site,
aggressive behaviour,
unpredictable metastatic pattern,
poor response to conventional systemic cytotoxic therapy.

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

211

Basic diagnostic-work-up in CUP
(ESMO guidelines)
• Patient’s history
• history of previous biopsies, spontaneously regressing lesions and family history

• Physical examination
• Including rectal and breast examination.

• Good quality tissue sample (ESENTIAL!):
• meticulous immunohistochemistry.

• Basic blood and biochemical analyses.
• CT of the chest, abdomen and pelvis.
• Mammography in women.
Diagnostic strategy should take in account the natural behaviour of the disease and the expected
duration of survival based on extent of the disease and PS.
Difficult and time-consuming diagnostic studies should not compromise patients' quality of life.
Ann Oncol 2015; 26(Suppl 5): v133-138.

Additional diagnostic-work-up in CUP (1)
• Additional procedures should be sign-, symptom-, lab. abnormalities guided.
• Breast MRI: in patients with isolated axillary lymph node metastases and
suspected occult primary breast carcinoma after negative mammography and
sonography results.
• Broader use of MRI in CUP diagnostics is questionable.
• Endoscopy: if the patient has symptoms or relevant signs.
• FDG-PET imaging in CUP diagnostics:
• in patients with cervical lymphadenopathy of primarily squamous histological subtype.
• PET-CT is useful (not been prospectively studied):
• Patients presenting with solitary metastatic disease who are candidates for curative loco-regional
treatment in purpose to exclude occult metastases before extensive surgery,
• Patients with known severe iodine dye allergy
• Patients with predominant bone disease who would otherwise require either multiple MRIs or bone
scans to evaluate response to therapy.

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

212

Additional diagnostic-work-up in CUP (2)
• Serum tumour markers have no proven prognostic, predictive or
diagnostic assistance.
• Increased values of some tumour markers may help in guiding further
diagnostics:
• Beta human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP):
• in patients with midline tumour masses with undifferentiated histology.

• Prostate Specific Antigen (PSA):
• in men with adenocarcinoma and predominantly bone disease.

Unfortunately, most tumour markers (CEA, CA125, CA19-9 and CA15-3) are not specific and thus are not
helpful in searching for the site of primary tumour.

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

Clinical presentation of patients with
CUP?
• There is no unique clinical picture.
• The majority of patients presents with symptoms and signs of metastatic
disease.
• There are patients with only or manly liver metastases, with lymph node
metastases in mediastinal or retroperitoneal region, with axillary lymph
nodes, with cervical lymph nodes, with peritoneal disease, with malignant
ascites, with lung disease only or pleural effusion only, bone only disease or
metastases to CNS only, although more often as a part of disseminated
disease.
• Clinical presentation depends on number of metastatic lesions and their
distribution.
• The majority of patients has metastatic disease in more than one organ,
the most often in liver, lung, bone and lymph nodes.
Ann Oncol 2015; 26(Suppl 5): v133-138.

213

How can pathologist help? (1)
• Challenging work! Direct communication between clinician and pathologist is
crucial.
• The trend across all cancer types is personalized medicine (CUP seem ideal
candidate).
• Core biopsy is preferred over fine needle aspirate specimen.
• Light microscopy (LM): the tissue specimen (paraffin sections stained with eosin
and haematoxylin)
• Based on established cytological criteria, the pathologist usually can classify the tumors into
broad groups:
• Carcinoma (5% SSC)OR adenocarcinoma (60%),
• Sarcoma,
• Lymphoma.

• Some specimens will lack any cytological distinguishing features:
• undifferentiated malignancy (35%).

Ann Oncol 2015; 26(Suppl 5): v133-138.

How can pathologist help? (2)
• IHC: significant role in the workup of CUP
• Define tumour lineage by using peroxidaselabelled antibodies against specific tumour
antigens.
• Have to be directed in terms of clinical and
radiological patient's data.
• Random use of large numbers of tissue
markers is rarely helpful.
• Staining for different CK (components of
cytoskeleton of epithelial tissue) may be very
helpful.
• Commonly used staining for CK7, 20, 5 and 6.
• From the pattern of theirs' expression, the most
likely site of origin can be identified.
The method has limitations:
• the majority of tissue markers are not specific for one organ
• no pattern is 100% specific,
• the absence of markers does not exclude the origin in certain organ/tissue.
Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

214

How can pathologist help? (3)
•
•
•
•

The value of some antibodies, such as AFP, beta-HCG, PSA is well established.
Some stainings are organ/tissue specific, such as ER, leukocyte common antigen.
The absence of certain marker does not exclude the origin in that organ/tissue.
The majority of tissue markers are not specific for one organ.

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

How can pathologist help? (4)
• Novel molecular approaches in CUP evaluation:
• Gene expression profiling tests (GEP) to identify the tissue of origin (ToO)
• Comprehensive genomic profiling tests (CGP) to find treatable (clinically
relevant) genomic aberrations (GA)

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

215

Gene expression profiling
• Methodology: RT-PCR or microarrays evaluating the expression od
different genes
• Several assays on the market (evaluating from 10 to 92 and more
genes)
• Tested in a randomized phase III trial (GEFCAPI 04)

Gene expression tests
• Are molecular cancer classifiers that help identify the site of origin for
cancers with indeterminate, uncertain, or differential diagnoses.
• CancerTYPE ID® uses real-time RT-PCR to measure the expression of 92 genes
in the patient’s tumor and classifies the tumor by matching the gene
expression pattern of the patient’s tumor to a database of known tumor types
and subtypes, encompassing 50 tumor types (not FDA approved).
• Tissue of Origin Test® is based on Affymetrix microarray. It compares the
expression for 2000 genes in a patient‘s tumor with a panel of 15 know tumor
types that were diagnosed according to current clinical and pathological
practice (FDA approved in June 2010).

216

GEFCAPI 04 (Study description)
• Phase III trial of empiric chemotherapy with cisplatin and gemcitabine (GC) or
systemic treatment tailored by molecular gene expression analysis in patients
with carcinomas of an unknown primary (CUP) site
• TOO (Pathwork; n=21) or CancerTYPE ID (Biotheranostics; n=222); N=243
• Primary endpoint: PFS
• Secondary endpoints:
• OS
• PFS in patients with cancers
likely insensitive to GC

Stratification: PS, LDH level

Ann Oncol30; 2019 (Suppl 5): v851–v934.

GEFCAPI 04 (Results)
• Primary cancers most often reported: pancreatico-biliary (19%), SCC
(11%), kidney cancer (8%), lung cancer (8%)
• 91/123 (arm B): tailored treatment
• PFS: 5.3 mos (arm A) vs 4.6 mos (arm B); HR 0.95 (0.72-1.25); p=0.7
• OS: 10.0 mos (arm A) vs 10.7 mos (mos) (arm B); HR 0.92 (0.69-1.23)
• 60 pts with suspected cancers likely insensitive to GC
Conclusion:
In GEFCAPI 04, using a molecular test followed by tailored systemic treatment did
not improve outcomes of pts with CUP.
Ann Oncol30 (Suppl 5); 2019: v851–v934.

217

Comprehensive genomic profiling
• Methodology: NGS
• Ongoing CUPISCO trial: A Phase II Randomized Study Comparing the
Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy
Versus Platinum-Based Chemotherapy in Patients With Cancer of
Unknown Primary Site (NCT03498521)

https://clinicaltrials.gov/ct2/show/NCT03498521.
Ross JS et al. The Oncologist 2021;26:e394–e402.

CUPISCO (Study description)
• Aim: to determine the efficacy and safety
of targeted therapies and cancer
immunotherapies for patients with a
subset of CUP syndrome.
• The selection of therapies is based on
results from CGP (FMT*)
• N=790; F II, global, 162 sites participate
• After 3 cycles of induction platinumbased ChT doublets the responders are
randomized to experimental arm
(targeted therapy tailored to the
molecular profile) or continue with
standard ChT. The non-responders go
directly to molecular guided therapy.

•
•
•

https://cup-syndrome.com/en/home/cupisco-study.html
*FMT: Foundation Medicine tissue or liquid Test

218

The primary endpoint: PFS or death from any cause.
The secondary endpoints: OS, RR, CBR, safety….
Estimated date of competition: 2023.

Do we (currently) have effective drugs for CUP
patients?
a responsive subset:

an unresponsive subset:

favourable prognostic subset

poor prognostic subset

• About 20% of CUP patients
• Have histopathology, biomarkers and clinical
presentation consistent with specific tissue
of origin
• Should be treated with primary-specific
therapy corresponding to most likely
primary site

• About 80% of CUP patients
• No type of ChT prolonged survival in
these patients

Int J Cancer 2014; 135, 2475–81.
Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

Favourable prognostic subset
• Traditionally defined favourable subset:
•
•
•
•
•

women with isolated axillary adenopathy,
women with serous papillary peritoneal carcinomatosis,
squamous cell carcinoma involving mid-high cervical lymph nodes,
poorly as well as well-differentiated neuroendocrine carcinoma,
poorly differentiated and undifferentiated carcinoma (extra gonadal germ cell
cancers),
• men with blastic bone metastases and elevated PSA
• patients with single, small and potentially resectable tumours

• Newly identified favourable CUP subset:
• patients who look like CRC (CK 20 pos, CK 7 neg, CDX pos), should be treated as
patients with advanced CRC (expected RR around 50% and mOS up to 3 years)

Abeloff’s Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1694-702.

219

Unfavourable prognostic subset (1)
• Sensitivity to chemotherapy is modest.
• Include the patient in clinical trial (if an option).
• Do the CGP to identify potentially treatable, clinically relevant GA and
treat accordingly.
• In many countries expensive molecular assays are not available or not covered by
insurance.
• Targeted drugs and check point inhibitors are not covered by insurance.
• At the time being we have no prove that such approach really influence patients'
survival. Data from well designed clinical trials are necessary (are ongoing).

Unfavourable prognostic subset (2)
• The majority of patients from this subset have poor prognosis.
• At presentation, two-thirds of patients have metastatic lesions in two or
more visceral sites (most often liver, lung, lymph nodes and/or
peritoneum).
• Patients are often in poor performance status.
•
•
•
•

For many of these patients BSC is the best option.
For selected patients empiric chemotherapy is justified.
Cisplatin or taxane-based doublets have been used, with little impact on survival.
Patients and relatives have to be informed that expected RR to ChT is only 20% to
30% and expected mOS not more than 9 to 11 mos. This might influence theirs'
decision about treatment.

NCCN guidelines

220

Burning questions
• 1. Does site-specific therapy determined by GEP improves outcome in patients with CUP?
• According to the result of GEFCAPI 04 study: NO
• The study has limitations!

• 2. If genomic profiling identifies a targetable mutation in a tissue sample of CUP and the
patients receives targeted therapy, is the outcome improved compared to standard
chemotherapy?
• It seems logical, but it is not necessary.
• A good lesion in terms of this is BRAF mutation. It can be effectively treated if CUP has metastasized
from melanoma but not from colon cancer.
• The study is underway.

Summary and assessment algorithm
(1)
• Does molecular profiling assay increases accuracy of identifying the
primary site?
• Most probably yes.

• Does molecular profiling (CGP) help us in directing effective targeted
treatment?
• We are not certain yet. Studies are ongoing.

• Does identification of primary site based on molecular assays (GEP
tests) and accordingly directed therapy improves patient survival?
• According to the results we have: NO.

• How to proceed knowing all these in current clinical practice?

221

Summary and assessment algorithm
(2)
• Try to search for primary site: clinically, by IHC, imaging, endoscopy studies.
• Rule out potentially treatable or curable tumours (breast cancer, germ cell
tumour, lymphoma)
• Select, which clinic-pathological entity the patient belongs to:
• If to favourable prognostic subset:
• treat accordingly

• If to poor prognostic subset:
•
•
•
•

Have a profound discussion with the patient and relatives about the disease
Evaluate patient performance, bear in mind patient’s condition and preferences
Choose either empirical ChT or BSC
Do CGP, look at targetable, clinically relevant GA and treat the patient on the bases of the results of
this test. Of note: without big evidence so far that this approach is beneficial.
• The best option: include the patient in a clinical study if available.

Conclusions
• CUP is a heterogeneous disease with poor prognosis.
• It is mandatory to establish to which prognostic group the patient belongs to.
• In patients belonging to a favourable prognostic subset long-term survival
can be achieved with appropriate treatment.
• Patients classified to unfavourable prognostic subset have to be informed
about benefits and disadvantages of empiric therapy. For many patients with
widespread disease on first presentation and poor PS BSC is the best option.
• Novel approaches (searching for clinically relevant GA) are promising,
present a fundamental shift in the paradigm of treatment of cancer patients
from tissue-specific to individual, patient/tumour customized treatment,
directed according to tumour specific GAs.

222

2nd Summer School in Medical Oncology
Precision oncology- Are we there yet?
7. - 10. September 2021

Systemic treatment of Ewing sarcoma
Where do we stand?
Mojca Unk, MD,MS
Institute of Oncology Ljubljana
Department of medical oncology

James Stephen Ewing
1866- 1943
American pathologist
the first Professor of pathology at Cornell University
1921: discovery of a form of bone cancer later named Ewing's sarcoma

223

Introduction
• a small, blue, round cell sarcoma (RCS)
gene fusion involving a member of
the FET family and a member of the ETS family
of transcription factors (definitive diagnosis)

• the 3rd most common bone sarcoma (incidence: ~0.1/100,000/year)
• children and adolescents (rarely adults)
• median age at diagnosis: 15 y
• male predominance
• extremity bones (50%), pelvis, ribs and vertebra (any bone, soft
tissue)
Rizk et al. Pharmgenomics Pers Med. 2019

Outcome
• historical series: 5-year survival <10 % (micrometastatic disease)
• current recommended multimodal approaches:
• Localised disease 5-year survival is ∼60 % - 75 %
• Metastatic disease 5-y survival ∼20 % - 40 % (metastatic sites, tumour burden)

Schuck et al. Int J Radiat Oncol Biol Phys 2003; Womer et al. J Clin Oncol 2012; Le Deley et al J Clin Oncol 2014.

224

Initial systemic treatment
•
•
•
•

Intensive chemotherapy: reported long term survival 60-70 %
No novel agents available
Different chemotherapy regimens standard in Europe and USA
Multi-agent regimen:
•
•
•
•
•

vincristine (V),
doxorubicin (D),
actinomycin D (DTIC)
cyclophosphamide (C)/ifosfamide (I)
etoposide (E).

Schuck et al. Int J Radiat Oncol Biol Phys 2003; Womer et al. J Clin Oncol 2012; Le Deley et al J Clin Oncol 2014.

Comparison of two chemotherapy regimens in Ewing sarcoma (ES):
Euro Ewing 2012 randomized trial (EE2012)

• randomised study
• localised or metastatic ES
• patients aged 5-50 years
• European regimen of VIDE induction and VAI or VAC (V, actinomycin D
and I or C) consolidation
• USA regimen of compressed VDC/IE induction and IE/VC
consolidation
Brennan et al. J Clin Oncol 2020

225

Results

Brennan et al. J Clin Oncol 2020

Conclusion
• The interval-compressed VDC/IE regimen is currently the preferred first-line
treatment in ES
• up to nine cycles of induction ChT
• local therapy
• consolidation chemotherapy

• The optimal timing for local control:
•
•
•
•
•

primary site,
size,
response,
anticipated morbidity from surgery
tolerability.

• Primary metastatic disease
• the same treatment approach
• worse prognosis
• local treatment with responding metastatic disease; outcome improvement

Bone sarcomas: ESMO–EURACAN–GENTURIS–ERNPaedCan: Ann Oncol 2021

226

Relapsed ES
• fatal
• prognostic factor: time to relapse (>2 years from initial diagnosis)
• no standard of care
• multiple regimens used at progression
• little prospective evidence

Stahl et al. Pediatr Blood Cancer 2011; Ferrari et al. Pediatr Blood Cancer 2009; Hunold et al. Pediatr Blood Cancer 2006

rEECur study
• first randomised controlled trial in this setting
• drug regimens:
•
•
•
•

Topotecan/cyclophosphamide (TC)
Irinotecan/temozolamid (TEMIRI)
HD ifosfamide
Gemcitabine/docetaxel (GD)

McCabe et al. J Clin Oncol 2020

227

Results

Irinotecan&temozolamid is less effective than
topotecan/cyclophosphamide and HD ifosfamide in
response rate
progression free survival
overall survival

McCabe et al. J Clin Oncol 2020

Targeted therapy

228

Cabozanitib: CABONE study
Multicentre, single arm, phase II
Partial response: 26 %
Stable disease: 49%
Clinical benefit: 75 %
Progressive disease 21%
mPFS 4·4 months (95% CI 3·7–5·6)

mOS 10·2 months (95% CI 8·5–18·5)

*2 pts NA

Cabozantinib produced high tumour shrinkage.
MET expression in Ewing sarcoma (negative prognostic factor).
MET inhibition might contribute to the clinical activity of cabozantinib.
Italiano et al. Lancet Oncol. 2020; DuBois et al. Cancer 2010

Regorafenib: REGOBONE study
• randomized, placebo -controlled phase II study
• efficacy and safety of regorafenib (REG) in pts with Ewing sarcoma

Regorafenib delays disease progression
Only modest activity- combination therapy???

229

Duffaud et al. ESMO 2020

Conclusion
• Ewing sarcoma a rare curable cancer
• Treatment in experienced reference centres
• Treatment of primary tumour complex and individualised
• Long term consequences of treatment very significant
• Recurrence remains frequently fatal
• Active new agents emerging
• Testing new strategies requires coordinated international collaboration
• Many improvements still needed

Institute of Oncology Ljubljana
a member of EURACAN

Thank you for your attention!

230

2nd Summer School in Medical Oncology
Institute of Oncology Ljubljana
September 7-10, 2021

Presentation of Two Patients with
Localised Ewing Sarcoma
Aleksandra Sokolova

Patient 1, December 2016: male, 27 years
First visit 6/1/17

US: tumour in left hemithorax

• no previous diseases
• 3 weeks lump above the left lower
ribs, slightly painful, growing
• no other symptoms

chest CT 21/12/16: 6x7 cm tumour
arising from destructed anterior part
of the 6th left rib, infiltrating
surrounding soft tissues

US guided fine needle aspiration
biopsy 21/12/16
citology: Ewing sarcoma (FISH
positive for EWS gene translocation)
bone scintigraphy 4/1/17: no other
bone lesions

• examination: 6x5 cm palpable lump
above lower left ribs

PET/CT 5/1/17: 8 cm tumour of the
6th left rib (SUV 17.3), infiltration of
surrounding soft tissues, no
metastases/pathologic lymph nodes

• CRP 35; LDH, AF - normal

Multidisciplinary sarcoma tumour
board

Dec/16: male, 27 years,
localised Ewing sarcoma of
6th left rib

231

January 2017 – October 2017: protocol INT-0091
neoadjuvant ChT

surgery

• 4 cycles VACA/IE at 3-week
intervals (vincristine,
doxorubicin (dactinomycin),
cyclophosphamide,
alternating with ifosfamide,
etoposide)
• after 2nd cycle the tumour
no more palpable

adjuvant ChT + adjuvant RT

• tumour excision (Apr/2017) resection of tumour with
anterior parts of 6th and 7th
left ribs
• histology: <5% residual Ewing
sarcoma, R0 resection,
narrow margins

• concomitant RT to the site
of the surgery (MayJul/2017, TD 50 Gy)

• CT (Feb/2017): good partial
regression, no new lesions

Dec/16: male, 27 years,
localised Ewing sarcoma of
6th left rib

INT-0091: ChT + surgery +
RT (Jan-Oct/17)

October 2017 ⇢ today:
Regular checkups (+ lab. + chest X-ray) every 3 months for the first 2 years,
later every 6 months
Chest CT and bone scintigraphy once a year
After almost 4 years no recurrence of the disease

last chest CT from 2 months ago

Dec/16: male, 27 years,
localised Ewing sarcoma of
6th left rib

• 8 cycles VACA/IE at 3-week
intervals (5th-12th cycle)
• after 9th and 10th cycle
febrile neutropenia gr. 4
and anemia gr. 3
• 11th and 12th cycle 75%
dose

INT-0091: ChT + surgery +
RT (Jan-Oct/17)

Follow-up Oct/17 ⇢ today:
no recurrence

232

Patient 2, August 2018: male, 23 years
first visit 11/9/18
• previous conditions: psoriasis
• symptoms:
• 9 months pain in left lumbar
region and left lower ribs
• progressing to both legs with
tingling, difficulty walking
• Aug/2018: acute paraparesis and
urine retention

MRI 22/8/18
9x7x6 cm left paravertebral tumour
(Th11-Th12) arising from posterior
part of the 12th left rib, spreading
intraspinally cousing compression of
medullary cone

Urgent surgery 22/8/18
hemilaminectomy of Th11 and Th12
and removal of intraspinal part of
the tumor -> after surgery residual
mild left lumbar pain and still some
weakness in legs with tingling
Histology: Ewing sarcoma (fusion
EWSR1-FLI1)
CT thorax & abdomen and PET/CT –
no distant metastases
Multidisciplinary sarcoma tumour
board

• CRP, LDH, AF – all normal

Aug/18: male, 23 years,
localised Ewing sarcoma of
12th left rib

September 2018 – June 2019: protocol INT-0091
neoadjuvant ChT

surgery

• 4 cycles VACA/IE at 3-week
intervals (vincristine,
doxorubicin,
cyclophosphamide,
dactinomycin alternating
with ifosfamide, etoposide)
•
- after 2nd cycle
complete resolution of
symptoms
• MRI (Oct/2018): good
partial regression (9 cm -> 5
cm), no new lesions
Aug/18: male, 23 years,
localised Ewing sarcoma of
12th left rib

adjuvant ChT + adjuvant RT

• tumour excision (Dec/2018) posterior spine mobilisation
with pediculotomy at Th12
and spine fixation at Th10-L1,
and resection of tumour with
left diaphragm and 12th rib
and posterior parts of 9-11th
ribs
• histology: residual Ewing
sarcoma with 40-50% tumour
necrosis, max diameter 5 cm,
R1 resection

INT-0091: ChT + surgery +
RT (Sep/18-Jun/19)

233

• 8 cycles VACA/IE at 3-week
intervals (5th-12th cycle)
• concomitant RT to the site
of first and second surgery
(Feb-Mar/2019, TD 58 Gy)

June 2019 ⇢
regular checkups (+ lab. + chest
X-ray) every 3 months, chest CT
every 6 months

June 2020: deterioration
dyspnea, cough, right pleuritic chest pain – right pleural effusion, pneumonia;
↑CRP 200 mg/L, ↑LDH 7 ukat/L, AF norm.
Chest x-ray and CT – metastases (lungs, pleura, mediastinum)

June 2020: metastatic disease
→ 2nd line ChT: gemcitabine and docetaxel
(gemcitabine day 1 and 8, docetaxel day 8, at 3-week intervals)
• after 1st cycle – no more symptoms
• chest X-ray after 3rd cycle: regression
• total 7 cycles (Jun-Nov/2019)
•PET/CT (Dec/2020): almost complete response, only one metabolically active
residual mass in right upper mediastinum behind right brachiocephalic vein (2 cm,
SUV 6.4) ➜ RT (Jan-Feb/2021, TD 58.8 Gy)
Aug/18: male, 23 years,
localised Ewing sarcoma of
12th left rib

INT-0091: ChT + surgery +
RT (Sep/18-Jun/19)

Jun/20: metastatic
2nd line ChT (Jun-Nov/20)
+ RT mediastinum (Feb/21)

March 2021: regular checkup
Follow-up chest X-ray 15/3/2021: progression (lungs, pleura)
mild stabbing pain in right chest and right shoulder, PS 0-1

CT 29/3/2021: progression – large tumour mass on right pleura infiltrating right
diaphragm and liver + bone metastasis in left iliac bone

3rd line ChT: topotecan and cyclophosphamide
(day 1-5 at 3-week intervals)
•at initiation of therapy (Apr/2021): right chest pain spreading to right shoulder and
legs, fatigue, no dyspnea or caugh; ↑CRP 200 mg/L, ↑LDH 22 ukat/L, ↑AF 3 ukat/L
•after 1st cycle – disappearance of all symptoms
•April/2021 ⇢ today: 6 cycles, 2-6th cycle 60% dose (3/5 days, fever on day 3)
•CT (Aug/2021): good partial regression
Aug/18: male, 23 years,
localised Ewing sarcoma of
12th left rib

INT-0091: ChT + surgery +
RT (Sep/18-Jun/19)

Jun/20: metastatic
2nd line ChT (Jun-Nov/20) +
RT mediastinum (Feb/21)

234

3rd line ChT (Mar/21 ⇢
today)

Conclusion
Patient 1: male, 27 years,
localised Ewing sarcoma of 6th
left rib

Patient 2: male, 23 years,
localised Ewing sarcoma of 12th
left rib

Best survival with neoadjuvant ChT followed by
surgery/RT if not resectable and adjuvant ChT
+/- RT.

1. biopsy in sarcoma reference
center
2. neoadjuvant ChT
3. surgery (R0)
4. adjuvant RT + ChT
5. follow-up – after 4 years no
recurrence

1. urgent surgery due to spine
compression
2. dignosis from resected part of
the tumour
3. neoadjuvant ChT
4. second surgery (R1)
5. adjuvant RT + ChT
6. early recurrence 1 year after
completment of treatment,
currently on 3rd line of ChT

All patients with radiological signs of sarcoma
should be referred to the reference centre for
bone sarcomas.

235

Biopsy and further treatment should be
descussed at multidisciplinary sarcoma tumour
board and carried out in sarcoma reference
center.
We should monitor cured patients for long
term toxicities and secondary malignancies >10
years after treatment.

Systemic treatment of prostate cancer –
standards and perspectives
Borislav Belev
Dpt of Medical Oncology
Clinic of Oncology
Clinical Hospital Center Zagreb

236

237

238

239

240

241

Conclusion
• 2 main trends in prostate cancer treatment:
• Tendency to earlier systemic aproach
• Genetic profiling being more important

• New treatment options should prolong OS in prostate cancer
• Personalized treatment more important and dictate optimal
treatment

242

Advances in Systemic Treatment
of Renal Cell Carcinoma (RCC)
Boštjan Šeruga, MD, PhD
Division of Medical Oncology
Institute of Oncology Ljubljana and University in Ljubljana
2nd Summer School in Medical Oncology
Ljubljana, September 9, 2021

Topics
 Adjuvant systemic therapy in RCC
‒ Anti-VEGF agents
‒ Immune checkpoint inhibitors (ICIs)

 Combined 1st line systemic therapy for advanced RCC

243

Adjuvant phase III trials in RCC

244

Adjuvant phase III trials in RCC

DFS
DFS
DFS
DFS
DFS

NEJM 2016

245

Adjuvant phase III trials in RCC

DFS
DFS
DFS
DFS
DFS

There is no role of adjuvant anti VEGF therapy

Similar results in ECOG-ACRIN E2810
study, which evaluated pazopanib in
this setting

There is no role of anti VEGF therapy after radical metastasectomy
Eur Urol Oncol 2019

246

Phase III Adjuvant Trials with Immunotherapy
Parameter

IMmotion010[1]
(NCT03024996)

PROSPER[2]
(NCT03055013)

Atezolizumab

Drug

KEYNOTE-564[3]
(NCT03142334)

CheckMate 914[4]
(NCT03138512)

Nivolumab

Pembrolizumab

Nivolumab + ipilimumab

Histology

Clear-cell ± sarcomatoid
histology

RCC of any histology

Clear-cell ± sarcomatoid
features

Clear-cell ± sarcomatoid
features

Dose
duration

1 yr

2 doses prior to surgery
and adjuvant nivolumab
for 9 mos

1 yr

6 mos

T2 grade 4, T3a grade 3/4,
T3b/c any grade, T4 any
grade, or TxN+ any grade

Clinical stage ≥ T2 or
any N+

pT2, grade 4; pT3/4, any
grade; N+ M0; M1 NED

pT2aN0, grade 3-4;
pT2b-T4; N+

Primary
endpoint

DFS

RFS at 5 yrs

DFS

DFS

BICR

Yes

Yes

Yes

Yes

Active, recruiting

Active, recruiting

Active, recruiting

Active, recruiting

Risk
classification

Status

1. Uzzo. ASCO 2017. Abstr TPS4598. 2. Harshman. ASCO 2018. Abstr TPS4597.
3. Choueiri. ASCO 2018. Abstr TPS4599. 4. Bex. ESMO 2018. Abstr 927TiP.

KEYNOTE-564: DFS (Primary Endpoint)
100

HR: 0.68 (95%: 0.35-0.87)
P = .0010*

DFS (%)

80
60
12-Mo Rate, %
85.7
76.2

40

24-Mo Rate, %
77.3
68.1

Pembro
Placebo

20
Median follow-up: 24.1 mo (14.9-41.5)

Events, % Median, Mo (95% CI)
22.0
NR (NR-NR)
30.3
NR (NR-NR)

0
0
Patients at Risk, n
Pembro 496
Placebo 498

5

10

15

20
Mo

25

30

35

40

45

457
436

414
389

371
341

233
209

151
145

61
56

21
19

1
1

0
0

*Crossed P value boundary for statistical significance of .0114.

Slide credit: clinicaloptions.com

Choueiri. ASCO 2021. Abstr LBA5. Reproduced with permission.

247

KEYNOTE-564: DFS by Subgroup (ITT)
Subgroup

Events/Patients, n/N

Overall

Pembro

Favors:

Placebo

HR (95% CI)

260/994

0.68 (0.53-0.87)

Age

 <65 yr
 ≥65 yr

166/664
94/330

0.62 (0.45-0.84)
0.84 (0.56-1.26)

Sex

 Male
 Female

79/288
181/706

0.75 (0.48-1.16)
0.66 (0.49-0.89)

ECOG PS

0
1

215/847
45/147

0.65 (0.49-0.85)
0.91 (0.50-1.63)

PD-L1 status

 CPS <1
 CPS ≥1

42/237
215/748

0.83 (0.45-1.51)
0.67 (0.51-0.88)

Region

 North America
 European Union
 Rest of world

65/258
97/375
98/361

0.87 (0.53-1.41)
0.49 (0.32-0.74)
0.81 (0.55-1.21)

Metastatic
staging

 M0
 M1 NED

234/936
26/58

0.74 (0.57-0.96)
0.29 (0.12-0.69)

0.1

0.5

1
Slide credit: clinicaloptions.com

Choueiri. ASCO 2021. Abstr LBA5. Reproduced with permission.

KEYNOTE-564: Interim OS
100
HR: 0.54 (95%: 0.30-0.96)
P = .0164*

OS (%)

80
60

12-Mo Rate, %
98.6
98.0

40

24-Mo Rate, %
96.6
93.5

Pembro
Placebo

20
Median follow-up: 24.1 mo (14.9-41.5)

Events, % Median, Mo (95% CI)
3.6
NR (NR-NR)
6.6
NR (NR-NR)

0
0
Patients at Risk, n
Pembro 496
Placebo 498

5

10

15

20
Mo

25

30

35

40

45

490
494

486
485

482
480

338
336

215
209

124
117

51
48

3
3

0
0

*Did not cross P value boundary for statistical significance of .0000093 for 51 OS events; final OS analysis to occur after ~200 OS events.

Slide credit: clinicaloptions.com

Choueiri. ASCO 2021. Abstr LBA5. Reproduced with permission.

248

Take home message (adjuvant therapy)
 No role of anti-VEGF adjuvant therapy in locoregional RCC
after nephrectomy and after "radical" metastasectomy
‒ Conflicting results for DFS, does not improve OS,
‒ Toxic treatment, deterioration of QoL

 ICIs promising new adjuvant therapy in RCC

IMDC (Heng) Prognostic Criteria
 Clinical

Favorable
Intermediate
Poor

‒ KPS < 80% (P < .0001)
‒ Time from diagnosis to tx < 1 yr (P =
.01)
 Laboratory

Probability of OS

1.0
0.8
0.6
0.4
0.2
0

‒ Hemoglobin < LLN (P < .0001)

0

12

24

48

36

60

Mos Since Therapy Initiation

‒ Calcium > ULN (P = .0006)

No. of Events/No. at Risk
Favorable
11/133
Intermediate 61/301
Poor
94/152

‒ Neutrophil count > ULN (P < .0001)

16/110
50/182
19/36

4/62
17/82
1/3

2/22
2/18
0/1

0/3
0/3
0/0

Favorable: 0 risk factors; intermediate: 1-2 risk factors;
poor: 3+ risk factors

‒ Platelet count > ULN (P = .01)
Heng. JCO. 2009;27:5794.

249

IMDC (Heng) Prognostic Criteria
Favorable: 0 risk factors; Intermediate: 1-2 risk factors;
Poor: 3+ risk factors
1.0

‒ KPS < 80% (P < .0001)
‒ Time from diagnosis to tx < 1 yr (P = .01)

 Laboratory
‒ Hemoglobin < LLN (P < .0001)

Probability of OS

 Clinical

0.8
Favorable

0.6

Intermediate

0.4
0.2
Poor
0

‒ Calcium > ULN (P = .0006)

0

12

24

36

48

60

Mos Since Therapy Initiation

‒ Neutrophil count > ULN (P < .0001)
‒ Platelet count > ULN (P = .01)

75% to 80% of patients with mRCC have ≥ 1 of these
risk factors (intermediate or poor risk)

Heng. JCO. 2009;27:5794.

Progress in the treatment of patients
with advanced RCC
2-year OS of all patients (all prognostic groups)
2001-2006

IFN

IFN

40%

KABOZANTINIB
SUNITINIB

60%

2017-2020
NIVOLUMAB
+ KABOZANTINIB
NIVOLUMAB+CABOZANTINIB

75%

0% 10% 20% 30% 40% 50% 60% 70% 80%
IFN: Interferon

Choueiri T, Check Mate 9ER,ESMO 2020; Gore ME, Lancet 2010

250

Phase III clinical trials in the 1st line therapy
Trial

Comparison

CheckMate 214
Motzer et al, NEJM, 2018

Keynote 426
Rini et al, NEJM,
2019

Javelin Renal 101
Motzer et al, NEJM, 2018

Immotion 151
Rini et al, Lancet,
2019

CheckMate 9ER
Choueiri et al, ESMO 2020

Clear
Motzer et al, NEJM 2021

Primary endpoint (s)

Ipilimumab+Nivolumab
vs. Sunitinib

OS, ORR, PFS in patients with
intermediate and poor prognosis

Pembrolizumab+Axitinib
vs. Sunitinib

OS in PFS in the ITT populations (allcomers)

Avelumab+Axitinib
vs. Sunitinib

OS in PFS in PD-L1+ patients

Atezolizumab+Bevacizumab
vs. Sunitinib

PFS in PD-L1+
OS in the ITT population

Nivolumab+Cabozantinib
vs. Sunitinib

PFS in the ITT population

Pembrolizumab+Lenvatinib
vs. Lenvatinib+Everolimus
vs. Sunitinib

PFS in the ITT population

Results of phase III trials in the 1st line
Trial
CheckMate 214
Motzer et al, NEJM, 2018

Keynote 426
Rini et al, NEJM,
2019

Javelin Renal 101
Motzer et al, NEJM, 2018

Immotion 151
Rini et al, Lancet,
2019

CheckMate 9ER
Choueiri et al, ESMO
2020

Clear
Motzer et al, NEJM 2021

Comparison

Results

Ipilimumab+Nivolumab
vs. Sunitinib

ORR: 42% vs. 27%, PFS: 11.6 vs 8.4 mo
(HR 0.82-ns), OS: at 4 yrs HR 0.65

Pembrolizumab+Axitinib
vs. Sunitinib

PFS: 15.1 vs. 11.1. mo (HR 0.69), at OS: 2
yrs 74% vs 66% (HR 0.68)

Avelumab+Axitinib
vs. Sunitinib

PFS (PD-L1+): 13.8 vs 7.2 mo (HR 0.61).
OS: HR 0.82 (ns-immature)

Atezolizumab+Bevacizumab PFS (PD-L1+): 11.2 vs 7.7 mo (HR 0.74)
vs. Sunitinib
OS (ITT): HR 0.93 -ns
Nivolumab+Cabozantinib
vs. Sunitinib

PFS (ITT): 16.6 vs. 8.3 mo (HR 0.51)
OS (ITT) @ 12 mo: 85.7% vs 75.6%

Pembrolizumab+Lenvatinib
vs. Lenvatinib+Everolimus
vs. Sunitinib

PFS (ITT): 23.9 vs. 9.2 mo (HR 0.39) for
P+L, OS (ITT): HR 0.66 for P+L

251

Phase III clinical trials in the 1st line therapy
Trial

Comparison

CheckMate 214
Motzer et al, NEJM, 2018

Keynote 426
Rini et al, NEJM,
2019

Javelin Renal 101
Motzer et al, NEJM, 2018

Immotion 151

Ipilimumab+Nivolumab
vs. Sunitinib

CheckMate 9ER
Choueiri et al, ESMO 2020

Clear
Motzer et al, NEJM 2021

42% vs. 27%
(9% vs 1%)

Pembrolizumab+Axitinib
vs. Sunitinib

59.3% vs. 35.7%
(5.8% vs. 1.9%)

Avelumab+Axitinib
vs. Sunitinib

51.4% vs. 25.7%
(3.4% vs. 1.8%)

Atezolizumab+Bevacizumab
vs. Sunitinib

Rini et al, Lancet,
2019

ORR (CR) (%)

Nivolumab+Kabozantinib
vs. Sunitinib
Pembrolizumab+Lenvatinib
vs. Lenvatinib+Everolimus
vs. Sunitinib

37% vs. 33%
(5% vs. 2%)
55.7% vs. 27.1%
(8% vs. 4.6%)
71% vs. 53.5% vs. 36.1%
(16.8% vs. 9.8 vs. 4.2%)

Long-term control of disease with ICIs
Patients with intermediate and poor prognosis
Checkmate 214
≈ 70%

+20%

1/3 of patients
long-term
control of
disease
Motzer RJ et al, J Immunother Cancer, 2020

252

Probability of OS

OS with Nivo + Ipi vs Sunitinib in CheckMate 214:
Intermediate/Poor-Risk Sarcomatoid Patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

Nivo + Ipi
Sun
(n = 60)
(n = 52)
Events, n (%)
31 (52)
39 (75)
Median OS, (95% CI), mos 31.2 (23.0‒NE) 13.6 (7.7‒20.9)
HR (95% CI)
0.55 (0.33-0.90)
P value
.0155

80% (67-88)

58% (45-70)

56% (22-47)

53% (39-65)
35% (22-47)

29% (17-41)

0

3

6

9

12

15

18

27

30

33

36

39

42

45

Patients at Risk, n
Nivo + ipi 60
Sun 52

21
24
Mos

56
48

52
36

49
32

47
29

45
23

43
22

37
19

30
17

29
15

22
15

10
9

5
3

1
1

0
0

32
18

Slide credit: clinicaloptions.com

McDermott. KCA 2018.

Which combination works earlier?

Porta C, ESMO, 2020

253

KEYNOTE 426
Absolute benefits of combined therapy
Subgroup

12-mo survival
Pembrolizumab+
Axitinib

Sunitinib

Favourable

95%

94%

Δ 1%

Intermediate

91%

77%

Δ 14%

Poor

70%

45%

Δ 25%

≥ 1%

90%

78%

Δ 12%

< 1%

92%

78%

Δ 14%

Prognostic group

PD-L1 CPS

IMDC denotes International Metastatic Renal Cell Carcinoma Database Consortium

Rini et al, NEJM, 2019

Take-home Messages (advanced disease)
 Combined therapy which involves ICIs is a new 1st line
standard of treatment in patients with advanced RCC (for
all?)
 With combination therapy durable remission can be
achieved also in patients with poor prognosis disease
 Combination of ICI and anti VEGF preferable 1st line therapy
in patients with symptomatic disease

254

255

Bladder cancer systemic treatment
Is something new going on?

Milena Gnjidić, UHC Zagreb, Croatia
9.2021

~ 3% of all new cancer
~ 550 000 new cases per year worldwide
~ 200 000 death annually (2018)

~ Until the advent of immunotherapy 2015. there
was no new treatment options for decades

Bray F at al. GLOBOCAN. CA Cancer J Clin. 2018.

256

Cystectomy
1. Non-muscle invasive

2. Muscle invasive

MULTIDISCIPLINARY TEAM
3. Metastatic

Radiotherapy

Bladder-sparing?!

Systemic therapy

Local disease
Dream of every bladder-cancer patient: NO cystectomy !
Early diagnosis

IMUNOTHERAPY

Bladder
sparing

NEW THERAPY

COMBINATIONS
CHEMOTHERAPY
RADIOTHERAPY

257

Neoadjuvant chemotherapy

Cisplatin-combinations better than mono Cis
ABC meta analysis. Eur Urol. 2005

Neoadjuvant chemotherapy

Kim I et al. Int J Mol Sci. 2021.

258

Neoadjuvant immunotherapy

Kim I et al. Int J Mol Sci. 2021.

Neoadjuvant therapy

Kim I et al. Int J Mol Sci. 2021.

259

Neoadjuvant therapy

Kim I et al. Int J Mol Sci. 2021.

Neoadjuvant therapy
Could neoadj CPIs replace neoadj chemo?

Combinations?
New combinations?
CPIs = checkpoint inhibitors

Kim I et al. Int J Mol Sci. 2021.

260

Adjuvant chemotherapy

Kim I et al. Int J Mol Sci. 2021.

Adjuvant immunotherapy

negative

Kim I et al. Int J Mol Sci. 2021.

261

Adjuvant immunotherapy
CheckMate 274

8.2021 FDA approved!

HR 0.70

HR 0.55

DFS 20.8 ~ 10.8mo

Adjuvant Nivolumab
CheckMate 274

Subgroup analysis
1. PD-L1 expression > 1% !
2. Neoadjuvant chemotherapy !
3. Urinary bladder !

Overall survival ?!
Follow-up 20 mo disease recurrence = 48.2% ~ 57.3%

Bajorin DF et al. N Engl J Med. 2021.

262

Neoadjuvant vs adjuvant therapy?
pro
• Better tolerance
• Less extensive surgery
• Response monitoring
• Primary tumor=more antigens

• Not delaying currative cystectomy
• Pathohistology

CYSTECTOMY
neoadjuvant

adjuvant

contra
• Delaying cystectomy
• Refractoriness to chemoth
or immunoth

Biomarkers !?

Advanced disease
Dream of every metastatic bladder-cancer patient: NO mets !

CHEMOTHERAPY

Longer
survival

IMUNOTHERAPY

NEW THERAPY

COMBINATIONS

263

mBC: EAU Guidelines 2021

1

1

1

1

2

1

3
3
17

mBC: First line - chemotherapy

First line

Setting

Regimen

ORR

mOS

Cisplatin eligible

MVAC1

40-50%

12-15
months

36-56%

7-9 months

~10%

5-8 months

Gemcitabine+cisplatin2
PGC3

First line

Cisplatin ineligible

Gemcitabine+
Carboplatin4-6

Second line

Single agent
chemotherapy7-9

Single agent
chemotherapy7-9

1.Loehrerer JCO 1992, 2. Van der Masse JCO 2000, 3. Bellmunt JCO 2012, 4. De Santis JCO 2012.
5. Linardou Urology 2004, 6. Nogue-Aliguer Cancer 2003, 7. Bellmunt NEJM 2017, 8.Bellmunt JCO
2009. 9. Petrilac JCO 2015.

264

mBC: First line - Chemotherpy

mBC: First line - Immunotherapy
only PDL1+

50% patients cisplatin ineligible

OS
all

▪ Pembrolizumab
▪ Atezolizumab

PDL+

Chemotherapy is still standard of care!
Combinations are still pending!
comb
Szabados B, et al. Eur Urol Oncol. 2021.

265

mBC: First line - Maintenance
JAVELIN Bladder 100

AVELUMAB
OS 21.4 vs 14.3 m

9.2020

EMA approved 10.2020
21

mBC: First line - Maintenance AVELUMAB
Subgroup analysis

Grivas P, et al. Cancer Treat Rev. 2021.

266

22

mBC: Second line - immunotherapy
EMA+

▪ Pembrolizumab – OS

5.2021

▪ Atezolizumab
▪ Nivolumab
▪ Avelumab
▪ Durvalumab
Advantages:
- longer duration - PFS
- better tolerability

mBC: Second line - chemotherapy

First line

Setting

Regimen

ORR

mOS

Cisplatin eligible

MVAC1

40-50%

12-15
months

Gemcitabine+cisplati
n2
PGC3

First line

Cisplatin
ineligible

Gemcitabine+
Carboplatin4-6

Second line

Single agent
Single agent
chemotherapy7-9 chemotherapy7-9

36-56%

7-9
months

~10%

5-8
months

TAXANS

VINFLUNINE

1.Loehrerer JCO 1992, 2. Van der Masse JCO 2000, 3. Bellmunt JCO 2012, 4. De Santis JCO 2012.
5. Linardou Urology 2004, 6. Nogue-Aliguer Cancer 2003, 7. Bellmunt NEJM 2017, 8.Bellmunt JCO
2009. 9. Petrilac JCO 2015.

267

mBC: Second line and beyond

ERDAFITINIB ( antiFGFR1-4)

ENFORTUMAB VEDOTIN (ADC)
Sacituzumab govitecan ( ADC)

3

Targeted therapy in mBC – today and tomorrow
New therapies:









New immunotherapy
New anti-FGFR
New antibody-drug conjugates
Anti EGFR, HER
Anti VEGF
New chemotherapy
Vaccines
CAR-T cell therapy

 Combinations

Nelson BE et al. Front Oncol. 2021.

268

Biomarkers

Yoshida T. In J Urol. 2019.

Predictive biomarkers for immunotherapy
Biomarker

tissue
blood

Predictive capacity

PD-L1

Increased = improved response

TMB - tumor mutational burden

Increased = improved response

STING – stimulator of interferon genes

Deficient = reduced response

ASC - apoptosis-associated speck-like protein containing CARD

Gene methylation = worse survival

TME - tumor microenvironment

High CD4+, CD8+, CD45RO+ T cells = better
survival

PBMCs – peripheral blood mononuclear cells

High CD4+, CD8+ T cells = better response

ctDNA – ciculating tumor DNA

Increased = worse survival

Exsomes – extracellular vesicles

Increased = better response

Cytokines

Predict irAEs

Metal chelators

Cooper chelating drugs = increase CD8+, NK

sPD-L1/sPD-1 – soluble PD-L1/PD-1

Low level = better survival

CTCs – circulating tumor cells

Presence = poor response

Microbiome

Some species = better response

269

Adam T et al. Cancers. 2021

Conclusions
▪ Immunotherapy in the earlier stages is at the door
▪ Perioperative therapy is required; neoadjuvant > adjuvant
▪ Bladder-sparing approach is increasingly being on the mind
▪ Trials with new targeted therapy or combinations are ongoing
▪ Urgent need for better biomarkers to guide the optimal choice of therapy

270

Systemic treatment of germ cell tumors
– could it get better
BREDA ŠKRBINC
INSTITUTE OF ONCOLOGY LJUBLJANA
2ND SUMMER SCHOOL IN MEDICAL ONCOLOGY
7-10 SEPTEMBER 2021

FACTS ABOUT GERM-CELL TUMORS (GCT)

• GCT the most common cancer in men aged 18-35 years
•

Testicular cancer accounts for ~1% of newly diagnosed cancer in men worldwide

Testicular cancer - NATURE REVIEWS | DISEASE PRIMERS 2018

271

FACTS ABOUT GERM-CELL TUMORS (GCT)

• GCT the most common cancer in men aged 18-35 years
•

Testicular cancer accounts for ~1% of newly diagnosed cancer in men worldwide

• Highly curable disease
• Since 1975 with platinum based chemotherapy - the most curable metastatic solid cancer in males
• Histology
• 50%seminoma, 40% NSGCT, 10% combined GCT
• Stage of the disease
• 60% of patients present with lokalised disease (stage I)
• Primary tumor location
• Testicular, retroperitoneal, mediastinal, intracranial
• Level of serum tumor markers AFP, β-hCG, LDH determine the treatment choice
• IGCCCG classification PROGNOSTIC CLASSIFICATION ( y 1997 + updates)
• Good prognostic group
• Intermediate prognostic group
• Poor prognostic group

Testicular cancer - NATURE REVIEWS | DISEASE PRIMERS 2018

FACTS ABOUT GERM-CELL TUMORS (GCT)

Testicular cancer - NATURE REVIEWS | DISEASE PRIMERS 2018

272

FACTS ABOUT GERM-CELL TUMORS (GCT)

Multidisciplinary treatment

FACTS ABOUT GERM-CELL TUMORS (GCT)
• Recidivant disease still curable (probability for cure signifficantly reduced)
• more efficient treatment modalities are needed for this group of GCT patients

Testicular cancer - NATURE REVIEWS | DISEASE PRIMERS 2018

273

Presented By Anja Lorch at 2018 ASCO Annual Meeting

Phase I / II studies
Kollmansberger C

trastuzumab

HER2/neu expressing
GCT

Ann Oncol 1999

platinum refractory GCT
Rick O

talidomid

Eur J Cancer 2006

Feldman DR

sunitinib

relapsed or refractory
GCT

Feldman DR

tivantinib

relapsed or refractory
GCT

Einhorn LH

imatinibmesilat

CTX refractory GCT
expressing KIT

J Clin Oncol 2006

Necchi A

pazopanib

relapsed or refractory
GCT

Ann Oncol 2017

Fenner M

everolimus

multiply relapsed GCT

Adra N

pembrolizumab

multiply relapsed GCT,
no other treatment
option

274

Invest New Drugs 2010
Invest New Drugs 2013

Journal of Cancer
Research and Clinical
Oncology, 2018
Annals of Oncology,
2018

Le et al., Science 357, 409–413 (2017)

the genomes of cancers deficient in MMR contain exceptionally high numbers of
somatic mutations
sensitivity to immune checkpoint blockade

The overall rate of mutations per megabase in cisplatin resistan GCT is low
(< 1 mutation/ MB) J Clin Oncol. 2016, 33:4000-4007.
low sensitivity to immune checkpoint blokade

FACTS ABOUT GERM-CELL TUMORS (GCT)

• Long term survivals
• risk for 2nd CA
• neuropathy / hearing loss
• nefropathy
• risk for cardiovascular events
• fertility impairment
• cognitive impairment
• suicidal tendencies

Testicular cancer - NATURE REVIEWS | DISEASE PRIMERS 2018

275

GCT SURVIVALS

How does treatment with platinum-based chemotherapy or radiotherapy influence the non–testicular
cancer mortality and causes of death in GTC survivors?

Investigation of cause specific non-GCT mortality with impact on previous treatment with platinum-based
chemotherapy or radiotherapy

The aim of the study was to assess non-TC mortality and causes of death in relation to TC treatment, including the impact
of number of cisplatin based chemotherapy cycles, in a population-based cohort with complete information on TC
treatment burden.

10.1200/JCO.21.00637 Journal of Clinical Oncology 2021

276

Testicular Cancer in the Cisplatin Era:
Causes of Death and Mortality Rates in
a Population-Based Cohort

METHODS
• Overall, 5,707 men identified by the Cancer Registry of
Norway diagnosed with TC from 1980 to 2009 were included
in this population-based cohort study.
• By linking data with the Norwegian Cause of Death Registry,
standardized mortality ratios (SMRs), absolute excess
risks (AERs; [(observed number of deaths – expected
number of deaths)/person-years of observation] x 10,000),
and adjusted hazard ratios (HRs) were calculated

5707 GCT patients diagnosed with GCT Jan 1st 1980-Dec 31st 2009
identified by the Cancer Registry of Norway

10.1200/JCO.21.00637 Journal of Clinical Oncology 2021

Testicular Cancer in the Cisplatin Era: Causes of Death
and Mortality Rates in a Population-Based Cohort

10.1200/JCO.21.00637 Journal of Clinical Oncology 2021

277

Testicular Cancer in the Cisplatin Era: Causes of Death
and Mortality Rates in a Population-Based Cohort

Results
•

Median follow-up was 18.7 years, during which non-TC death was registered for 665 (12%) men.



Overall excess non-TC mortality 23% (SMR, 1.23 - AER, 11.14) compared with the general population,



Increased risks after PBCT (SMR, 1.23 - AER, 7.68)



Compared with surgery, increased non-TC mortality appeared after 3, 4, and more than 4 cisplatin-based chemotherapy cycles
after > 10 years of follow-up



Increased risk after RT (SMR, 1.28 - AER, 19.55).

•

The highest non-TC mortality was in those < 20 years at TC diagnosis (SMR, 2.27 - AER, 14.42).

•

The most important cause of death was non-TC second cancer with an overall SMR of 1.53 - AER, 7.94), with increased risks after
PBCT and RT.

•

Overall noncancer mortality was increased by 15% (SMR 1.15 - AER, 4.71).

•

Excess suicides appeared after PBCT (SMR 1.65 - AER, 1.39).

10.1200/JCO.21.00637 Journal of Clinical Oncology 2021

Testicular Cancer in the Cisplatin Era: Causes of Death
and Mortality Rates in a Population-Based Cohort

Conclusions
•

GCT surviviors treated with platinum based CTX or RT suffer increased mortality rates compared with the general population.

•

The most notable excess mortality was caused by seconnd cancers,
• measures to avoid delayed SC diagnosis are essential ( extende follow up)

•

Citotoxic treatment ( CTX / RT ) seems to be the main risk factor for increased mortality.

•

The increased mortality risk might be reduced by lifestyle improvements, which should be recommended following GTC treatment.

•

It is crucial that GCT surviviors and health personnel involved in the follow-up should be aware of the increased premature mortality risk.

RISK ADAPTED TREATMENT

10.1200/JCO.21.00637 Journal of Clinical Oncology 2021

278

• Validation of the 1997 prognostic classification and update of the survival probabilities in a modern
cohort
• Identification of additional prognostic factors to refine the IGCCCG prognostic classification

J Clin Oncol 39:1563-1574. 2021

• 30 Institutions
• Complete patients database
1980-2013

J Clin Oncol 39:1563-1574. 2021

279

J Clin Oncol 39:1563-1574. 2021

J Clin Oncol 39:1563-1574. 2021

280

Nomograms of the final prognostic model for patients

Without nonpulmonary visceral metastases

J Clin Oncol 39:1563-1574. 2021

Nomograms of the final prognostic model for patients

With nonpulmonary visceral metastases

J Clin Oncol 39:1563-1574. 2021

281

https://eortc.shinyapps.io/IGCCCG-Update/

• IGCCCG database is the largest dataset on metastatic NSGCT worldwide
• Improved treatment outcomes
• stage migration because of earlier diagnosis and better diagnostic tools,
• improved supportive care,
• superiority of cisplatin- and etoposide-based first-line treatment over other combinations,
• use of upfront dose-intensified regimens,
• more stringent use and higher quality of postchemotherapy surgery,
• better salvage strategies in nonresponding or relapsing patients,
• more stringent guideline adherence,
• centralization of care at experienced expert centers,
• a combination of these factors

J Clin Oncol 39:1563-1574. 2021

282

 In future trials, patients with a particularly favorable prognosis in the nomogram may be
subjected to de-escalation strategies to further reduce treatment burden in patients likely to be
cured.
 In contrast, trials evaluating dose-escalation strategies should be pursued in patients with the
worst prognosis according to the new IGCCCG update model

J Clin Oncol 39:1563-1574. 2021

The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major
advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated
between 1975 and 1990.
 To reassess the original International Germ-Cell Cancer Collaborative Group (IGCCCG) classification for seminoma with modern
treatment data and to screen for additional prognostic variables

J Clin Oncol 39:1553-1562.2021

283

• 30 Institutions
• Complete patients database
1980-2013

J Clin Oncol 39:1553-1562.2021

J Clin Oncol 39:1553-1562.2021

284

J Clin Oncol 39:1553-1562.2021

• LDH above 2.5 x ULN levels before chemotherapy an additional adverse prognostic factor that
allowed splitting the good prognostic group further.
• Good prognosis patients with an elevated LDH above 2.5 x ULN before chemotherapy
experienced significantly worse outcomes.

• Other variables such as age, extragonadal primary tumor, elevated levels of β-hCG, or the
presence of lung metastases did not add significant prognostic information in good prognosis
patients once LDH elevations were considered

Until the availability of prospective trials results of this analysis do not allow to recommend using intensified
CTX schemes instead of three cycles BEP in good (according to the original classification) prognosis patients
who have an LDH level above 2.5 x ULN

J Clin Oncol 39:1553-1562.2021

285

Given 5-year PFS and OS survival probabilities of 88% (95% CI, 87 to 89) and 95%
(95% CI, 94 to 96), respectively, across all prognostic groups,
metastatic seminoma represents the most curable metastatic cancer in males

J Clin Oncol 39:1553-1562.2021

numerous challenges and pitfalls in testis cancer care that need to be addressed

Testicular Cancer Biomarkers

•

Clinical management greatly relies on sTM measurements

•

AFP, β-hCG, LDH – specific cellular proteins secreted into the bloodstream,
• conventional panel of serum tumor markers of GCT (sTMs)
• standard in GCT diagnosis and treatment monitoring
• Special S stage in the TNM sistem

•

Poor specificity and sensitivity of clasical sTM (https://doi.org/10.1155/2019/5030349)
• Elevated in seminomas: bhCG 28% and LDH 29.1% , (AFP never)
• Elevated in NSGCT: bhCG 53%, AFP 60.1%, and LDH 37.8%
• sTMs may be elevated nonspecifically by processes other than GCT and may be normal in the setting of
radiographically and serologically occult metastatic disease
• Need for novel biomarkers with superior performance characteristics compared to conventional sTMs

286

https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf

on horizon there is an important change in the field of GCT sTMs

•

In the past decade, nucleic acid–based markers, specifically microRNAs (miRNAs), have garnered attention

•

miRNAs - small noncoding RNA molecules of approximately 22 nucleotides
• involved in epigenetic regulation of mRNA translation by direct interaction with the larger messenger RNA
molecules regulating the level of gene expression on a post-transcriptional level
• influencing cellular differentiation and other physiological processes
as well as
•

carcinogenesis, for which they can operate as oncogenes or tumor suppressors

Nat Rev Clin Oncol 2011;8:467–77

https://doi.org/10.1016/j.eururo.2021.06.006

287

•
•

Serum miRNA - the most exciting discovery in the GCT field
Emerged as promising biomarkers in diagnosing and monitoring of patients with GCT

• Several clusters of miRNA that are expressed in testicular cancer tissue and measurable in the serum have
been identified on historical samples / retrospective studies
• miR-371a-3p specifically exhibited greater accuracy than traditional sTMs in GCT

https://doi.org/10.1016/j.eururo.2021.06.006

• to prospectively evaluate the utility of the M371 test in a large and representative patient
population enrolled from a large number of European institutions
• to involve various histologies and clinical stages
and in particular
• to evaluate the diagnostic sensitivity and specificity of the test for the primary diagnosis of
GCT
• to assess its usefulness for monitoring GCT treatment

J Clin Oncol 37:1412-1423; 2019

288

J Clin Oncol 37:1412-1423; 2019

Receiver operating characteristic curves that discriminate controls from
all patients with germ cell tumors, clinical stage (CS) I only or CS II/III only

ROC = the measure of the
usefulness of any test
(a greater AUC area means a more useful test)

J Clin Oncol 37:1412-1423; 2019

289

• The median expression of miR-371a-3p was significantly higher in the entire GCT group and in all the
CS subgroups compared with the controls
• Patients with CS greater than I had a higher serum level than those with CS I (all P < 0.001) (fig A)

• Seminoma was found to have significantly lower miR-371a-3p values than nonseminoma (fig B)
• difference only detectable in CS I patients
• Teratoma had the lowest expression values of all subtypes (fig C)

J Clin Oncol 37:1412-1423; 2019

Expression of miR-371a-3p in controls and patients with GCT
recurrence.

J Clin Oncol 37:1412-1423; 2019

290

Sensitivity of miR-371a-3p in all GCTs compared with the classic GCT markers b-human chorionic gonadotropin (bHCG), afetoprotein (AFP), and lactate dehydrogenase (LDH) and all three classic markers combined

J Clin Oncol 37:1412-1423; 2019

Sensitivity of miR-371a-3p
compared with the classic GCT
markers in all GCTs CS I

Sensitivity of miR-371a-3p
compared with the classic GCT
markers in all GCTs CS II / III

Sensitivity of miR-371a-3p
compared with the classic GCT
markers in NSGCTs CS II / III

Sensitivity of miR-371a-3p
compared with the classic GCT markers
in seminoma GCTs CS II / III

J Clin Oncol 37:1412-1423; 2019

291

Post-treatment decrease of microRNA (miR)-371a-3p
Decrease of miR-371a-3p
serum levels over the course of
chemotherapy
in CS II patients

Decrease of miR-371a-3p expression
after surgical removal of the primary
tumor
in clinical stage (CS) I , CS II, and CS III

Decreas of miR-371a-3p serum
levels over the course of
chemotherapy
in CS III patients

Decrease of miR-371a-3p
expression
in recurrent germ cell
tumors (GCTs) after treatment

J Clin Oncol 37:1412-1423; 2019

This study provides a considerable body of evidence that supports the usefulness of miR371a-3p serum levels as a new biomarker of GCTs.
Five features of the M371 test are noteworthy:
• the test has a 90.1% sensitivity and a 94.0% specificity for establishing the primary
diagnosis of GCT;
• it is relevant for the two main histologic subgroups of GCT;
• miR serum levels correlate with primary tumor size, local stage, and CSs;
• miR levels mirror treatment-related disease changes;
• miR levels are elevated in recurrences

• the study strongly confirmed previous data regarding to the usefulness of the M371 test as a
new serum biomarker of GCT that is informative in both seminoma and nonseminoma;
• because of its high sensitivity and specificity, M371 test involves the potential of simplifying
clinical pathways of the management of GCT
• further validation in an independent cohort is needed

J Clin Oncol 37:1412-1423; 2019

292

The Lange-Winfild criteria for biomarkers

The ideal TM is a substance that
(1) is produced only by the malignancy itself;
(2) is secreted into body fluids in such a way that it can easily
be measured in a reproducible fashion;
(3) correlates well with the amount of tumor present;
(4) can be detected at an early stage of the disease;
(5) has a half-life which is short enough so as not to
accumulate in
body tissues and result in false-positive
results;
(6) correlates with the response of the tumor to treatment

•
•

M371 test has the potential of simplifying clinical pathways of the management of GCT
further validation in an independent cohort is needed

Cancer 60:464-472. 1987

https://doi.org/10.1016/j.eururo.2021.06.006

Systemic treatment of germ cell tumors – could it get any better?

Yes it cann
and
it should still get better

293

Provided that
• GCT patients are treated strictly according the international guidelines on diagnosis and
treatment of GCT
• The patients are treated by expirienced physicians dedicated to the treatment of GCT
patients
• GCT poor prognostic group patients are treated by multidisciplinary teams dedicated to the
treatment of GCT patients

294

A new era in the treatment of endometrial cancer integrated with Molecular Classification
of Endometrial Cancer-advance and reccurent disease
Prof dr Aljoša Mandić
President of Society for Gynecological Oncology of Serbia (UGOS)
Institute for oncology of Vojvodina, Medical Faculty, University of Novi Sad, Serbia
e-mail: aljosa.mandic@mf.uns.ac.rs

Introduction
Endometrial cancer (EC) is the most common gynecological cancer in high income countries,
and the second most common in low income countries (1). In Serbia it is the fourth most
common cancer in the female population – behind breast, lung and colorectal cancer (2). The
molecular classification of EC introduced by the Cancer Genome Atlas (TCGA) (3) has ushered
in a change in the way we view and classify EC. This project used genomic, transcriptomic, and
proteomic analyses to characterize over 370 ECs. Four molecular subgroups and several
predictive biomarkers have been defined based on based the genetic architecture of tumor cells.
The Cancer Genome Atlas (TCGA) Research Network suggested 4 genomic classifications for
endometrial cancers:
a)
b)
c)
d)

polymerase ε (POLE) ultramutated,
microsatellite instability hypermutated (MSI-H),
copy-number low,
and copy-number high.

POLE ultra-mutated cancers are relatively rare (5% to 10% of endometrial cancers), highly
immunogenic, and typically have a favorable prognosis.(3) MSI-H tumors have high rates of
genomic mutations related to altered or defective DNA repair, including dysfunction in
mismatch repair (dMMR).(3,4) Approximately 20% to 30% of endometrial cancers exhibit an
MSI-H phenotype or loss of MMR. Alterations in PI3K/AKT/mTOR signaling are also
common.Copy-number low tumors, or microsatellite stable (MSS) tumors, represent the majority
of low-grade endometrioid cancers and have an intermediate prognosis.(3,4) These tumors have
low mutation rates with few TP53 mutations, but often have mutations in PTEN, CTNNB1,
PIK3CA, ARID1A, or KRAS.Copy-number high or serous-like tumors are generally high-grade
with low estrogen and progesterone receptor expression and low mutation rates.(3,4) As the
name suggests, these malignancies have extensive copy number variations and frequent mutation
of TP53.
These groups display distinct prognostic outcomes, clinical and pathological features.
Although prognosis is favorable for patients with early stage disease, outcomes are poor for
patients with recurrent or advanced disease. Numerous therapeutic options are available for
1

295

patients with recurrent or metastatic endometrial cancer, primarily focused on platinum-based
regimens. Carboplatin in combination with paclitaxel is the option of choice (5).
Recent years have witnessed the emergence of newer options for progressive disease, including
bevacizumab, pembrolizumab, lenvatinib, and everolimus/letrozole. These expanded options
have the potential to improve patient outcomes and provide more individualized care for patients
with advanced or recurrent endometrial cancer.
Patients with HER2-positive uterine serous carcinoma should be considered for the addition of
trastuzumab to platinum-based doublet chemotherapy, while those with low-grade endometrioid
histology may benefit from the use of hormone therapies.

Targeted Therapy
Antiangiogenic Therapies.
In patients with advanced endometrial cancers early research indicated that there is a role for
bevacizumab in certain subsets of patients, leading to phase 2 trials such as GOG-86P and MITO
END-2 with the goal of testing the effectiveness of bevacizumab in combination with
carboplatin/paclitaxel. (6,7). The GOG-86P trial, which also evaluated combinations with
temsirolimus, did not show a significant PFS benefit for the addition of bevacizumab to
platinum-doublet chemotherapy.(8). However, the ORR was 60% and median OS was
significantly increased compared with historical controls from the GOG209 study (HR 0.71; P <
.039). PFS was not significantly increased in any experimental arm compared to historical
controls.The MITO END-2 trial failed to demonstrate a significant PFS or OS benefit for
bevacizumab plus chemotherapy, although the rate of 6-month disease control was significantly
higher (91% vs 70%).(7) Current NCCN Guidelines® list bevacizumab alone as an option after
progression on chemotherapy or in combination with platinum-based chemotherapy for advanced
disease.(5). The multi-targeted tyrosine kinase inhibitors (TKIs) lenvatinib and cediranib have
also demonstrated efficacy in patients with advanced endometrial cancers.(9,10).
Inhibitors of HER2 and mTOR.
Uterine serous carcinomas are an aggressive variant of endometrial cancer and often have
dysregulated HER2 signaling, leading to investigation of trastuzumab in combination with
carboplatin/paclitaxel in this patient subset. A randomized phase 2 trial showed a 4.6-month
improvement in median PFS with the addition of trastuzumab to chemotherapy (HR 0.44; P =
.005) in patients with HER2-positive uterine serous carcinomas. The PFS benefit was consistent
in both treatment-naive and pretreated patients, and the combination was well tolerated.(11). The
phase 2 GOG-3007 trial compared hormone therapy alone with everolimus (an mTOR inhibitor)
plus letrozole in patients with advanced endometrial cancer and showed an improvement in
median PFS from 3.8 to 6.3 months.(12)
PFS benefit from everolimus/letrozole was particularly evident in patients who had received no
prior chemotherapy (median PFS: 21.6 months). This combination was well tolerated, although
2

296

rates of grade 3/4 anemia and hyperglycemia were increased compared with hormone therapy
alone.
Immunotherapy
Several checkpoint inhibitors have demonstrated some efficacy in patients with advanced
endometrial cancers.(13-20). Pembrolizumab has a tumor-agnostic approval for patients with
MSI-H or dMMR advanced solid tumors and is listed in current NCCN Guidelines® as an option
for advanced endometrial cancers. (5,21)
Another PD-1 inhibitor, dostarlimab (TSR-042), was evaluated in the phase 2 GARNET trial, in
advanced endometrial cancer. The ORR was 29.6% overall, but reached 48.8% in patients with
MSI-H tumors (compared with 20.3% for those with MSS tumors). A total of 85% of patients
with MSI-H endometrial cancer experienced a reduction in total tumor burden of over 50%. The
DCR was 63% for MSI-H tumors vs 46.8% for those with MSS tumors.(15) Responses were
durable in both cohorts, with 50% of responders remaining on therapy longer than 1 year.
Dostarlimab had a manageable safety profile and was most commonly associated with fatigue,
diarrhea, and nausea. Grade 3 or higher immune-mediated AEs only occurred in 5.6% of patients
and included increases in alanine aminotransferase and aspartate aminotransferase,
hyperglycemia, autoimmune hemolytic anemia, colitis, and infusion-related reaction.
A phase 2 study evaluated avelumab in patients with dMMR and those with proficient MMR
proteins.(22) The MMR-proficient cohort was closed early due to futility, while the dMMR
subgroup demonstrated an ORR of 26.7%. PFS at 6 months was 40%, and responses were
observed independent of PD-L1 expression. The most frequent any-grade treatment-related AEs
were fatigue, nausea, hypothyroidism, neutropenia, anemia, and diarrhea. Grade 3 AEs included
anemia and diarrhea, and no grade 4 toxicities were reported.
A phase 1b trial recently reported data on the activity of atezolizumab in patients with advanced
solid tumors, including 15 patients with recurrent or metastatic endometrial cancers. Benefit was
modest, with an ORR of 13%, median PFS of 1.4 months, and median OS of 9.6 months. Benefit
was more substantial in patients with high PD-L1 expression (n = 5), with an ORR of 40% and
median PFS and OS of 4.2 and 38.2 months, respectively.(23)
Combination regimens. Potential synergy between targeted agents and immunotherapies
continues to be explored based on the hypothesis that the action of targeted therapies may prime
the immune system, thus increasing the anti-immune response elicited by immunotherapies.[44]
Targeted agents may enhance immunotherapy activity by improving the function or activation of
immune cells, creating neoantigens, or eliciting immune cell infiltration of the tumor
microenvironment.
The KEYNOTE-146 trial investigated the co-inhibition of VEGF and PD-1 signaling by
combining these 2 agents, lenvantinib and pembrolizumab.(25) Lenvatinib plus pembrolizumab
had an ORR of 40% and a DCR of 87%. Responses were durable, with 65% having a response
lasting at least 12 months. The most common any-grade AEs were fatigue, hypothyroidism,
diarrhea, hypertension, decreased appetite, nausea, and stomatitis. The most frequent grade 3/4
3

297

side effects included hypertension, palmar-plantar erythrodysesthesia syndrome, and fatigue.
Based on these data, lenvatinib combined with pembrolizumab recently received accelerated
FDA approval for the treatment of patients with previously treated advanced endometrial
carcinoma that is not MSI-H or dMMR.(21) Also concidering AE patients should be monitored
regularly and educated regarding the potential for AEs to protect patient quality of life (QoL) and
avoid unnecessary treatment delays or interruptions.
Some others ongoing clinical trials continue to investigate immunotherapeutic combination
approaches for endometrial cancer, including combinations with chemotherapy such as phase 2
trial is evaluating pembrolizumab with carboplatin/paclitaxel in patients with advanced
endometrial carcinoma.(26) The phase 3 RUBY trial is directly comparing carboplatin/paclitaxel
with placebo or dostarlimab in patients with recurrent or primary advanced endometrial
cancer.(27) The phase 3 AtTEnd trial is evaluating atezolizumab plus carboplatin/paclitaxel in
patients with advanced or recurrent endometrial cancer.(28)
Another area of interest is the potential efficacy of combining immune checkpoint inhibitors with
inhibitors of poly(ADP-ribose) polymerase (PARP). Ongoing phase 2 trials are investigating
combinations such as olaparib/durvalumab (DOMEC trial), rucaparib/atezolizumab/bevacizumab
(EndoBARR trial), and niraparib/dostarlimab in patients with recurrent or metastatic endometrial
cancers.(29-31)
Highlights
Given the molecular subtypes of endometrial cancer outlined by TCGA, optimal patient selection
for emerging therapies is going to be paramount to ensuring patients receive the most effective
therapy without compromising safety and QoL.
Despite randomized phase II trials suggesting that adding bevacizumab to chemotherapy
carboplatin and paclitaxel in frontline endometrial cancer was feasible and may result in some
benefit, no randomized phase III trials have been conducted to confirm those results
Immune checkpoint inhibitors have shown efficacy in patients with recurrent MSI-H/dMMR
solid tumors, including endometrial cancers, with a prolonged duration of response in those who
respond
Single-agent immunotherapy with anti–PD-1 monoclonal antibodies, either dostarlimab or
pembrolizumab, is approved for patients with recurrent endometrial cancer with MSI-H/dMMR.
Still, experts suggest that adding lenvatinib to pembrolizumab monotherapy in patients with
MSI-H tumors is likely to result in added toxicity, but not meaningfully improve response
Response with single-agent pembrolizumab in MSI-H endometrial cancer in KEYNOTE-158 is
comparable to that of the combination of lenvatinib plus pembrolizumab in MSI-H/dMMR
endometrial cancers from KEYNOTE-146 (57.1% vs 63.6%)
Single-agent checkpoint inhibitor is the preferred choice in MSI-H/dMMR endometrial cancer
4

298

Also have to notice that many of the currently available therapies are associated with AEs that
can negatively affect patient QoL and lead to early treatment discontinuation. Unique targets
continue to be identified, and ongoing clinical trials will hopefully elucidate promising therapies
to improve survival and QoL for patients with advanced disease.

References:
1. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries
2. World Health Organization International Agency for Research on Cancer (IARC).
GLOBOCAN 2020: Corpus uteri fact sheet. [homepage on the internet]; 2020 [cited 2032
Apr 23]. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/24-Corpusuteri-fact-sheet.pdf
3. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated
genomic characterization of endometrial carcinoma. Nature 2013; 497: 67-73.
4. Di Tucci C, Capone C, Galati G, et al. Immunotherapy in endometrial cancer: new
scenarios on the horizon. J Gynecol Oncol. 2019;30:e46.
5. National Comprehensive Cancer Network. Clinical practice guidelines in oncology.
Uterine
neoplasms.
Version
5.2019.
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed February 10,
2020.
6. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or
persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol.
2011;29:2259-2265.
7. Lorusso D, Ferrandina G, Colombo N, et al. Carboplatin-paclitaxel compared to
carboplatin-paclitaxel-bevacizumab in advanced or recurrent endometrial cancer: MITO
END-2 - a randomized phase II trial. Gynecol Oncol. 2019;155:406-412.
8. Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline
paclitaxel/carboplatin/bevacizumab,
paclitaxel/carboplatin/temsirolimus,
or
ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol
Oncol. 2018;150:274-281.
9. Vergote I, Powell MA, Teneriello MG, et al. Second-line lenvatinib in patients with
recurrent endometrial cancer. Gynecol Oncol. 2020. doi: 10.1016/j.ygyno.2019.12.039.
[Epub ahead of print]
10. Bender D, Sill MW, Lankes HA, et al. A phase II evaluation of cediranib in the treatment
of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology
Group study. Gynecol Oncol. 2015;138:507-512.
11. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel
versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress
human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36:2044-2051.
12. Slomovitz BM, Filiacic VL, Coleman RL, et al. GOG 3007, a randomized phase II (RP2)
trial of everolimus and letrozole (EL) or hormonal therapy (medroxyprogesterone
5

299

acetate/tamoxifen, PT) in women with advanced, persistent or recurrent endometrial
carcinoma (EC): a GOG Foundation study. Presented at: 49th Annual Meeting of the
Society of Gynecologic Oncology; March 24-27, 2018; New Orleans, LA. Abstract 1.
13. Ott PA, Bang YJ, Berton-Riqaud D, et al. Safety and antitumor activity of
pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer:
results from the KEYNOTE-028 study. J Clin Oncol. 2017;35:2535-2541.
14. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with
noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results
from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1-10.
15. Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and
pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical
trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or
advanced MSI-H and MSS endometrial cancer. Presented at: 50th Annual Meeting of the
Society of Gynecologic Oncology; March 16-19, 2019; Honolulu, HI. Abstract 33.
16. Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repairdeficient noncolorectal cancers: results from arm Z1D-A subprotocol of the NCIMATCH (EAY131) study. J Clin Oncol. 2020;38:214-222.
17. Konstantinopoulos PA, Luo W, Liu JF, et al. Phase II study of avelumab in patients with
mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial
cancer. J Clin Oncol. 2019;37:2786-2794.
18. Antill YC, Kok PS, Robledo K, et al. Activity of durvalumab in advanced endometrial
cancer (AEC) according to mismatch repair (MMR) status: the phase II PHAEDRA trial
(ANZGOG1601). J Clin Oncol. 2019;37(suppl): Abstract 5501.
19. Fleming GF, Emens LA, Eder JP, et al. Clinical activity, safety and biomarker results
from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer
(rEC). J Clin Oncol. 2017;35(suppl): Abstract 5585.
20. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients
with advanced endometrial cancer: an interim analysis of a multicentre, open-label,
single-arm, phase 2 trial. Lancet Oncol. 2019;20:711-718.44.
21. KEYTRUDA (pembrolizumab) [prescribing information]. Whitehouse Station, NJ:
Merck & Co., Inc.; Approved 2014. Revised January 2020.
22. Konstantinopoulos PA, Luo W, Liu JF, et al. Phase II study of avelumab in patients with
mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial
cancer. J Clin Oncol. 2019;37:2786-2794.
23. Fleming GF, Emens LA, Eder JP, et al. Clinical activity, safety and biomarker results
from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer
(rEC). J Clin Oncol. 2017;35(suppl): Abstract 5585.
24. Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy
combinations for the treatment of cancer. Trends Immunol. 2016;37:462-476.
25. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients
with advanced endometrial cancer: an interim analysis of a multicentre, open-label,
single-arm, phase 2 trial. Lancet Oncol. 2019;20:711-718.44.
6

300

Pembro/carbo/taxol
in
endometrial
cancer.
26. Clinicaltrials.gov.
https://clinicaltrials.gov/ct2/show/NCT02549209. Accessed February 26, 2020.
27. Clinicaltrials.gov. A study of dostarlimab (TSR-042) plus carboplatin-paclitaxel versus
placebo plus carboplatin-paclitaxel in patients with recurrent or primary advanced
endometrial cancer (RUBY). https://clinicaltrials.gov/ct2/show/NCT03981796. Accessed
February 26, 2020.
28. Clinicaltrials.gov. Atezolizumab trial in endometrial cancer - AtTEnd (AtTEnd).
https://clinicaltrials.gov/ct2/show/NCT03603184. Accessed February 26, 2020.
29. Clinicaltrials.gov. Durvalumab and olaparib in metastatic or recurrent endometrial cancer
(DOMEC). https://clinicaltrials.gov/ct2/show/NCT03951415. Accessed February 27,
2020.
30. Clinicaltrials.gov. The EndoBARR trial (Endometrial Bevacizumab, Atezolizumab,
Rucaparib) (EndoBARR). https://clinicaltrials.gov/ct2/show/NCT03694262. Accessed
February 27, 2020.
31. Clinicaltrials.gov. Study of niraparib and TSR-042 in recurrent endometrial cancer.
https://clinicaltrials.gov/ct2/show/NCT03016338. Accessed February 27, 2020.

7

301

The Early and locally advanced hormone dependant
Breast cancer – where do we stand?

Semir Beslija
Oncology Division
KCUS

EARLY BREAST CANCER: WHO NEEDS ADJUVANT ET?

•

(almost) All ER+ EARLY BREAST CANCER patients!

302

Identifying Patients at Biological High Risk for
Recurrence
Genomic features

Proliferation features

 Gene expression assays

 Ki-67 by immunohistochemistry

– 21-gene (Oncotype DX)
– 70-gene (MammaPrint)

– Cutoff values of High vs Low

WSG PlanB Trial: DFS by Oncotype RS and Ki-67
DFS in HR+/Ki-67 >10% and <40%

80
60
40

RS Group
RS 0-11
20
RS 12-25
RS >25

0

0

12

24

36
Mo

48

60

DFS by Ki-67 Expression Levels: HR+

100
Disease-Free Survival

Disease-Free Survival

100

PlanB: DFS by Ki-67[a]
80
60
40

HR+/Ki-67 0-10%
HR+/Ki-67 >10% - <40%
HR+/Ki-67 ≥40%
HR-/HER2-

20
0

72

0

12

24

36
Mo

48

60

72

Nitz. Breast Cancer Res Treat. 2017;165:573.

TAILORx: Treatment Assignment and Randomization
 Randomized, parallel-assignment phase III study

Patients with
node-negative
HR+, HER2-,
breast cancer
T1c-T2 (high-risk T1b)
(N = 10,273)

Stratified by RS (11-15, 16-20, 2125), menopausal status (pre vs
post), planned chemotherapy
(taxane vs not), and planned
radiation

Baseline biopsy
evaluated for
RS
(Oncotype DX)

RS ≤10

Arm A: ET Alone
(n = 1629)
Arm B: ET Alone
(n = 3399)

RS 11-25
Arm C: ET + Chemotherapy
(n = 3312)

9719 patients
randomized
RS ≥26

Statistical Design
Noninferiority - iDFS
Hazard Ratio: 1.332
(90 vs. 87% 5-yr DFS)
Type I 10%, type II
5%
Full info: 835 iDFS
events

Arm D: ET + Chemotherapy
(n = 1389)

 Primary endpoint: iDFS, secondary primary cancer, or death
 Key secondary endpoints: freedom from breast cancer recurrence at distant site, freedom
from breast cancer recurrence at distant or local-regional site, OS
NCT00310180. Sparano. NEJM. 2018;379:111

303

TAILORx: ITT Population—RS 11-25 (Arms B & C)
 836 iDFS events (after median of 7.5 yr), including 338 (40.4%) with recurrence as
first event, of which 199 (23.8%) were distant

DFS Probability

1.0

Distant Recurrence-Free
Probability

Primary Endpoint
Invasive Disease–Free Survival

0.8 P =.26
Hazard ratio, ET alone vs CT + ET:
0.6 1.08 (95% CI: 0.94-1.24)

0.4
0.2
0

Patients at 0
Risk, n
CT + ET 3312
ET alone 3399

CT + ET
ET alone

12

24

36

48 60
Mo

72

84

96 108

3204
3293

3104
3194

2993
3081

2849
2953

2335
2431

1781
1859

1130
1197

2645
2741

523
537

Secondary Endpoint
Distant Relapse-Free Interval

1.0
0.8 P =.48

Hazard ratio, ET alone vs CT + ET:

0.6 1.10 (95% CI: 0.85-1.41)
0.4
0.2
0

Patients at 0
Risk, n
CT + ET 3312
ET alone 3399

CT + ET
ET alone

5

12

24

36

48 60
Mo

72

84

96 108

3215
3318

3142
3239

3059
3147

2935
3033

2432
2537

1866
1947

1197
1267

2734
2833

554
581

Sparano. NEJM. 2018;379:111.

RxPONDER: Adjuvant ET ± Chemotherapy in HR+/HER2EBC With 1-3 Positive Lymph Nodes and RS ≤25
 Randomized phase III trial
Stratified by RS (0-13 vs 14-25), menopausal status
(pre vs post), axillary surgery (ALND vs SLNB)

Adults with HR+/HER2- EBC and
1-3 positive LN without distant mets*;
able to receive adjuvant taxane
and/or anthracycline-based CT†;
axillary staging by SLNB or ALND;
RS 0-25‡
(N = 5015)

Chemotherapy Followed by ET
(n = 2509)
ET Alone
(n = 2506)

Baseline
characteristics
generally well
balanced between
treatment arms

*Protocol amended to exclude patients with pN1mic as only nodal disease after 2493 patients
randomized. †Approved CT regimens: TC, FAC (or FEC), AC/T (or EC/T), FAC/T (or FEC/T); AC alone or
CMF not allowed. ‡Patients with RS > 25 recommended to be treated with CT followed ET off study.

 Primary endpoint: iDFS
 Key secondary endpoints: OS, distant DFS, local DFI, toxicity, QoL
Kalinsky. SABCS 2020. Abstr GS3-00.

304

RxPONDER: iDFS (Primary Endpoint)
 In this population of node positive,
hormone receptor–positive BC with RS
0-25, RS did not predict relative CT
benefit for iDFS

iDFS in Overall Population
iDFS Probability

1.0

‒ HR: 1.02 (95% CI: 0.98-1.06; P = .30)

 CT use and RS independently prognostic
for iDFS
‒ iDFS events less likely among patients
who received CT

0.8
CT + ET
(n = 2509)

0.6
Events

198

249

5-yr iDFS, %

92.4

91.0

0.4
0.2
0

ET
(n = 2506)

Absolute difference, %
1.4
HR: 0.81 (95% CI: 0.67-0.98; P = .026)

0

1

2

3

4

5

6

7

Patients at
Yr Since Randomization
Risk, n
CT + ET 2509 2277 2104 1893 1648 1397 857 403
ET 2506 2327 2161 1910 1696 1404 846 397

‒ HR: 0.81 (95% CI: 0.67-0.96; P = .026)

‒ iDFS events more likely among patients
with higher RS

8

9

122
135

4
11

 At median follow-up of 5.1 yr, 447 iDFS
events were observed (54% of expected
at final analysis)

‒ HR: 1.06 (95% CI: 1.04-1.07; P <.001)
Kalinsky. SABCS 2020. Abstr GS3-00.

RxPONDER: iDFS by Menopausal Status
Postmenopausal

Premenopausal
1.0

0.8
CT + ET
(n = 1675)

0.6

0.2
0

ET
(n = 1675)

Events

147

158

5-yr iDFS, %

91.6

91.9

0.4

Absolute difference, %

iDFS Probability

iDFS Probability

1.0

NS

HR: 0.97 (95% CI: 0.78-1.22; P = .82)

0

1

2

3 4 5 6 7
Yr Since Randomization

Patients at
Risk, n
CT + ET 1675 1514 1400 1268 1113
ET 1675 1567 1462 1308 1167

943
975

585
601

287
298

8

9

88
104

3
9

0.8
CT + ET
(n = 834)

0.6
Events

0.4

5-yr iDFS, %

0.2
0

ET
(n = 831)

51

91

94.2

89.0

Absolute difference, %

5.2

HR: 0.54 (95% CI: 0.38-0.76; P = .0004)

0

Patients at
Risk, n
CT + ET 834
ET 831

1

2

3 4 5 6 7
Yr Since Randomization

763
760

704
699

625
602

535
529

454
429

272
245

116
99

8

9

34
31

1
2

 Absolute difference in distant recurrence as
first site: 2.9% (3.1% CT + ET vs 6.0% ET)

 Absolute difference in distant recurrence as
first site: 0.3% (2.3% CT + ET vs 2.6% ET)
Kalinsky. SABCS 2020. Abstr GS3-00.

305

Chemotherapy for ER+/HER2- BC With 0-3 LN
RS 0-10

RS 11-15

RS 16-20

RS 21-25

RS ≥26

Postmenopausal
LN positive
LN negative
Premenopausal
LN positive

▲ 6.2% (RS 14-25)

▲ 3.9% (RS 0-13)

LN negative
Low Clin Risk

▲ 0.2%

▲ 6.4%

High Clin Risk

▲ 6.5%

▲ 8.7%

ET alone

CT (discuss OFS + AI as
alternative)

CT + ET

▲ Denotes benefit (dDFS for LN- and iDFS for LN+) with addition of CT
Kalinsky. SABCS 2020. Abstr GS3-00. Sparano. NEJM. 2019;380:2395.

ADAPT HR+/HER2-: Adjuvant ET ± Chemotherapy in
Intermediate/High-Risk, HR+/HER2- Luminal EBC
 2-part, prospective phase III trial
‒ Part 1: Current analysis evaluated prognostic impact of RS <26 and Ki-67 decrease after shortcourse of preoperative ET in the ET alone arm and is not a randomized comparison
Adult patients
with HR+/HER2unilateral luminal EBC;
cT1-4c, cN0-3;
candidates for adjuvant CT
by conventional
prognostic criteria*
(N = 4691)

Baseline biopsy evaluated
for RS (Oncotype DX) and
Ki-67 expression; surgical
specimen evaluated for
Ki-67 expression† after
short ET run-in

*cT2 or G3 or Ki-67 ≥15% or <35 yr old or cN+.
†Ki-67
post ≤10% = ET response.

 Primary endpoint: 5-yr iDFS
‒ Part 1: NI* for pN0-1/RS 12-25/Ki-67post
≤10% vs pN0-1/RS 0-11
Harbeck. SABCS 2020. Abstr GS4-04.

 pN2-3
 pN0-1/RS >25
 pN0-1/RS 12-25/
Ki-67post > 10%

CT Followed by ET
(n = 2335)

 pN0-1/RS 12-25/
Ki-67post ≤10%
 pN0-1/RS 0-11

ET Alone
(n = 2356)

 Key secondary endpoints: dDFS, OS,
translational research

*NI defined as ≤3.3% 1-sided 95% CL of 5-yr iDFS
difference (α = .05, 80% power; 5% dropouts)

306

ADAPT HR+/HER2-: 5-Yr iDFS (Primary Endpoint)
 Primary endpoint met

100

─ 5-yr iDFS difference: -1.3%
(95% CI: -3.3% to 0.6%)

iDFS (%)

80
5-Yr iDFS, %
(95% CI)
RS 0-11 93.9 (91.8-95.4)
RS 12-25/Ki-67 ≤10% 92.6 (90.8-94.0)

60
40

─ 95% lower confidence limit of
-3.3% met prespecified criterion for
noninferiority of pN0-1/RS 12-25/
Ki-67post ≤10% vs pN0-1/RS 0-11
(P = .05)

20
0

0

Patients at Risk, n
RS 0-11 865
RS 12-25/Ki-67 ≤10% 1414

12
796
1289

24
36
Follow-up (Mo)
705
1124

657
1019

48

60

603
938

431
671

 5-yr OS rate
─ 97.3% for pN0-1/RS 12-25/Ki-67
≤10% vs 98.0% for pN0-1/RS 0-11
(P = .160)

Harbeck. SABCS 2020. Abstr GS4-04.

Treatment De-Escalation Strategies in HR+/HER2- EBC:
Summary
TAILOR-x :In LN-negative breast cancer:



‒ Age >50 yr: RS ≤25 have no chemotherapy benefit
‒ Age ≤50 yr: RS 16-25 may derive chemotherapy benefit
RxPONDER: analysis of adj CT for HR+/HER2- EBC with 1-3 positive nodes and RS ≤25, postmenopausal
women did not benefit, whereas premenopausal women did1



‒ Premenopausal patients experienced a 46% decrease in iDFS events and a 53% decrease in deaths, leading
to a 5-yr OS absolute improvement of 1.3%


ADAPT HR+/HER2-: primary endpoint reached: patients with luminal EBC and 0-3 positive nodes, RS 12-25 and
endocrine response
(Ki-67post ≤10%)2 after short preoperative ET had a 5-yr iDFS (92.6%) comparable
to those with 0-3 LN and RS 0-11 (93.9%)


Outcome was excellent in both groups with adj ET alone: 5-yr dDFS (95.6% vs 96.3%) and 5-yr OS (97.3% vs
98.0%)

1. Kalinsky. SABCS 2020. Abstr GS3-00. 2. Harbeck. SABCS 2020. Abstr GS4-04.

307

Is There a Role for CDK4/6 Inhibition for
Early-Stage HR+ Disease?
PENELOPE-B
palbociclib

Estimated Annual Hazard Rate

Risk of First Recurrence After Primary Treatment
0.25

Stage

I

II

After neoadjuvant,
high risk

III

0.20

monarchE

0.15

abemaciclib
High-risk CPR factors, Ki-67

0.10

PALLAS
palbociclib

0.05

Stage II, III

0
0

2

4

6

8

10

Follow-up Time After Primary Diagnosis of
Breast Cancer (Yr)

NATALEE
ribociclib
Stage II, III

Cheng. Cancer Epidemiol Biomarkers Prev. 2012;21:800.

PALLAS: Phase III Open-Label Study of
Adjuvant Palbociclib + Endocrine Therapy
 Multicenter, open-label, randomized phase III trial
Stratified by stage (IIA vs IIB/III), chemotherapy
(yes vs no), age (≤50 vs >50 yr), geographic
region (N America vs Europe vs other)

Palbociclib x 2 yr*+
Endocrine therapy†
(n = 2883)

Patients with stage II-III HR+/HER2breast cancer; completion of prior
surgery, ± CT, RT within 12 mo of
diagnosis or within 6 mo of starting
adjuvant endocrine treatment;
FFPE tumor block submitted
(N = 5760)

Endocrine therapy†
(n = 2877)
*125 mg QD, 3 wk on/1 wk off †Aromatase
inhibitor or tamoxifen ± LHRH agonist.

 Primary endpoint: invasive disease–free survival
Mayer. ESMO 2020. Abstr LBA12. Mayer. Lancet Oncol. 2021;22:212.

308

PALLAS: Primary Endpoint iDFS
iDFS
100

100

90

90

80

80

60
50
40
30
20

iDFS

Palbociclib + ET

ET Alone

88.2%

88.5%

70

DRFS (%)

70

iDFS (%)

DRFS

Hazard ratio: 0.93 (95% CI: 0.76-1.15; P = .51)

Arm
Events
Palbociclib + ET 170
ET
181

10 P = .51
Hazard ratio: 0.93 (95% Cl: 0.76-1.15)
0
0
6
12
18

60
50

20

0
36

90.7%

P = .9997
Hazard ratio: 1.00 (95% Cl: 0.79-1.27)

10
30

ET Alone

89.3%

Arm
Events
Palbociclib + ET 136
135
ET

30

24

Palbociclib + ET

Hazard ratio: 1.00 (95% CI 0.79-1.27; P = .9997

40

Mo From Randomization


DRFS

0

6

12

18

24

30

Mo From Randomization

At a median follow-up of 23.7 mo, no significant difference in either 3-yr iDFS or DRFS was observed

Mayer. ESMO 2020. Abstr LBA12. Mayer. Lancet Oncol. 2021; 22:212.

monarchE: Adjuvant Abemaciclib + ET in High-Risk,
Node-Positive, HR+/HER2- EBC
 International, randomized, open-label phase III trial
ITT Population (Cohorts 1 + 2)
Women or men with high-risk,
node-positive, HR+/HER2- EBC;
prior (neo)adjuvant CT permitted;
pre- or postmenopausal
no distant metastasis;
≤16 mo from surgery to
randomization; ≤12 wk of ET after
last non-ET
(N = 5637)

Stratified by prior CT, menopausal
status, region

Cohort 1
≥4 positive ALN or 1-3 positive
ALN plus histologic grade 3
and/or tumor ≥5 cm

Abemaciclib 150 mg BID up to 2 yr +
ET per standard of care of physician’s
choice for 5-10 yr as clinically indicated
(n = 2808)

Cohort 2
1-3 positive ALN, Ki-67 ≥20%
per central testing, not grade
3, tumor size <5 cm

ET per standard of care of physician’s
choice for 5-10 yr as clinically indicated
(n = 2829)

 Primary endpoint: iDFS
‒ Planned for after ~390 iDFS events (~85% power, assumed iDFS hazard ratio of 0.73, cumulative 2-sided
α = 0.05)
‒ Current primary outcome efficacy analysis occurred after 395 iDFS events in ITT population

 Key secondary endpoints: iDFS in Ki-67 high (≥20%) population, distant RFS, OS, safety, PRO, PK
Johnston. JCO. 2020;38:3987. Rastogi. SABCS 2020. Abstr GS1-01.

309

36

iDFS (%)

monarchE: iDFS (Primary Endpoint)
100
90
80
70
60
50
40
30
20
10
0

Median f/u: 19.1 mo in both arms.
Curves should not be interpreted
beyond 24 mo due to limited f/u.

0

Patients
at Risk, n
Abe + ET 2808
ET 2829

Abemaciclib + ET
(n = 2808)

ET
(n = 2829)

Events, n

163

232

2-yr iDFS, %

92.3

89.3

Hazard ratio: 0.713 (95% CI: 0.583-0.871; P = .0009)

3

6

9

12

15

2680
2700

2619
2653

2573
2609

2519
2548

2076
2093

18

21

24

27

30

33

36

1487
1499

1029
1033

619
627

133
131

94
102

1
0

0
0

Mo

Johnston. JCO. 2020;38:3987. Rastogi. SABCS 2020. Abstr GS1-01.

Why Did MonarchE Succeed Where PALLAS Failed?
MonarchE iDFS

PALLAS iDFS
100
90

iDFS (%)

80
70
60

Palbociclib + ET

ET Alone

88.2

88.5

3-yr iDFS, %

50

HR: 0.93 (95% CI: 0.76-1.15; log-rank P = .51)

40

Event, n
Palbociclib + ET 170
ET
181

30
20
10

Log-rank P = .51

0
0

Patients at Risk, n
Palbociclib + ET 2883
ET 2877

6
2634
2649

12

18

24

30

36

2563
2535

1946
1953

1257
1295

583
574

163
172

Mo From Randomization

Differences between the drugs themselves/drug exposure and discontinuations/
level of risk within patient populations?
Johnston. JCO. 2020;38:3987. Mayer. ESMO 2020. Abstr LBA12. Mayer. Lancet Oncol. 2021;22:212.

310

monarchE NAC Subgroup Analysis: Prior NAC Regimen
Prior NAC
Regimen, n (%)

Abemaciclib +
ET
(n = 1025)

ET Alone
(n = 1031)

Anthracycline +
taxane

903 (88.1)

931 (90.3)

Anthracycline
without taxane

71 (6.9)

59 (5.7)

Taxane +
cyclophosphamide

28 (2.7)

23 (2.2)

Other*

23 (2.2)

18 (1.7)

 NAC subgroup comprised 36%
of ITT population
 Most patients received standard
NAC regimen of anthracycline +
taxane
‒ Use of standard NAC regimen
was consistent between
treatment arms

*Includes taxane only, cyclophosphamide only, other CT.

Martin. ASCO 2021. Abstr 517.

monarchE NAC Subgroup Analysis: iDFS
(Primary Endpoint)
100

iDFS (%)

80

NAC Subgroup

60

Abemaciclib +
ET

ET
Alone

92

148

iDFS events, n

40

HR (95% CI)

20
0

0.614 (0.473-0.797;
nominal P = .0002)

2-yr iDFS
rate, %

87.2

Abemaciclib + ET
ET alone

ITT Population
Abemaciclib +
ET

ET
Alone

--

--

0.713 (0.583-0.871)

80.6

--

--

Difference: 6.6%

0

Patients at Risk, n
Abemaciclib + ET 1025
ET alone 1031

3

6

9

12

15

976
971

948
948

922
923

904
891

728
717

 In the NAC subgroup, abemaciclib + ET
demonstrated a clinically meaningful 38.6%
reduction in risk of an iDFS event vs ET alone

18
Mos
500
499

21

24

27

30

33

36

347
334

203
194

43
33

29
23

1
0

0
0

 The 2-yr iDFS rate was higher with
abemaciclib + ET vs ET alone in the NAC
subgroup (87.2% vs 80.6%; difference: 6.6%)

Martin. ASCO 2021. Abstr 517. Reproduced with permission.

311

monarchE NAC Subgroup Analysis: Conclusions
 In this preplanned subgroup analysis of the monarchE trial, abemaciclib + adjuvant ET
demonstrated clinically meaningful improvements in iDFS and distant RFS vs ET alone in
patients with high-risk HR+/HER2- EBC who received prior NAC1
‒ Reduction in risk: iDFS, 38.6%; distant RFS, 39.1%
‒ Benefits were numerically greater than those observed in ITT population and were maintained
independent of tumor size at diagnosis and surgery

 Among those treated with ET alone, the NAC subgroup exhibited a lower 2-yr iDFS rate vs
the ITT population consistent with a higher risk of recurrence1-3
‒ 2-yr iDFS rate comparable to that reported in control arm of phase III PENELOPE-B trial, which
compared palbociclib + ET vs placebo + ET in women with high-risk HR+/HER2- EBC after NAC4

 Safety profile in this population consistent with prior reports for abemaciclib1
21

1. Martin. ASCO 2021. Abstr 517. 2. Rastogi. SABCS 2020. Abstr GS1-01. 3. Johnston. JCO. 2020;38:3987.
4. Loibl. JCO. 2021;39:1518.

PENELOPE-B: Palbociclib + ET in HR+/HER2- BC at
High Risk of Relapse After Neoadjuvant Chemotherapy
 Randomized, double-blind, placebo-controlled phase III trial
Stratified by age (≤50 vs >50 yr), nodal status (ypN0-1 vs ypN2-3), Ki-67
(>15% vs ≤15%), region (Asia vs non-Asia), and CPS-EG score (≤3 vs 2 and ypN+)

Adult patients with confirmed
HR+/HER2- BC with residual
disease after ≥16 wk of
neoadjuvant CT*;
CPS-EG score ≥3 or
2 with ypN+
(N = 1250)

Palbociclib 125 mg QD Days 1-21
28-day cycles x 13
+ ET by local standard
(n = 631)

Surgery ±
radiotherapy†

Placebo QD Days 1-21
28-day cycles x 13 +
+ ET by local standard
(n = 619)

*Includes 6 wk of taxanes.
†Time between locoregional
therapy and randomization:
<16 wk from final surgery or
<10 wk from RT completion.

 Primary endpoint: iDFS
 Secondary endpoints include: iDFS excluding second primary invasive non-breast cancers,
distant DFS, locoregional RFS, OS, safety, compliance, QoL
Loibl. JCO 2021;10:1200.

312

PENELOPE-B: iDFS (Primary Endpoint)
2-Yr iDFS
88.3% 3-Yr iDFS
81.2% 4-Yr iDFS
73.0%
84.0%
77.7%
72.4%

100

iDFS (%)

80
60

 Median f/u: 42.8 mo
 Types of iDFS events
– 74% distant recurrences
– 116 with palbociclib,
111 with placebo

iDFS
Events, n
Palbociclib + ET
152
Placebo + ET
156

40

– 16% invasive
locoregional recurrences

Hazard ratio: 0.93 (95% CI: 0.74-1.17; P = .525)

20

– 21 with palbociclib,
27 with placebo

+ Censored

0
Patients at
0
Risk, n
Palbociclib 631
Placebo 619

12
571
553

24

36

48

60

72

528
497

Mo
389
349

169
161

38
24

0
1

Loibl. JCO 2021;10:1200.

CDK4/6 Inhibition in High-Risk HR+/HER2- EBC:
Summary
 monarchE: In a preplanned interim analysis, adj abemaciclib + ET continued to
demonstrate improved iDFS vs ET alone for HR+/HER2- EBC at high risk of relapse after
locoregional tx and/or (neo)adj CT (hazard ratio: 0.75; 95% CI: 0.60-0.93; P = .01)1,2
‒ 2-yr iDFS rates: 92.2% with abemaciclib + ET vs 88.7% with ET
‒ Significant iDFS improvement observed in Ki-67 high (≥20%) tumors
‒ Distant RFS also improved (hazard ratio: 0.72; 95% CI: 0.56-0.92; P = .01), with 2-yr distant
RFS rates of 93.6% vs 90.3%, respectively

 PENELOPE-B: In the first interim analysis, the addition of 1 yr of adjuvant palbociclib to
ET in the curative setting failed to demonstrate a benefit in patients with higher-risk
HR+/HER2- EBC after locoregional tx and neoadjuvant CT3

1. Johnston. JCO. 2020;38:3987. 2. Rastogi. SABCS 2020. Abstr GS1-01. 3. Loibl. SABCS 2020. Abstr GS1-02.

313

Why Different Outcomes Across These Trials
(or Are There)?


Different definitions of high risk?
‒



Was there more luminal B (high proliferation) in monarchE than in PALLAS or PENELOPE-B?

Differences in therapy adherence?
‒ May explain PALLAS results but adherence much higher in PENELOPE-B (though shorter
duration of therapy with only 1 yr)



Is abemaciclib a more effective CDK inhibitor?
‒ Possible, although not supported by metastatic first-line trials that have remarkably similar
hazard ratios (continuous dosing, more potent inhibition of CDK4, monotherapy activity)



Durations of CDK inhibitor therapy?
‒ Possible PENELOPE-B would have been positive if palbociclib had been given for longer
‒ Await NATALEE results with 3 yr of ribociclib

O’Regan. SABCS 2020. Abstr GS1-03.

Why Should Neoadjuvant Endocrine Therapy Be Given?
 Down-stage tumor prior to surgery
‒ NET and chemotherapy have similar rates of clinical response, radiographic response,
and rates of BCS, but lower rates of toxicity
‒ AI superior to tamoxifen in terms of clinical response, radiographic response, and rates
of BCS
‒ Longer duration of NEC allows for higher rates of BCS and pCR

 Identify HR+ tumors that may not require chemotherapy
 Gain insights into the biology of the tumors
‒ Biomarkers response/resistance to treatment
‒ Predict phase III trial results
Barchiesi. Int J Mol Sci. 2020;21:3528.

314

No Significant Improvement in ORR/BCS With
Neoadjuvant Chemotherapy vs Endocrine Therapy
Objective
Response

Breast Cancer
Survival

3 mo

Objective
response by
clinical palpation

A: 63%
B: 64%

A: 24%
B: 33%
P = .058
(statistically
significant)

GEICAM 2006-03

A: CT
(EC -> doxetaxel)
B: Exe (+ goserelin if
premenopausal)

--

Response rate by
MRI

A: 66%
B: 48%

A: 47%
B: 56%

NEO CENT

A: CT (n = 22)
B: Letrozole (n = 22)

18-23 wk

Recruitment
feasibility and
tissue collection

A: 54%
B: 59%

--

A: CT (n = 53)
B: Letrozole/ palbociclib (n = 53)

20 wk

Residual cancer
burden index

A: 76%
B: 75%

A: 69%
B: 69%

Trial

Treatment Arm

Duration

Primary Endpoint

Semiglazov et al.

A: CT (n = 118)
(dox + paclitaxel)
B: ET (total n = 121)
Ana (n = 60) + Exe (n = 61)

UNICANCER-NEO Pal

Reinert. Curr Treat Options Oncol. 2018;19:23.

Neoadjuvant ET vs CT: Systematic Review/
Meta-analysis of 20 RCTs Through 2015 (N = 3490)
 AIs showed significantly higher rates of clinical response, radiologic response, and BCS vs tamoxifen;
radiologic response rate higher with CT + ET vs ET
Clinical Response
Source

Favors Favors
Endocrine Chemotherapy

OR (95% CI)

Pathologic CR
Source

Alba 2012

2.11 (0.92-4.82)

Alba 2012

Palmieri 2014

0.34 (0.6-1.98)

Palmieri 2014

Semiglazov 2007

0.93 (0.55-1.57)

Semiglazov 2007

1.84 (0.53-6.47)

Total

1.08 (0.50-2.35)

Total

1.99 (0.62-6.39)

Heterogeneity: x22 = 4.47 (P = .11), I2 = 55%.
Test for overall effect: z = 0.19 (P = .85).

0.01

Radiologic Response
Source

0.1
1.0
10
OR (95% CI)

100

Favors
Chemotherapy

3.13 (0.12-78.77)
Not estimated

Heterogeneity: x22 = 0.09 (P = .76), I2 = 0%.
Test for overall effect: z = 1.16 (P = .25).

0.01

0.1
1.0
10
OR (95% CI)

100

0.01

0.1
1.0
10
OR (95% CI)

100

Breast Conservation Response

OR (95% CI)

Alba 2012

2.11 (0.92-4.82)

Source

Palmieri 2014

0.83 (0.25-2.74)

Alba 2012

0.68 (0.30-1.54)

Semiglazov 2007

1.28 (0.77-2.14)

Semiglazov 2007

0.63 (0.36-1.11)

Total

1.38 (0.92-2.07)

Total

0.65 (0.41-1.03)

Heterogeneity: x22 = 1.77 (P = .41), I2 = 0%
Test for overall effect: z = 1.54 (P = .12)

Favors
Endocrine

OR (95% CI)

0.01

0.1
1.0
10
OR (95% CI)

100

OR (95% CI)

Heterogeneity: x22 = 0.03 (P = .87), I2 = 0%
Test for overall effect: z = 1.83 (P = .07)

Spring. JAMA Oncol. 2016;2:1477.

315

Summary of Endocrine Therapy Alone
 Neoadjuvant endocrine therapy yields similar ORR response to
chemotherapy
‒ AI > tamoxifen in terms of ORR and BCS

 Endpoints of trials in ER+ breast cancer challenging
‒ Achievement of pCR rare (<5%)
‒ Use of Ki67 and PEPI may correlate with long-term outcome and may
allow triage of patients with no drop in Ki67 to chemotherapy
‒ ALTERNATE: fulvestrant = AI = AI + fulvestrant in terms of Ki67 response,
PEPI; long-term outcomes are awaited

neoMONARCH: Neoadjuvant Abemaciclib, Anastrozole,
and Abemaciclib + Anastrozole in HR+/HER2- BC
 RNAseq analysis of biopsy samples from multicenter, randomized, open-label
phase II trial
2-wk lead-in

Postmenopausal
women with stage I-IIIB
HR+/HER2- BC

B
I
O
P
S
Y

14 wk

Abemaciclib + ANZ
(n = 11)*

B
I
O
P
S
Y

Abemaciclib
(n = 21)
ANZ
(n = 17)

Abemaciclib + ANZ
(n = 10)
Abemaciclib + ANZ
(n = 16)
Abemaciclib + ANZ
(n = 17)

B
I
O
P
S
Y

n=8
n=9
n=9

n = number of biopsy samples.

 Primary endpoint: percent change in Ki67 from baseline to 2 wk of treatment
 Secondary endpoints: pCR, OR, radiologic response
Hurvitz. Clin Cancer Res. 2020;26:566.

316

neoMONARCH: Antiproliferative Effects of Abemaciclib,
Anastrozole, and Combination Tx on HR+/HER2- BC
Response per CCCA (Ki67 ≤2.7%) at Wk 2

-20
-40
-60
-80
-100

Outcome, %

Abema
+ ANZ

Abema

ANZ

Geometric
mean change
in Ki67
at 2 wk

-93

-91

-63

40

CCCA

68

58

14

20

 ORR: 46% (5% CR,
42% PR)

100

0
Patients With Tumors Exhibiting
CCCA (%)

Geometric Mean Change in Ki67 (%)

Change in Ki67 From BL to 2 Wk

P <.001
P <.001

80
60

0
P <.001
P <.001

Abemaciclib + ANZ (n = 59)
Abemaciclib (n = 52)
ANZ (n = 56)

Abemaciclib + ANZ (n = 40)
Abemaciclib (n = 30)
ANZ (n = 8)

 pCR: 4%

Hurvitz. Clin Cancer Res. 2020;26:566.

PALLET: Palbociclib + Neoadjuvant Letrozole
in ER+/HER2- EBC


Randomized phase II trial (parallel protocols in North America and UK)
Stratified by
country

Postmenopausal
women with
ER+/HER2-invasive
EBC, tumors ≥2 cm by
ultrasound, no
metastatic disease
(N = 307)

Group A
Letrozole* for 14 wk
Group B
Letrozole for 2 wk →
Letrozole + palbociclib† to wk 14

3:2:2:2

Group C
Palbociclib for 2 wk →
Letrozole + palbociclib to wk 14
Group D
Letrozole + palbociclib for 14 wk

*Letrozole 2.5mb/day PO. †Palbociclib 125 mg/day PO (3 wk on, 1 wk off).
Dose reduction to 100 mg and 75 mg available.



Coprimary endpoints (for group A vs B + C +
D): change in Ki67 (protein between
baseline and
14 wk and clinical response (ordinal and
Johnston. JCO. 2019;37:178.
ultrasound) after 14 wk


317

S
U
R
G
E
R
y

Follow-up 30 days after
last treatment and 12 mo
after randomization

Core cut biopsies taken at:
 Baseline (post randomization)
 2 wk (prior to start of second drug in groups B
and C)
 14 wk or at discontinuation treatment
(within 48 hr of last dose)

Secondary endpoint: pCR

PALLET: Clinical Response (Coprimary Endpoint)
Response Categories

Patients in Response Category (%)

100
80

5.4

3.2

1.6

4.8

3.2

45.2

47.6

41

38.7

42.5

 No significant difference in ORR
with letrozole (Group A) vs
letrozole + palbociclib (Groups B
+ C + D)

60
40
54.8
47.3

0

54.1

47.6

20
2.2

LET alone
14 wk
(Group A)

1.6

3.3

LET 2 wk then
LET+PAL 12 wk
(Group B)

PAL 2 wk then
PAL+LET 12 wk
(Group C)

■ PD

52.2

‒ ORR: 49.5% vs 54.4%; P = .20
per Mann-Whitney test
(ordinal)

■ SD

1.6

■ PR

PAL+LET 14
wk
(Group D)

2.2
PAL+LET
regimens
(Groups B+C+D)

■ CR

Johnston. JCO. 2019;37:178.

PALLET Summary
 Compared to letrozole, palbociclib + letrozole:
‒ Enhanced Ki67 suppression (P <.001)
‒ Increased CCCA rate (58.5% to 90.4%; P <.001)
‒ Did not improve ORR (49.5% to 54.4%; P = .2)
‒ pCR rate: 1%

Johnston. JCO. 2019;37:178.

318

FELINE: Neoadjuvant Ribociclib + Letrozole
vs Placebo + Letrozole in ER+/HER2- Breast Cancer
 Randomized, open-label phase II trial (patients accrued Feb 2016 to Aug 2018)
 6 28-day cycles

Postmenopausal women
with HER2- breast cancer,
stage II/III, primary >2 cm;
ER+ >66%
(N = 120)

Ribociclib 400 mg/day PO, continuously
Letrozole 2.5 mg PO QD
(n = 41)

 Surgery between D8-21 of cycle 6

Ribociclib 600 mg/day PO, 3 wk on/off
Letrozole 2.5 mg PO QD
(n = 41)

 Clinical response measurement:
ultrasound, MRI

Letrozole 2.5 mg PO QD +
Placebo
(n = 38)

 Treatment continued until day
before surgery

 Tissue samples: baseline, Day 14
of cycle 1, and at surgery
 If Ki-67 > 10% at Day 14 of cycle 1,
patient removed from trial

 Primary endpoint: Proportion reaching PEPI score 0 at surgery (ie, removing need for adjuvant chemo)
− PEPI 0: tumor ≤5 cm, node negative, Ki-67 ≤2.7%, Allred ER score 3-8

 Secondary endpoints: complete cell-cycle arrest, responses (RECIST), safety
Khan. ASCO 2020. Abstr 505.

FELINE: Ki67 Change Between
Baseline and Day 14 of Cycle 1

Group A: Change in Ki67 (Baseline to D14C1)
80

Group A
Placebo +
Letrozole

Groups
B+C

P Value

Group B
Ribociclib
Intermittent
+ Letrozole

Group C
Ribociclib
Continuous
+ Letrozole

Baseline Ki67,
median %

15.8

21.4

.9129

16.5

24.7

Day 14 Ki67
> 10%, % (n/N)

17.24
(5/29)

4.05
(3/74)

.025

2.86
(1/35)

5.13
(2/39)

Mean change
Ki67% (baseline
to D14C1)

-15.7

-23.3

.047

-20.6

-25.7

CCCA at Day 14,
% (n/N)

51.7
(15/29)

91.9
(68/74)

<.0001

97.1
(34/35)

87.2
(34/39)

40
20
0
BL
Day 14
Groups B+C: Change in Ki67 (Baseline to D14C1)
80
60

Ki67 (%)

Parameter

Ki67 (%)

60

40
20
0
BL

Khan. ASCO 2020. Abstr 505.

319

Day 14

FELINE: Summary
 Adding ribociclib to letrozole did not
 Increase number of patients with PEPI = 0
 Improve ORR

 Adding ribociclib to letrozole did
 Improve complete cell cycle arrest at C1D14
 But this was not maintained at surgery (acquired resistance?)

NeoPal: Neoadjuvant Letrozole + Palbociclib vs CT


Randomized, parallel, non-comparative phase II trial

Patients with ER+/HER2- BC;
Prosigna-defined luminal B or
luminal A/N+; stage II-III; not
candidate for breast conserving
surgery
(N = 106)

Letrozole 25 mg QD +
Palbociclib 125 mg QD 3/4 wk x 19 wk
(n = 53)
FEC100* x 3 cycles then
Docetaxel 100 mg/m2 x three 21-day cycles
(n = 53)

S
U
R
G
E
R
y

Final Analysis
Outcome, n (%)

LET + PAL
(n = 52)

CT
(n = 51)

RCB 0-I

4 (7.7)

8 (15.7)

RCB II-III

48 (92.3)

43 (84.3)

2 (3.8)

3 (5.9)

pCR

*FEC100: 5-FU 500 mg/m2, epirubicin 100 mg/m2,
cyclophosphamide 500 mg/m2.



Primary endpoint: rate of RCB 0-I



Secondary endpoints: clinical response,
proliferation-based markers, safety



Cottu. Ann Oncol. 2018;29:2334.

320

Sample size: null hypothesis (p0) was RCB 0-I in
20% of cases; alternative hypothesis was 40%,
type I error of 0.045, type II error of 0.042
(power: 95.8%); required sample size n = 60/arm

NeoPal Conclusion
 Neoadjuvant LET + PAL or CT was associated with poor pathologic
response for Prosigna-defined high-risk luminal breast cancer
– RCB 0-1 rate: 7.7% with LET + PAL; 15.7% with CT
– pCR rate: 3.8% with LET + PAL; 5.9%% with CT

 Neoadjuvant LET + PAL or CT led to similar rates of clinical or radiologic
response and BCS
 PEPI = 0 was numerically higher with LET + PAL (17.6% vs 8.0% with CT)

Cottu. Ann Oncol. 2018;29:2334.

CORALLEEN: Neoadjuvant Letrozole + Ribociclib vs CT


Multicenter, randomized, open-label phase II trial
Stratified by tumor size (T1/2 vs T3),
nodal involvement

Postmenopausal women with
HR+/HER2- BC; stage I-IIIA;
tumor size ≥2 cm; PAM50
luminal B (Prosigna)
(N = 106)

Letrozole 2.5 mg/day +
Ribociclib 600 mg/day for 3/4 wk
(n = 52)

AC* Q3W x 4
Paclitaxel 80 mg/m2 wkly x 12
(n = 54)





Surgery performed within
7 days of last dose of
ribociclib or within 2 wk of
last dose of CT
ET in the ribociclib +
letrozole group continued
until day of surgery

*Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2.
PAM50 + RNA/DNA seq and plasma samples collected at
baseline, Day 15, and post surgery.



At baseline, ~40% of patients had node-positive disease, median Ki67 expression was 30-35, median ROR
score was 70-77, and ≥85% had ROR high-risk disease

Prat. Lancet Oncol. 2020;21:33.

321

CORALEEN: Primary Endpoint
ROR

Ribociclib + Letrozole
(n = 49)

Chemotherapy
(n = 52)

n (%)

95% CI

n (%)

95% CI

Low

23 (46.9)

32.5-61.7

24 (46.1)

32.9-61.5

Intermediate

15 (30.6)

18.2-45.4

13 (30.8)

19.1-45.9

High

11 (22.5)

11.8-36.7

11 (21.2)

11.2-35.2

NA

NA

1 (1.9)

NA

Missing

Prat. Lancet Oncol. 2020;21:33.

Summary: Neoadjuvant CDK4/6 Inhibitors
 Addition of CDK4/6 inhibitors to ET shows biologic activity (potent reduction
in Ki67 at 2 wk)
 Addition of CDK4/6 inhibitors to ET does not appear to improve ORR or
pathologic response vs ET alone or CT, with low rates of pCR or RCB 0-1
 Cross-trial comparisons suggest similar level of benefit across the 3 CDK4/6
inhibitors; however, there was no head-to-head comparison
 The optimum endpoint is unknown; it has not been firmly established that
increasing the rate of pCR and RCB 0-1 improves long-term outcomes for
luminal cancers
 Without long-term outcomes, neoadjuvant CDK4/6 inhibitors remain
investigational

322

Summary
 Use of genomic assays in the preoperative setting may help us best
select patients who may benefit from preoperative endocrine therapy
vs chemotherapy
 Assessing endpoint to assess response to endocrine therapy + CDK4/6
inhibition not clearly established

323

Metastatic breast cancer–
standards and perspectives
Simona Borštnar
Division of Medical Oncology
Institute of oncology Ljubljana

2nd Summer School in medical oncology
September 2021

Targeted treatment in MBC

Anti-HER2 therapy (trastuzumab,
pertuzumab, lapatinib, T-DM1,
T-Dx, tucatinib

HER2+

gBRCA1/2 mut

TNBC

HR+,HER2PIK3Ca mut

324

HR+ HER2- MBC

Peri/premenopausal

VISCERAL CRISIS: leptomeningeal
carcinomatosis; hepatic
metastases with endangered liver
function: increasing bilirubin
levels with biliary obstruction
excluded, elevated liver
transaminases with diffuse
hepatic infiltration; pulmonary
lymphangitic carcinomatosis; large
lung metastases with respiratory
insufficency present

YES

Visceral crisis1

NO

ChT

Postmenopausal

Until best response

Ovariectomy or MOS
Low disease burden, long disease free interval
YES

NO

AI or fulvestrant or tamoxifen

AI+ CDK4/6i , or fulvestrant + CDK4/6i if <12
months from adjuvant AI

PIK3CA mut.

NO

BRCA1/2 mut.

YES

NO

YES

ful + alpelisib

PARPi

Everolimus + ET(e.g.. eksemestan, tamoksifen), not used Ai (steroidal or nonsteroidal) fulvestrant, megestrol acetat
CHT (monotherapy , not used before)

HER2 +MBC
No prior treatment with
anti-HER2 therapy

Prior (neo) adjuvant treatment
with anti-HER2 therapy

Taxanes+ trastuzumab +
pertuzumab

Taxanse + trastuzumab + pertuzumab (if
the free disease interval is > 12 months)
or T-DM1 (if the free disease interval is<
12 months or ChT1 + trastuzumab

Patients unsuitable for CT or
long free interval and minimal
disease extent, HR+

ET+ anti-HER2 therapy
(trastuzumab ali lapatinib or
trastuzumab+pertuzumab)

Without progression
Maintenance
anti-HER2 therapy

Disease progression

The optimal duration of maintenance anti-HER2
therapy is unknown; possible to stop after several
years of complete remission of the disease.

T-DX

Tukatinib + trast.+
capecitabin 3

capecitabin+
lapatinib

T-DM1

CHT3+or HT4
+trastuzumab

325

1 noncardiotoxic CT (taxanes, vinorelbine,
paclitaxel / carboplatin)
2 non-cardiotoxic CT not previously used
3 preferred in CNS metastases
4 in HR + HER2 + BC

trastuzumab +
lapatinib

TRIPLE NEGATIVE ABC
Tumor testing for PD-L1, Testing for g BRCA1/2 mutation
PD-L1
neg

PD-L1
pos

Atezolizumab+
nabpaklitaksel

BRCA1/2
neg

BRCA1/2
pos

Rapidly progressing
disease, visceral crisis
YES

NO

monotherapy

without prior treatment with
anthracyclines and taxanes

PARP inhibitors

polichemotherapy

Previously treated with
anthracyclines and taxanes

1

with anthracyclines can be treated
up to the maximum total dose
2 taxanes can be reused if the free
disease interval after (neo) adjuvant
treatment is> 12 months

Anthracyclines or taxanes

carbo/cisplatine

capecitabine

vinorelbine

eribulin

Other unused ChTs, selection according to previous efficacy, side effects, performance status

Conclusion
 Approximately 20% to 30% of woman initially diagnosed with early stage
disease will develop metastatic breast cancer.
 The goals of treatment are: maximizing the quality of life, prevention
and palliation of symptoms, and prolongation of survival. Treatment is
lifelong, characterized by remissions and relapses.
 When choosing a treatment, it is necessary to know the tumor
characteristics and identify molecular targets.
 Targeted drugs such are anti-HER2 therapies in HER2 positive subtype,
CDK4/6, mTOR and PIK3CA inhibitors in HR+/HER2- subtype and immune
check point inhibitors in TNBC have significantly improved disease
control.
 New promising drugs are under way, however we need clinical trials and
continued basic and translational research to make new breakthroughs.

326

The diffuse large B cell
lymphoma – recommendations
and current knowledge

Barbara Jezeršek Novaković
Onkološki inštitut Ljubljana

Conclusion
LBCL are a heterogeneous group of diseases with different clinical and
biological features – for an adequate treatment, histopathological evaluation
of an extirpated lymph node is a prerequisite.

327

Conclusion
With current treatment, only 50 to 60% of patients will be cured. In relapsed
disease, salvage chemotherapy results in long term disease free survival in a
small minority of patients. Additional curative option is offered through high
dose therapy and autologous SCT. Multiply relapsed lymphomas can be
treated with CAR T cell therapy and allogeneic SCT, other treatments are
predominately palliative.

And results…
Oncol Lett. 2018 Mar; 15(3): 3602–3609.
Published online 2018 Jan 11. doi: 10.3892/ol.2018.7774
PMCID: PMC5796369

Diffuse large B-cell lymphoma: 10 years' real-world clinical experience
with rituximab plus cyclophosphamide, doxorubicin, vincristine and
prednisolone
Matej Horvat,1 Vesna Zadnik,2 Tanja Južnič Šetina,1 Lučka Boltežar,1 Jana
Pahole Goličnik,1 Srdjan Novaković,3 and Barbara Jezeršek Novaković1

328

And results…
Table I. Patient clinical and demographic characteristics at the start of treatment (n=624).
Sex
Male 297 (48%)
Female 327 (52%)
Median age
67.0 (19-89)
<60 years, 208 (33%)
ECOG performance status
0: 299 (48%)
1: 183 (29%)
2: 90 (14%)
3: 33 (5%)
4: 19 (3%)
Disease stage
I: 73 (12%)
II: 178 (29%)
III: 111 (18%)
IV: 245 (39%)
Elevated LDH level
311 (50%)
Extranodal involvement
439 (70%)
Treatment regimen
Rituximab + CHOP 575 (92%)
Rituximab + other chemotherapy 32 (5%)
Chemotherapy alone 17 (3%)
IPI score
0: 63 (10%)
1: 122 (20%)
2: 143 (23%)
3: 141 (23%)
4: 108 (17%)
5: 44 (7%)

And results…

329

And results…
Survival rate (%)

1-year

2-year

3-year

5-year

10-year

Median survival
(months)

Age, <60 years

88

85

84

83

79

NR

Age. ≥60 years

84

80

79

78

70

NR

93

90

89

87

77

NR

83

79

79

79

79

NR

Age, <60 years

93

85

81

81

76

NR

Age, ≥60 years

82

70

64

56

41

80.1

98

95

91

91

87

NR

87

76

71

71

67

NR

Outcome
Progression-free
survival

Age, <60 years, IPI 0
or 1
Age, <60, IPI ≥2
Overall survival

Age, <60 years, IPI 0
or 1
Age, <60, IPI ≥2

And results…

330

Marginal zone lymphoma (MZL)

Summer school 2021
Oncology institute of Ljubljana
Milica Miljković, medical oncologist

Introduction
Indolent (slow growing) Non – Hodgkin B cell lymphomas
5-15% of Non-Hodgkin lymphomas
Average age at diagnosis is 60 years
Slightly more common in women

331

WHO classification
Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ)
Nodal marginal zone lymphoma (NMZL)
Splenic marginal zone lymphoma (SMZL)
Extranodal marginal zone lymphoma (EMZL) or Mucosa –Associated Lymphoid
Tissue (MALT) : The stomach is the most common site, followed by ocular
adnexa, lung and salivary glands.

Treatment of EMZL, NMZL, SMZL
Treat just symptomatic systemic disease
It means:
-B simptomps: fewer, night sweats and weight loss
-Bulky disese
-Symptomatic splenomegaly and/ or any progressive cytopaenias
- Hb < 100 g/L
- Platelets < 80x10/L
- Neutrophils < 1 x10/L

332

Treatment of EMZL, NMZL, SMZL
Stage I and II: surgery +/- RT (25,2GY)
Stage III and IV and with B simptoms:
6-8 x R-LP (rituximab,chlorambucil, prednisolone)
4-6 x R-Bendamustine
6-8 x R-Lenalidomide
4 x Rituksimab + RT for old and unfit patients
6-8 x R-CHOP for aggressive disease
(rituximab,ciklofosfamid,doxorubicin,vincristine,prednisolone)

Treatment algorithm for localised gastric MZL

333

Treatment algorithm for advanced gastric MZL

334

Sekcija internistične onkologije pri SZD, Onkološki inštitut Ljubljana in Katedra za onkologijo
2nd Summer School in medical oncology –
Precision oncology – Are we there yet
7-10 September 2021
Institute of Oncology Ljubljana, Zaloška 2, Ljubljana

Standards and perspectives in the systemic treatment
of Lymphomas –
Follicular lymphoma

dr. Tanja Južnič Šetina, dr.med
Institute of Oncology, Ljubljana

Follicular lymphoma
• Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma
• It accounts for 20% of all NHL cases and around 70 % of indolent lymphomas
• The clinical presentation is usually characterized by asymptomatic peripheral lymphadenopathy in
cervical, axillary, inguinal and femoral regions. Most patients are diagnosed with advanced stage
disease. Bone marrow involvement is present in more than >80%.
• The course of FL is quite variable. The disease is usually characterized by an indolent clinical
course and response to initial therapy, but relapses are common.
• The prognosis of FL is good. The median survival of FL is over 15 years but considering it`s
indolent nature, survival can often be measured in decades.
• Histologic transformation of FL to a DLBCL has been reported in up to 70 percent of patients over
time, and is associated often with a poor prognosis.

335

PRIMA – PI

•

B2M increased

•

Bone marrow involvement

•
•
•

FLIPI - outcome according to risk group

5 year OS %

10-year OS %

Low

Risk group

0 to 1

score

91

71

Intermediate

2

78

51

High

>3

52

36

score

1.
2.

2- yr OS %

2-yr PFS %

mPFS (months)

98

84

84

2

94

72

70

>3

87

65

42

OS by FLIPI risk groups¹

OS by FLIPI risk groups for R-containing regimens²

FLIPI score applied to patients in the rituximab era (68%
received R, n=2192)
0 to 1

low risk: B2M normal and bone
marrow not involved
intermediate risk: B2M normal
and bone marrow involved
high risk: B2M elevated

Solal-Celigny, P, Roy, P, Colombat, P, et al. Follicular lymphoma international
prognostic index. Blood 2004; 104:1258
Nooka AK, Nabhan C, Zhou X, et al.. Ann Oncol 2013; 24:441.

336

Initial treatment of stage I to IV follicular lymphoma
 treatment of FL depends on the stage of disease at presentation
 introduction of anti-CD20 monoclonal antibody rituksimab into first line FL treatment or relapsed
disease significantly improved the outcome of FL patients

Stage I/II
• 10-20% of FL patients present with limited stage I/II disease
• radiotherapy (24-30 Gy) is generally the treatment of choice for limited stage FL, and results in 10-year OS rates of
60% to 80%;
• 2 x 2 Gy schedule is less durable but might be used in special situations to minimize side-effects (e.g. lacrimal gland,
parotid glands)
• In selected cases (e.g. limited life expectancy, large abdominal fields), observation or rituximab monotherapy may be
considered

Stage III/IV
• Initial observation ("watch and wait" ) is the standard approach in asymptomatic, stable patients with stage II (high
tumor burden), III, or IV
• Immunotherapy-based treatment (rituximab, obinutuzumab and chemotherapy)
• Radioimmunotherapy
• lenalidomide-rituximab
• rituximab monotherapy or R in combination with chlorambucil

Indications for treatment
• local symptoms due to progressive or bulky nodal disease
• vital organ compression
• presence of systemic B symptoms ( fevers >38°C, weight loss, night sweats)
• presence of symptomatic extranodal disease, such as effusions
• cytopenias due to extensive bone marrow infiltration, autoimmune
hemolytic anemia or thrombocytopenia, or hypersplenism
• rapid lymphoma progression

337

First-line therapy
• Preferred regimens
• R – bendamustin, R-CHOP or R-CVP
• Obinutuzumab / bendamustin, CHOP or CVP
• Rituximab+ lenalidomide

• Less preferred
• Rituximab – monotherapy (4 weekly doses)
• Rituximab+chlorambucil
• Radioimmunotherapy

• Rituximab maintenance (every 8 weeks for 2 years) - improves PFS
and OS
• Obinutuzumab maintenance (every 8 weeks, 12 doses)

Randomized trials in first-line FL treatment (R-chemotherapy)
Study

Treatment, n

Median
FU,
months

ORR, %

PFS
%

Median
TTP/ TTF/
EFS, mo

OS,
%

Marcus
et al. 2006

CVP, 159
R-CVP, 162

53

57
81

15
34
p<0.0001

77(4-y)
83 (4-y)
p = 0.029

Hiddemann
et al. 2005

CHOP-IFN, 205
R-CHOP-IFN, 223

18

90
96

29
NR
p<0.001

90(2-y)
95 (2-y)
p = 0.016

Herold
et al. 2006

MCP-IFN, 96
R-MCP-IFN, 105

47

75
92

71

26
NR
p<0.0001

74 (4-y)
87 (4-y)
p = 0.009

Salles
et al.2008

CHVP-IFN, 183

73

37

84

53

33
p<0.0004
67

79(5-y)
p = 0.07
84 (5-y)

69

70 (10-y)

31
p<0.0001,HR 0.58

66 (10-y)

Schulz H, 2007
metaanalysis

60
R-CHVP-IFN, 175

PFS: R-ChT vs ChT ( HR 0,62, CI 0,55-0,71, p<0,001)
OS: R-ChT vs ChT, 1480 (1.line+relapses)
(HR 0,63; 95 % CI 0,51-0,79, p<0,001)

92,7

R-Bendamustine, 279
Rummel
et al. 2009

Morschhauser et al.
2018

R- CHOP, 275
R-CHOP/BR
+ R maint., 517
R-lenalidomide
+ R maint., 513

45

38

84

38

89

PFS 78% (3y)
77% (3y)

338

94 (3 y)
94 (3 y)

 With the introduction of R,
survival of FL has improved.
 The improvement was established
in at least four prospective firstline trials and a systematic metaanalysis.

Maintenance treatment with rituximab
(PRIMA study)
PFS (PRIMA)

1. Long-Term Results of the PRIMA Study (9y FU)
Study

FU, n

Treatment

Median
PFS

OS

PRIMA, 2011
First-line FL

9y of FU

R-ChT+observation
vs
R-ChT+mainten R

4.1y

>80 (10-y)

10.5y
p<0,001

>80 (10-y)
p= NS

1018 pts

CONCLUSION (PRIMA)
• rituximab maintenance after induction immunochemotherapy provides a
significant PFS benefit over observation
• no OS benefit

OS (PRIMA)

2. Meta-analysis (Vidal et al, 2017); seven trials including PRIMA, 2315 pts
with FL evaluating rituximab maintenance on OS
CONCLUSION: Maintenance rituximab improved PFS (HR 0.57; 95% CI 0.510.64) and OS (HR 0.79; 95% CI 0.66-0.96)
1. Bachy E, et al. J Clin Oncol. 2019;37(31):2815-2824. Sustained Progression-Free Survival Benefit of Rituximab
Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study.
2. Vidal L, Gafter-Gvili A, Salles G, et al. Eur J Cancer. 2017;76:216

GALLIUM Study
(randomised phase III study in previously untreated FL patients)

Induction

Grade 1–3a

ECOG PS 0–2
(N=1202)

R

R-chemo (601 pts)
R 375mg/m2 IV on D1 of
C1–8 (q3w) or C1–6 (q4w)
plus CHOP,CVP or
bendamustine

Primary endpoint
• PFS

CR or PR† at EOI visit

Previously
untreated FL
Stage III/IV or stage II
bulky (≥7cm) requiring
treatment

Maintenance

G-chemo (601 pts)
G 1000mg IV on D1, D8,
D15 of C1 and
D1 of C2–8 (q3w) or C2–6
(q4w) plus chop,CVP or
bendamustine

Follow-up

G
G 1000mg IV q2m for
2 years or until PD
Median follow-up: 34
months
R
R 375mg/m2 IV q2m for
2 years or until PD

Marcus, et al NEJM 2017;
377(14):1331-1344

339

GALLIUM study results : PFS and OS in patients with FL
(first-line)

R-ChT,
n=601
3-y PFS,%
(95% CI)
HR (95% CI), =p=0.001

73,3
(68.8-77.2)

3-y OS
HR 0.75, P=0,21

G-ChT,
n=601
80,0
(75.9-83.6)

92

94

Conclusion:
 Obinutuzumab/chemo + maintenance
is superior to similar R-based regimens
with improvement of PFS
 no difference in OS

Marcus, et al NEJM 2017;
377(14):1331-1344

RELEVANCE: Phase III Trial Design (previously untreated FL patients)
Treatment period 1
(~6 months)

Treatment period 2
(~1 year)

Treatment period 3
(~1 year)

R2

Rituximab

n = 513

Previously untreated
advanced FL requiring
treatment per GELF
(N = 1,030)

R2
1:1

R-chemo
n = 517

Rituximab

(R-CHOP, R-B,
R-CVP)

R2 = lenalidomide/rituximab; R = rituximab;
B = bendamustine; CVP = cyclophosphamide/
vincristine/prednisone

Total treatment duration: 120
weeks

Primary endpoints: CR/CRu at 120 weeks and PFS
Morschhauser F, Fowler NH, et al. N Engl J Med. 2018;379(10):934

340

RELEVANCE: Interim PFS (first-line FL patients)
Interim PFS

R2
(n = 513)
3-year PFS

R-chemo

R-chemo
(n = 517)

77%

78%

HR

1.10

p-value

0.48

Conclusions
• similar rates of CR (48% in R2 vs 53 % in R chemo)
• similar 3-y PFS (77% vs 78 %, HR 1.10, 95% CI
0.85-1.43)
• similar OS (94 vs 94 %, HR 1.16, 95% CI 0.72-1.86)
• more rash, diarrhea and tumor flare, less
neutropenia in the R2

R2

• At median follow-up of 37.9 mo, interim PFS was similar in both arms
• 3-y OS = 94% (R2) vs 94% (R-chemo), HR 1.16
Morschhauser F, Fowler NH, et al. N Engl J Med. 2018;379(10):934.

Treatment of R/R FL
• 20 to 30 % of patients with FL relapse after first- line therapy
• rule out histologic transformation
• patients who progress within 24 months have significantly worse OS than those who do not
• asymptomatic recurrent FL do not necessarily require immediate treatment

341

Treatment regimens for R/R FL
• Preferred regimens
•
•
•
•

Bendamustin + rituximab or obinutuzumab
CHOP or R-CVP + obinutuzumab or rituximab
Lenalidomide + rituximab or obinutuzumab
PI3K inhibitors (after 2 prior therapies)

• Less preferred (eldery, frail pts)
•
•
•
•

Rituximab alone (4 weekly doses)
Chlorambucil +/- R
Cyclophosphamide +/- R
Radioimmunotherapy

• Rituximab maintenance (every 3 months for 2 years)
• Obinutuzumab maintenance for R-refractory (every 8 weeks, 12 doses)
• Other
• High dose therapy with ASCT, allogeneic transplant for selected patients
• Novel treatments (CAR-T-cell therapy, tazemetostat – EZH2 mut posit after 2 prior
therapies or EZH2 WT in pts with no other alternative), mosunetuzumab
R, rituximab

Randomised phase III study for R/R FL patients

+

342

Obinutuzumab
maintenan. (1000 mg
every 2 months) for up
to 2 years

OS (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027)

median follow-up 31,8 months

Conclusion: the addition of obinutuzumab improves PFS and
OS. Toxicity was similar in both treatments.
Cheson BD. J Clin Oncol. 2018;36(22):2259.

AUGMENT: R2 versus Rituximab/Placebo for R/R FL or
Marginal Zone Lymphoma - randomised phase III study

343

Conclusions:
• improved PFS with R2 vs R alone (39 mo vs 14 mo)
• 2-year OS was 95% for R2 and 86% for R/placebo
• similar efficacy to chemoimmunotherapy

Idelalisib
• oral PI3K inhibitor that has shown therapeutic activity in initial studies of patients with multiple
relapsed FL
• approved by EMA and FDA as a single agent for the treatment of patients with relapsed FL who
have received at least two prior systemic therapies
• approval based on a phase 2 study of idelalisib (n=72) in patients with FL who have received at
least 2 prior lines of therapy1
• ORR was 57 % with a median duration of response of 12.5 months
• The starting dose is 150 mg twice daily
• toxicity:
• diarrhea – 14%
• cytopenias – 28%
• infections – 21%

pneumonitis - 4%
hepatotoxicity – 18%
hypertriglyceridemia, hyperglycemia

• anti-infectious prophylaxis

1.Gopal AK, et al. N Engl J Med. 2014

344

Avtologous, allogeneic transplantation
• an appropriate consolidative therapy for patients in second or third remission
• may have the greatest benefit in patients with early treatment failure, refractory FL and
those with histologic transformation to a more aggressive histology
• there is a plateau in the survival curves between 10 and 15 years after autologous HCT,
suggesting that this procedure may be curative for one-quarter to one-third of transplanted
patients1,2
• allogeneic transplantation can be considered in highly selected patients (lower rates of
relapse vs autoHCT, high TRM up to 20%)

1. Metzner B, et al. Ann Oncol. 2013
2. Casulo C, et al. Biol Blood Marrow Transplant. 2018

Conclusions
•

FL is a chronic, incurable disease with a long natural history

•

a small subgroup of patients presenting with limited stage disease may be cured with radiation

•

observation is the first approach in asymptomatic patients

•

for those who require therapy : multiple treatment regimens, anti-CD20 +/- chemotherapy and
chemotherapy-free alternatives, novel agents,…
o

antiCD20 +/- chemotherapy

o

lenalidomide +/- rituximab

o

PI3K inhibitors

o

autologous and allogeneic stem cell transplantation

o

novel agents (tazemetostat - EZH2 inhibitor, mosunetuzumab - bispecific antibody ,…)

o

CAR-T cell therapy - may dramatically alter the prognosis for heavily pretreated patients
(ZUMA-5 study with high ORR more than 90%, median PFS at 2 years 78%, CR rate 80 %,..)

•

disease can still be fatal in patients with histologic transformation

345

MANTLE CELL LYMPHOMA

Monika Jagodic, MD, PhDmmd

SUMMARY: Mantle cell lymphoma (MCL)
Histology: the image is of mantle zone cells surrounding normal germinal centre follicles
Biology: the translocation t (11;14) (q13; q32) leading to cyclin-D1 overexpression is typical
Prognosis: Clinical and biological prognosticators (combined mantle cell lymphoma International Prognostic Index, MIPI-c) should be
used routinely to estimate clinical behaviour) including age, ECOG, LDH, WBC count, Ki-67 index. Other prognosticators: SOX-11
expression, TP 53 mutations
Initial treatment approach: a short course of watch-wait under close observation is recommended for suspected indolent cases with low
tumour burden and asymptomatic disease at diagnosis.
When starting of treatment is required (symptoms, high tumour burden) initial treatment is conventional chemoterapy (ChT) with rituximab
(Rx) +/-consolidation RT. In younger patients are used aggresive regimens by autologous stem-cell transplantation (SCT) as 1st line.
In older patients are used conventional ChT combinations and less intense immunoChT or low- toxicity single agent targeted therapy
in frail patients.
Maintenance with rituximab significantly improves progression-free survival and overall survival.
Relapse disease treatment: salvage therapy: in early relapses (<12-24 months) a non-cross resistant scheme after R-CHOP or vice versa
is recommended, with Rx maintenance.
Molecular targeted substances (ibrutinib, lenalidomide) should be considered in refractory disease. Additional options: temsirolimus,
bortezomid.
AlloSCT transplantation should be considered in younger patients as potentially curative treatment in early relapse and refractory disease.

346

T-CELL LYMPHOMA
Jana Pahole MD
Institute of Oncology Ljubljana
10/09/2021

T-CELL LYMPHOMA – short facts
•
•
•
•

7-10% of all NHL
Most are clinically aggressive
Heterogenous in their presentation, features and prognosis
Lack of efficient treatment

• Most can be healed not cured
• Outcomes are poor
•
•
•
•

Low response rates
5-year OS ~32%
5-year failure-free survival ~20%
Most patients relapse within 2-3 years

347

T-CELL LYMPHOMA SUBTYPES
LEUKEMIC
• T-cell prolymphocite
leukemia
• Adult T-cell
leukemia/lymphoma
• T-cell large granular
lymphocytic leukemia
• NK cell leukemia

NODAL
• Peripheral T-cell
lymphoma NOS
• Nodal PTCL with TFH
• Angioimmunoblastic
lymphoma
• Follicular T-cell
lymphoma
• Anaplastic largecell
lymphoma (ALK+/ALK/breast implant)

EXTRANODAL
• Extranodaln NK/T cell
• Hepatosplenic
• Entheropathy associated T-cell
lymphoma
• Mycosis fungoides
• Sezary syndrom
• Primary cutaneous CD30+

Swerdlow et al Blood 2016

348

2nd Summer School in medical oncology

Standards and perspectives in
the systemic treatment of
Hodgkin lymphoma
Urska Rugelj, MD
Ljubljana, 10.9.2021

Conclusions
• Incidence in EU 2.3/100.000, most often affects young adults
• Multiple signaling pathways/transcription factors deregulated activities in RS cells
involved in pathogenesis
• 5-FDG PET-CT scan an important part of diagnostic and treatment modifying
decisions
• Type of treatment depends on clinical stage and risk factors
• Combined approach of treatment in early stages, chemotherapy-based treatment
for advance disease
• Overall >80% achieve long remission – are cured
• Standard care of relapse in young fit patient is high-dose ChT + AutoSCT
• In relapse settings already approved use of some novel drugs as antibody-drug
conjugates, anti PD-1 antibodies, others as small molecule inhibitors, cellular
therapies in study settings

349

PRINCIPLES OF RADIOTHERAPY
INLYMPHOMAS
Assist. Prof. PhD Lorna Zadravec Zaletel, MD

2nd Summer School in medical oncology, 2021

Conclusions
• malignant lymphomas are radiosensitive.
• RT may be a stand-alone treatment for some indolent
NHL and for low stage HL- type lymphocyte
predominance .
• in indolent NHL of higher stages, RT is reserved for
treating the rest of the disease after CT or low-dose
RT of larger infiltrates in order to delay CT.
• in aggressive lymphomas, radiation
associated with systemic treatment.

is

always

• life-long follow-up of late sequelae of treatment is of
vital importance.

350

SAMO ZA STROKOVNO JAVNOST

ZAUSTAVITE NAPREDOVANJE
BOLEZNI IN PODALJŠAJTE PREŽIVETJE
Pri bolnikih z mHSPC, zdravljenje samo z ADT ni dovolj.
ZDRAVILO ERLEADA® JE SEDAJ ODOBRENO TUDI ZA ZDRAVLJENJE BOLNIKOV S
HORMONSKO OBČUTLJIVIM, METASTATSKIM RAKOM PROSTATE (mHSPC).¹
Zgodnja uporaba zdravila ERLEADA+ADT v primerjavi z ADT pomembno podaljša preživetje bolnikov in zmanjša
tveganje za napredovanje bolezni, hkrati pa prihrani druge oblike zdravljenja za kasnejše stadije bolezni.1-3

▼ Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o
njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem
učinku zdravila. Glejte poglavje 4.8 povzetka glavnih značilnosti zdravila, kako poročati o neželenih učinkih.
Ime zdravila: Erleada 60 mg filmsko obložene tablete. Kakovostna in količinska sestava: 60 mg
apalutamida; pomožne snovi: brezvodni koloidni silicijev dioksid, premreženi natrijev karmelozat,
hipromeloza acetat sukcinat, magnezijev stearat, mikrokristalna celuloza, mikrokristalna celuloza
(silicifirana), črni in rumeni železov dioksid, makrogol, polivinilalkohol (delno hidroliziran), smukec,
titanov dioksid. Indikacije: Zdravljenje odraslih moških z nemetastatskim, na kastracijo odpornim rakom
prostate (nmCRPC), pri katerih obstaja veliko tveganje za razvoj metastatske bolezni. Za zdravljenje
odraslih moških s hormonsko občutljivim metastatskim rakom prostate (mHSCP) v kombinaciji z
zdravljenjem z odtegnitvijo androgenov. Odmerjanje in način uporabe: Priporočeni odmerek je 240 mg
(štiri 60‑miligramske tablete) v enkratnem peroralnem odmerku na dan. Med zdravljenjem je treba pri
bolnikih, ki niso bili kirurško kastrirani, nadaljevati medicinsko kastracijo z analogom gonadoliberina. V
primeru izpuščenega odmerka je treba zdravilo vzeti čimprej še isti dan, naslednji dan pa naj odmerjanje
nadaljuje po običajnem razporedu. Dodatnih tablet za nadomestitev pozabljenega odmerka se ne sme
vzeti. Če se pri bolniku pojavijo toksični učinki ≥ 3. stopnje ali nesprejemljivi neželeni učinki, je treba
uporabo zdravila prekiniti začasno in ne dokončno, dokler se simptomi ne izboljšajo na ≤ 1. stopnjo
oziroma na začetno stopnjo, nato pa z zdravljenjem nadaljevati z enakim ali manjšim odmerkom (180 mg
ali 120 mg), če je potrebno. Starejšim bolnikom, bolnikom z blago do zmerno okvaro ledvic ali jeter
odmerka ni treba prilagajati. Pri bolnikih s hudo okvaro ledvic je potrebna previdnost, pri bolnikih s hudo
okvaro jeter pa uporaba ni priporočljiva. Tablete je treba pogoltniti cele in se jih lahko jemlje s hrano ali
brez nje. Apalutamid ni namenjen za uporabo pri pediatrični populaciji. Kontraindikacije: Preobčutljivost
na učinkovino ali katero koli pomožno snov, nosečnice in ženske, ki bi lahko zanosile. Posebna opozorila
in previdnostni ukrepi: Uporaba zdravila ni priporočljiva pri bolnikih z anamnezo konvulzij ali drugimi
predispozicijskimi dejavniki, med drugim tudi pri bolnikih s poškodbo možganov, nedavno kapjo (v
zadnjem letu), pri bolnikih s primarnimi možganskimi tumorji ali metastazami v možganih. Pri bolnikih, ki
so prejemali apalutamid je prišlo do padcev in zlomov, zato je treba pred uvedbo zdravljenja pri bolnikih
oceniti tveganje za zlome in padce, bolnike pa spremljati po ustaljenih smernicah in premisliti o uporabi
učinkovin, ki delujejo na kosti. Bolnike je treba spremljati tudi glede znakov in simptomov ishemične
bolezni srca in ishemičnih možganskožilnih bolezni ter optimatizirati obvladovanje dejavnikov tveganja,
kot so hipertenzija, diabetes ali dislipidemija, skladno s standardno oskrbo. Sočasni uporabi apalutamida z
zdravili, ki so občutljivi substrati več presnovnih encimov ali prenašalcev, se je načeloma treba izogibati, če
je terapevtski učinek teh zdravil za bolnika zelo pomemben in njihovega odmerjanja ni mogoče enostavno
prilagajati na osnovi spremljanja učinkovitosti ali koncentracij v plazmi. Sočasni uporabi z varfarinom
ali kumarinskimi antikoagulansi se je treba izogibati. Če se predpiše apalutamid, je treba pri bolnikih s
klinično pomembnimi boleznimi srca in ožilja spremljati dejavnike tveganja kot so hiperholesterolemija,
hipertrigliceridemija ali druge srčno presnovne bolezni. Zdravljenje z odtegnitvijo androgenov lahko

Janssen, farmacevtski del Johnson & Johnson d.o.o., Šmartinska cesta 53, 1000 Ljubljana,
tel: 01 401 18 00, e-mail: info@janssen-slovenia.si

podaljša interval QT. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Apalutamid
je induktor encimov in prenašalcev in lahko povzroči povečan obseg odstranjevanja številnih pogosto
uporabljanih zdravil. Pri sočasnem odmerjanju tega zdravila s katerim od močnih zaviralcev CYP2C8
ali močnih zaviralcev CYP3A4 začetnega odmerka ni treba prilagajati, premisliti pa velja o zmanjšanju
odmerka zdravila Erleada na osnovi prenašanja zdravila. Ni pričakovati, da bi induktorji CYP3A4 ali CYP2C8
klinično pomembno vplivali na farmakokinetiko apalutamida in aktivnih frakcij. . Pri sočasni uporabi s
substrati CYP2B6 je treba spremljati neželene učinke in oceniti izgubo učinka substrata ter za zagotovitev
optimalnih plazemskih koncentracij morda prilagoditi odmerek substrata. Sočasna uporaba z zdravili, ki
se primarno presnavljajo s CYP3A4 (kot so darunavir, felodipin, midazolam in simvastatin), s CYP2C19
(kot sta diazepam in omeprazol) ali s CYP2C9 (kot sta varfarin in fenitoin), lahko povzroči zmanjšanje
izpostavljenosti tem zdravilom. Pri sočasni uporabi s substrati UDP‑glukuronil transferaze je potrebna
previdnost. Pri sočasni uporabi s substrati P‑gp, BCRP ali OATP1B1 je potrebna ocena obsega zmanjšanja
učinka ter za zagotovitev optimalnih plazemskih koncentracij morda prilagoditi odmerek substrata. Ni
mogoče izključiti možnosti, da apalutamid in njegov N‑desmetil presnovek zavirata prenašalce OCT2,OAT3
in MATE. Pri preiskovancih z mHSPC, ki so prejemali levprorelinijev acetat (analog GnRH), sočasna uporaba
apalutamida ni bistveno vplivala na izpostavljenost leuprolidu v stanju dinamičnega ravnovesja. Skrbna
presoja je potrebna tudi pri sočasni uporabi z zdravili, za katera je ugotovljeno, da podaljšujejo interval QT,
oziroma z zdravili, ki lahko izzovejo Torsades de pointes. Plodnost, nosečnost in dojenje: Ni znano, ali so
apalutamid ali njegovi presnovki prisotni v spermi, zato lahko to zdravilo škoduje plodu v razvoju. Bolniki,
ki imajo spolne odnose z žensko v rodni dobi, morajo med zdravljenjem in še 3 mesece po zadnjem
odmerku zdravila Erleada uporabljati kondome skupaj s še katero od drugih visoko učinkovitih metod
kontracepcije. Zdravilo je kontraindicirano pri nosečnicah in ženskah , ki bi lahko zanosile in se ne sme
uporabljati med dojenjem. Neželeni učinki: Hipotiroidizem, zmanjšan apetit, hiperholesterolemija,
hipertrigliceridemija, disgevzija, ishemične možganskožilne bolezni, konvulzije, ishemična bolezen srca,
podaljšanje intervala QT, vročinski oblivi, hipertenzija, driska, kožni izpuščaj, srbenje, alopecija, TEN, zlomi,
artralgija, mišični krči, utrujenost, zmanjšanje telesne mase, padci. Za popoln seznam neželenih učinkov
glejte Povzetek glavnih značilnosti zdravila. Imetnik DzP: Janssen-Cilag International NV, Turnhoutseweg
30, 2340 Beerse, Belgija Predstavnik imetnika DzP v Sloveniji: Johnson & Johnson d.o.o., Šmartinska
cesta 53, Ljubljana.
Režim izdajanja zdravila: Rp/Spec. Datum zadnje revizije besedila: 10. junij 2021
Povzetek glavnih značilnosti zdravila s podrobnejšimi informacijami o zdravilu je dostopen pri
predstavniku imetnika dovoljenja za promet.
Viri:
1. Povzetek glavnih značilnosti zdravila ERLEADA® (apalutamid).
2. Chi KN, et al. N Engl J Med. 2019;81(1):13–24
3. Chi KN, et al. N Engl J Med. 2019;81(1):13–24. Supplementary information.

(apalutamid) tablete

CP-198062/020921

Skrajšan povzetek glavnih značilnosti zdravila ERLEADA®

SAMO ZA STROKOVNO JAVNOST

Prevzemite nadzor nad
KLL, MCL in WM z zdravilom IMBRUVICA®1-6

ENA TABLETA ENKRAT
NA DAN DOMA
Dolgotrajno izboljšanje preživetja po 8 letih spremljanja.2-3
Poznan in obvladljiv varnostni profil.2-6
Enostavno, enkrat dnevno jemanje zdravila na domu.1

tablete

KLL=kronična limfocitna levkemija; MCL=limfom plaščnih celic; WM=Waldenströmova makroglobulinemija.
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Ime zdravila: IMBRUVICA 140 mg/280 mg/420 mg/560 mg filmsko obložene tablete
Kakovostna in količinska sestava: 140/280/420 ali 560 mg ibrutiniba, brezvodni koloidni silicijev dioksid, premrežen
natrijev karmelozat, laktoza monohidrat, magnezijev stearat, mikrokristalna celuloza, natrijev lavrilsulfat (E487),
povidon; filmska obloga: makrogol, polivinilalkohol, smukec, titanov dioksid (E171), črni železov oksid (E172), rumeni
železov oksid (E172 – 140, 420 in 560 mg), rdeči železov oksid (E172 – 280 in 560 mg) Indikacije: Kot samostojno
zdravilo: zdravljenje odraslih bolnikov s ponovitvijo limfoma plaščnih celic (MCL) ali z na zdravljenje neodzivno obliko
te bolezni, zdravljenje odraslih bolnikov z Waldenstromovo makroglobulinemijo (WM - Waldenström’s
macroglobulinaemia), ki so predhodno prejeli vsaj eno vrsto zdravljenja oziroma v prvi liniji pri bolnikih, ki niso
primerni za kemoimunoterapijo. Kot samostojno zdravilo ali v kombinaciji z obinutuzumabom za zdravljenje odraslih
bolnikov s predhodno neozdravljivo kronično limfocitno levkemijo (KLL)/z bendamustinom in rituksimabom za
zdravljenje odraslih bolnikov s KLL, ki so predhodno prejeli vsaj eno vrsto zdravljenja; samostojno zdravilo indicirano.
V kombinaciji z rituksimabom za zdravljenje odraslih bolnikov z WM. Odmerjanje: Zdravilo je treba jemati peroralno
enkrat na dan s kozarcem vode, in sicer vsak dan ob približno istem času. Tablete je treba pogoltniti cele z vodo. Tablet
se ne sme drobiti ali žvečiti. Zdravljenje mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo onkoloških
zdravil. MCL: priporočeni odmerek je 560 mg enkrat na dan. KLL (samostojno ali v kombinaciji) in WM: priporočeni
odmerek je 420 mg enkrat na dan. Z zdravljenjem je treba nadaljevati do napredovanja bolezni oz. dokler bolnik
zdravilo prenaša. Pri odmerjanju tega zdravila v kombinaciji z zdravilom, ki je usmerjeno proti CD20, je priporočljivo
vzeti ibrutinib pred zdravilom, ki je usmerjeno proti CD20, kadar ju je treba vzeti na isti dan. Podrobna navodila za
odmerjanje pri posebnih skupinah bolnikov in za prilagajanje odmerkov v primeru sočasne uporabe z zmernimi in
močnimi zaviralci CYP3A4 in ob pojavu hematološke toksičnosti so navedena v Povzetku glavnih značilnosti zdravila. Če
bolnik izpusti odmerek, ga lahko vzame čimprej istega dne, naslednjega dne pa spet začne z odmerjanjem po običajnem
razporedu. Bolnik naj ne jemlje dodatnih tablet, da bi nadomestil pozabljeni odmerek. Kontraindikacije:
Preobčutljivost na učinkovino ali katero koli pomožno snov, sočasna uporaba pripravkov rastlinskega izvora s šentanževko
(Hypericum perforatum). Posebna opozorila in previdnostni ukrepi: Poročali so o krvavitvah s trombocitopenijo ali
brez nje (vključno z manjšimi hemoragičnimi dogodki (podplutbe, krvavitev iz nosu, petehije) ter večjimi krvavitvami
(gastrointestinalna in intrakranialna krvavitev, hematurija)). Sočasno se ne sme jemati varfarina in drugih antagonistov
vitamina K. Izogibati se je treba prehranskim dopolnilom (npr. pripravki ribjega olja ali vitamina E). Pri sočasnem
zdravljenju z antikoagulanti je potrebna posebna previdnost. Zdravila se ne sme jemati najmanj 3 do 7 dni (odvisno od
vrste kirurškega posega in tveganja za krvavitev) pred kirurškim posegom in po njem. Poročali so o primerih levkostaze.
Po prekinitvi zdravljenja z ibrutinibom so poročali o primerih rupture vranice. Veliko število cirkulirajočih limfocitov
(> 400.000/mikroliter) lahko pomeni povečano tveganje; treba je razmisliti o začasni prekinitvi jemanja zdravila,
bolnika skrbno spremljati in po potrebi uvesti podporne ukrepe vključno s hidracijo in/ali citoredukcijo. Opažali so
okužbe; bolnike je treba spremljati glede morebitnega pojava zvišane telesne temperature, nenormalnih izvidov
preiskav delovanja jeter, nevtropenije in okužbe ter po potrebi uvesti ustrezno antimikrobno zdravljenje. Pri bolnikih s
povečanim tveganjem za oportunistične okužbe razmislite o standardnih ukrepih za njihovo preprečevanje. Po uporabi
ibrutiniba so poročali so o primerih invazivnih glivičnih okužb, vključno s primeri aspergiloze, kriptokokoze in okužbe s
Pneumocystis jiroveci. Pri uporabi ibrutiniba ob predhodni ali sočasni uporabi imunosupresivnega zdravljenja so poročali
o PML, vključno s smrtnimi primeri. PML je treba upoštevati v diferencialni diagnozi pri bolnikih z novimi ali s
poslabšanjem obstoječih nevroloških, kognitivnih ali vedenjskih znakov ali simptomov. Če obstaja sum za PML, je treba
opraviti diagnostične preiskave in zdravljenje prekiniti dokler ni izključena. Pri bolnikih, zdravljenih z ibrutinibom so se
pojavili primeri hepatotoksičnosti, reaktivacije virusa hepatitisa B in primeri hepatitisa E, ki so lahko kronične narave,
prišlo je tudi do odpovedi jeter, vključno s smrtnimi izidi. Pred uvedbo zdravila je treba preveriti delovanje jeter in
prisotnost virusa hepatitisa. Poročali so tudi o citopenijah, zato je treba enkrat mesečno določati celotno krvno sliko.
Pri bolnikih, ki so jemali ibrutinib so poročali tudi o primerih atrijske fibrilacije, atrijske undulacije, ventrikularne
tahiaritmije in srčnega popuščanja. Zaradi možnosti pojava srčnih bolezni, vključno s srčnimi aritmijami in srčnim
popuščanjem je treba vse bolnike občasno klinično pregledati. Pri bolnikih, pri katerih so se pojavili simptomi in/ali
znaki ventrikularne tahiaritmije je treba zdravljenje s tem zdravilom začasno prekiniti, pred ponovno uvedbo je treba
temeljito oceniti klinično razmerje med koristjo in tveganjem. Bolnike, pri katerih se pojavijo simptomi aritmije ali se
na novo pojavi zadihanost, omotica ali omedlevica, je treba klinično pregledati in jim po potrebi posneti EKG. Pri
bolnikih z obstoječo atrijsko fibrilacijo, ki potrebujejo zdravljenje z antikoagulanti, je treba razmisliti o drugih
možnostih zdravljenja. Če se atrijska fibrilacija pojavi med zdravljenjem, je treba temeljito oceniti tveganje za
trombembolične bolezni. Pri bolnikih z velikim tveganjem in kadar druge možnosti zdravljenja niso primerne, je treba
razmisliti o skrbno nadzorovanem zdravljenju z antikoagulanti Bolnike je treba med zdravljenjem skrbno spremljati
glede znakov in simptomov srčnega popuščanja. Pri bolnikih, ki so jemali to zdravilo so poročali o primerih ILD. Bolnike
spremljajte glede pljučnih simptomov ILD. Če se simptomi pojavijo, je treba zdravljenje prekiniti in ILD ustrezno
zdraviti. Če simptomi vztrajajo je treba oceniti tveganje in korist zdravljenja in upoštevati smernice za prilagoditev
odmerjanja. Pri bolnikih, ki so prejemali ibrutinib so poročali o primerih cerebrovaskularnega insulta, prehodnega
ishemičnega napada in ishemične možganske kapi s sočasno atrijsko fibrilacijo in/ali hipertenzijo ali brez njiju. Med
primeri, ki so bili poročani z zakasnitvijo, je od začetka zdravljenja do pojava ishemičnih žilnih bolezni osrednjega

Izkušnje, na katere
se lahko zanesete

živčevja večinoma minilo nekaj mesecev. Bolnike z večjo maso tumorja pred začetkom zdravljenja je treba skrbno
spremljati zaradi večjega tveganja za pojav sindroma razpada tumorja. Med zdravljenjem je treba bolnike spremljati
glede morebitnega pojava nemelanomskega kožnega raka. Bolnikom, ki prejemajo ibrutinib, je treba med celotnim
potekom zdravljenja redno meriti krvni tlak in jim po potrebi uvesti ali prilagoditi odmerjanje antihipertenzivnih
zdravil. Poročali so tudi o primerih hemofagocitne limfohistiocitoze, vključno s smrtnimi primeri. Pri sočasni uporabi z
zmernimi/močnimi zaviralci CYP3A4 lahko pride do povečane izpostavljenosti ibrutinibu in večjega tveganja za pojav
toksičnosti, pri sočasni uporabi z indukdorji CYP3A4 pa do zmanjšane izpostavljenosti in tveganja za pomanjkanje
učinkovitosti. Zato se je treba sočasni uporabi z močnimi zaviralci CYP3A4 in močnimi ali zmernimi induktorji CYP3A4
izogibati. O sočasni uporabi lahko razmislite samo, kadar pričakovane koristi nedvoumno presegajo morebitno tveganje.
Pri bolnikih, ki morajo jemati zaviralce CYP3A4, je treba skrbno spremljati morebitne znake toksičnega delovanja
zdravila; pri tistih, ki jemljejo induktorje CYP3A4 pa znake pomanjkanja učinkovitosti. Bolniki z redko dedno
intoleranco za galaktozo, odsotnostjo encima laktaze ali malabsorpcijo glukoze/galaktoze ne smejo jemati tega
zdravila. Ena filmsko obložena tableta vsebuje manj kot 1 mmol natrija (23 mg) kar v bistvu pomeni ‘brez natrija’.
Interakcije: Sočasna uporaba z zdravili, ki močno/zmerno zavirajo CYP3A4, lahko poveča izpostavljenost ibrutinibu,
zato se je treba uporabi močnih zaviralcev CYP3A4 izogibati. Če mora bolnik jemati katerega od močnih/zmernih
zaviralcev CYP3A4, je treba odmerek zdravila Imbruvica prilagoditi (glejte Povzetek glavnih značilnosti zdravila),
bolnike pa skrbno spremljati. V kombinaciji s šibkimi zaviralci prilagajanje odmerjanja ni potrebno. Bolnike je treba
skrbno spremljati in po potrebi upoštevati smernice za prilagajanje odmerka. Med zdravljenjem se je treba izogibati
uživanju grenivk in seviljskih pomaranč, ker vsebujejo zmerne zaviralce CYP3A4. Sočasna uporaba zdravila Imbruvica z
induktorji CYP3A4 lahko zmanjša koncentracijo ibrutiniba v plazmi. Razmisliti velja o uporabi drugih učinkovin, ki v
manjši meri inducirajo CYP3A4. Če je potrebna uporaba močnega ali zmernega induktorja CYP3A4 in pričakovana korist
presega morebitno tveganje, je treba bolnika skrbno spremljati glede znakov pomanjkanja učinkovitosti. Zdravilo se
lahko sočasno uporablja z blagimi induktorji, vendar je treba bolnike skrbno spremljati glede znakov pomanjkanja
učinkovitosti. Topnost ibrutiniba je odvisna od pH, zato lahko zdravila, ki zvečajo pH v želodcu (npr. zaviralci protonske
črpalke), zmanjšajo izpostavljenost ibrutinibu. In vitro ibrutinib zavira P‑glikoprotein in BCRP, zato je treba substrate
P‑glikoproteina in BCRP, ki imajo ozko peroralno terapevtsko okno (npr. digoksin, metotreksat) jemati najmanj 6 ur pred
oz. najmanj 6 ur po odmerjanju zdravila Imbruvica. Ibrutinib lahko zavira tudi BCRP v jetrih in zveča izpostavljenost
zdravilom, katerih izločanje skozi jetra je povezano z BCRP (rosuvastatin). V študiji medsebojnega delovanja z drugimi
zdravili pri bolnikih z malignomi celic B, ibrutinib v enkratnem, 560 mg odmerku ni klinično pomembno vplival na
izpostavljenost substratu CYP3A4 midazolamu. V isti študiji, 2 tedensko zdravljenje z ibrutinibom v odmerku 560 mg na
dan, ni klinično pomembno vplivalo na farmakokinetiko oralnih kontraceptivov (etiniletradiol in levonorgestrel),
substrata CYP3A4 midazolama ali substrata CYP2B6 bupropiona. Nosečnost, dojenje in plodnost: Ženske v rodni dobi
morajo med zdravljenjem in še tri mesece po zaključku zdravljenja uporabljati zelo učinkovito metodo kontracepcije.
Zdravila ne smete uporabljati pri nosečnicah. Med zdravljenjem je treba prenehati z dojenjem. Podatkov o vplivu
ibrutiniba na plodnost pri ljudeh ni na voljo. Vpliv na sposobnost vožnje in upravljanja strojev: Zdravilo ima blag vpliv
na sposobnost vožnje in upravljanja strojev. Pri nekaterih bolnikih so poročali o utrujenosti, omotičnosti in asteniji, kar
je treba upoštevati pri presoji bolnikove sposobnosti za vožnjo in upravljanje strojev. Neželeni učinki: pljučnica,
okužba zgornjih dihal, sinusitis, sepsa, kriptokokna/pnevmocistična okužba, okužba z aspergilusom, reaktivacija
hepatitisa B, nemelanomski kožni raki, okužba sečil, okužba kože, nevtropenija, trombocitopenija, limfocitoza,
anemija, febrilna nevtropenija, levkocitoza, sindrom levkostaze, ILD, dehidracija, hiperurikemija, sindrom razpada
tumorja, omotičnost, glavobol, periferna nevropatija, cerebrovaskularni insult, prehodni ishemični napad, ishemična
možganska kap, zamegljen vid, očesna krvavitev, srčno popuščanje, atrijska fibrilacija, ventrikularna tahiaritmija,
krvavitev, podplutba,petehije, subduralni hematom, krvavitev iz nosu, diareja, bruhanje, stomatitis, navzea,
obstipacija, suha usta, odpoved jeter, izpuščaj, angioedem, panikulitis, nevtrofilne dermatoze, urtikarija, eritem,
lomljenje nohtov, Stevens-Johnsonov sindrom, artralgija, mišičnoskeletne bolečine, zvišana telesna temperatura,
periferni edem, zvišanje kreatinina v krvi (vsi NU so opisani v povzetku glavnih značilnosti zdravila) Način in režim
izdajanja zdravila: Rp/Spec. Imetnik DzP: Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgija
Predstavnik Imetnika DzP v Sloveniji: Johnson & Johnson d.o.o., Šmartinska cesta 53, 1000 Ljubljana
Datum zadnje revizije besedila: 20. 08. 2021
Povzetek glavnih značilnosti zdravila s podrobnejšimi informacijami o zdravilu je dostopen pri predstavniku imetnika
dovoljenja za promet.
Viri:
1. Povzetek glavnih značilnosti zdravila IMBRUVICA® (ibrutinib).
2. Byrd JC et al. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927.
3. Burger JA, et al. Leukemia 2020;34(3):787-798.
4. Munir T, et al. Am J Hematol 2019;94(12):1353-1363.
5. Treon SP, et al. Haem Onc 2019;37(S2):184-185.
6. O’Brien S, et al. Clin Lymphoma Myeloma Leuk 2018;18(10):648-657.

Janssen, farmacevtski del Johnson & Johnson d.o.o.
Šmartinska 53, 1000 Ljubljana, Slovenia, Tel: 01 401 18 00, e-mail: info@janssen-slovenia.si, www.janssen.com/slovenia

CP-214010/020921

(pembrolizumab, MSD)

Kolorektalni
rak1
Nedrobnocelični
pljučni rak1

Rak ledvičnih
celic1

Melanom1
Referenca: 1. Keytruda EU SmPC
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti
zdravila!
Ime zdravila: KEYTRUDA 25 mg/ml koncentrat za raztopino za infundiranje vsebuje
pembrolizumab. Terapevtske indikacije: Zdravilo KEYTRUDA je kot samostojno
zdravljenje indicirano za zdravljenje: napredovalega (neoperabilnega ali metastatskega)
melanoma pri odraslih; za adjuvantno zdravljenje odraslih z melanomom v stadiju III, ki se
je razširil na bezgavke, po popolni kirurški odstranitvi; metastatskega nedrobnoceličnega
pljučnega raka (NSCLC) v prvi liniji zdravljenja pri odraslih, ki imajo tumorje z ≥ 50 %
izraženostjo PD-L1 (TPS) in brez pozitivnih tumorskih mutacij EGFR ali ALK; lokalno
napredovalega ali metastatskega NSCLC pri odraslih, ki imajo tumorje z ≥ 1 % izraženostjo
PD-L1 (TPS) in so bili predhodno zdravljeni z vsaj eno shemo kemoterapije, bolniki s
pozitivnimi tumorskimi mutacijami EGFR ali ALK so pred prejemom zdravila KEYTRUDA
morali prejeti tudi tarčno zdravljenje; odraslih in pediatričnih bolnikov, starih 3 leta ali več,
s ponovljenim ali neodzivnim klasičnim Hodgkinovim limfomom (cHL), pri katerih
avtologna presaditev matičnih celic (ASCT) ni bila uspešna, ali po najmanj dveh
predhodnih zdravljenjih kadar ASCT ne pride v poštev kot možnost zdravljenja; lokalno
napredovalega ali metastatskega urotelijskega raka pri odraslih, predhodno zdravljenih s
kemoterapijo, ki je vključevala platino; lokalno napredovalega ali metastatskega
urotelijskega raka pri odraslih, ki niso primerni za zdravljenje s kemoterapijo, ki vsebuje
cisplatin in imajo tumorje z izraženostjo PD-L1 ≥ 10, ocenjeno s kombinirano pozitivno
oceno (CPS); ponovljenega ali metastatskega ploščatoceličnega raka glave in vratu
(HNSCC) pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS), in pri katerih je
bolezen napredovala med zdravljenjem ali po zdravljenju s kemoterapijo, ki je vključevala
platino in za prvo linijo zdravljenja metastatskega kolorektalnega raka z visoko
mikrosatelitsko nestabilnostjo (MSI-H – microsatellite instability-high) ali s pomanjkljivim
popravljanjem neujemanja pri podvojevanju DNA (dMMR - mismatch repair deficient) pri
odraslih. Zdravilo KEYTRUDA je kot samostojno zdravljenje ali v kombinaciji s
kemoterapijo s platino in 5-fluorouracilom (5-FU) indicirano za prvo linijo zdravljenja
metastatskega ali neoperabilnega ponovljenega ploščatoceličnega raka glave in vratu pri
odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1. Zdravilo KEYTRUDA je v
kombinaciji s pemetreksedom in kemoterapijo na osnovi platine indicirano za prvo linijo
zdravljenja metastatskega neploščatoceličnega NSCLC pri odraslih, pri katerih tumorji
nimajo pozitivnih mutacij EGFR ali ALK; v kombinaciji s karboplatinom in bodisi
paklitakselom bodisi nab-paklitakselom je indicirano za prvo linijo zdravljenja
metastatskega ploščatoceličnega NSCLC pri odraslih; v kombinaciji z aksitinibom je
indicirano za prvo linijo zdravljenja napredovalega raka ledvičnih celic (RCC) pri odraslih;
v kombinaciji s kemoterapijo s platino in fluoropirimidinom indicirano za prvo linijo
zdravljenja lokalno napredovalega neoperabilnega ali metastatskega raka požiralnika ali
HER-2 negativnega adenokarcinoma gastroezofagealnega prehoda pri odraslih, ki imajo
tumorje z izraženostjo PD-L1 s CPS ≥ 10. Odmerjanje in način uporabe: Testiranje PD-L1:
Če je navedeno v indikaciji, je treba izbiro bolnika za zdravljenje z zdravilom KEYTRUDA
na podlagi izraženosti PD-L1 tumorja potrditi z validirano preiskavo. Testiranje MSI-H/
dMMR pri bolnikih s CRC: Za samostojno zdravljenje z zdravilom KEYTRUDA je
priporočljivo opraviti testiranje MSI-H/dMMR statusa tumorja z validirano preiskavo, da se
izbere bolnike s CRC. Odmerjanje: Priporočeni odmerek zdravila KEYTRUDA pri odraslih je
bodisi 200 mg na 3 tedne ali 400 mg na 6 tednov, apliciran z intravensko infuzijo v 30
minutah. Priporočeni odmerek zdravila KEYTRUDA za samostojno zdravljenje pri
pediatričnih bolnikih s cHL, starih 3 leta ali več, je 2 mg/kg telesne mase (do največ 200
mg) na 3 tedne, apliciran z intravensko infuzijo v 30 minutah. Za uporabo v kombinaciji
glejte povzetke glavnih značilnosti sočasno uporabljenih zdravil. Če se uporablja kot del
kombiniranega zdravljenja skupaj z intravensko kemoterapijo, je treba zdravilo
KEYTRUDA aplicirati prvo. Bolnike je treba zdraviti do napredovanja bolezni ali
nesprejemljivih toksičnih učinkov. Pri adjuvantnem zdravljenju melanoma je treba
zdravilo uporabljati do ponovitve bolezni, pojava nesprejemljivih toksičnih učinkov
oziroma mora zdravljenje trajati do enega leta. Če je aksitinib uporabljen v kombinaciji s
pembrolizumabom, se lahko razmisli o povečanju odmerka aksitiniba nad začetnih 5 mg
v presledkih šest tednov ali več. Pri bolnikih starih ≥ 65 let, bolnikih z blago do zmerno
okvaro ledvic, bolnikih z blago okvaro jeter prilagoditev odmerka ni potrebna. Odložitev
odmerka ali ukinitev zdravljenja: Zmanjšanje odmerka zdravila KEYTRUDA ni priporočljivo.
Za obvladovanje neželenih učinkov je treba uporabo zdravila KEYTRUDA zadržati ali
ukiniti, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Kontraindikacije:
Preobčutljivost na učinkovino ali katero koli pomožno snov. Povzetek posebnih
opozoril, previdnostnih ukrepov, interakcij in neželenih učinkov: Imunsko pogojeni
neželeni učinki (pnevmonitis, kolitis, hepatitis, nefritis, endokrinopatije, neželeni učinki

Ploščatocelični
karcinom
glave in vratu1
Hodgkinov
limfom1

Rak
požiralnika1

Urotelijski
karcinom1

na kožo in drugi): Pri bolnikih, ki so prejemali pembrolizumab, so se pojavili imunsko
pogojeni neželeni učinki, vključno s hudimi in smrtnimi primeri. Večina imunsko
pogojenih neželenih učinkov, ki so se pojavili med zdravljenjem s pembrolizumabom, je
bila reverzibilnih in so jih obvladali s prekinitvami uporabe pembrolizumaba, uporabo
kortikosteroidov in/ali podporno oskrbo. Pojavijo se lahko tudi po zadnjem odmerku
pembrolizumaba in hkrati prizadanejo več organskih sistemov. V primeru suma na
imunsko pogojene neželene učinke je treba poskrbeti za ustrezno oceno za potrditev
etiologije oziroma izključitev drugih vzrokov. Glede na izrazitost neželenega učinka je
treba zadržati uporabo pembrolizumaba in uporabiti kortikosteroide – za natančna
navodila, prosimo, glejte Povzetek glavnih značilnosti zdravila Keytruda. Zdravljenje s
pembrolizumabom lahko poveča tveganje za zavrnitev pri prejemnikih presadkov čvrstih
organov. Pri bolnikih, ki so prejemali pembrolizumab, so poročali o hudih z infuzijo
povezanih reakcijah, vključno s preobčutljivostjo in anafilaksijo. Pembrolizumab se iz
obtoka odstrani s katabolizmom, zato presnovnih medsebojnih delovanj zdravil ni
pričakovati. Uporabi sistemskih kortikosteroidov ali imunosupresivov pred uvedbo
pembrolizumaba se je treba izogibati, ker lahko vplivajo na farmakodinamično aktivnost
in učinkovitost pembrolizumaba. Vendar pa je kortikosteroide ali druge imunosupresive
mogoče uporabiti za zdravljenje imunsko pogojenih neželenih učinkov. Kortikosteroide
je mogoče uporabiti tudi kot premedikacijo, če je pembrolizumab uporabljen v
kombinaciji s kemoterapijo, kot antiemetično profilakso in/ali za ublažitev neželenih
učinkov, povezanih s kemoterapijo. Ženske v rodni dobi morajo med zdravljenjem s
pembrolizumabom in vsaj še 4 mesece po zadnjem odmerku pembrolizumaba
uporabljati učinkovito kontracepcijo, med nosečnostjo in dojenjem se ga ne sme
uporabljati. Varnost pembrolizumaba pri samostojnem zdravljenju so v kliničnih študijah
ocenili pri 6.185 bolnikih z napredovalim melanomom, kirurško odstranjenim
melanomom v stadiju III (adjuvantno zdravljenje), NSCLC, cHL, urotelijskim rakom, HNSCC
ali CRC s štirimi odmerki (2 mg/kg telesne mase na 3 tedne, 200 mg na 3 tedne in 10 mg/
kg telesne mase na 2 ali 3 tedne). V tej populaciji bolnikov je mediani čas opazovanja
znašal 7,6 mesece (v razponu od 1 dneva do 47 mesecev), najpogostejši neželeni učinki
zdravljenja s pembrolizumabom so bili utrujenost (32 %), navzea (21 %) in diareja (21 %).
Večina poročanih neželenih učinkov pri samostojnem zdravljenju je bila po izrazitosti 1.
ali 2. stopnje. Najresnejši neželeni učinki so bili imunsko pogojeni neželeni učinki in hude
z infuzijo povezane reakcije. Varnost pembrolizumaba pri kombiniranem zdravljenju s
kemoterapijo so ocenili pri 1.437 bolnikih NSCLC, HNSCC ali rakom požiralnika, ki so v
kliničnih študijah prejemali pembrolizumab v odmerkih 200 mg, 2 mg/kg telesne mase ali
10 mg/kg telesne mase na vsake 3 tedne. V tej populaciji bolnikov so bili najpogostejši
neželeni učinki naslednji: navzea (55 %), anemija (51 %), utrujenost (39 %), zaprtost (37
%), zmanjšanje apetita (34 %), diareja (33 %), nevtropenija (29 %) in bruhanje (28 %).
Pojavnost neželenih učinkov 3. do 5. stopnje je pri bolnikih z NSCLC pri kombiniranem
zdravljenju s pembrolizumabom znašala 67 % in pri zdravljenju samo s kemoterapijo 66
%, pri bolnikih s HNSCC pri kombiniranem zdravljenju s pembrolizumabom 85 % in pri
zdravljenju s kemoterapijo v kombinaciji s cetuksimabom 84 %, ter pri bolnikih z rakom
požiralnika pri kombiniranem zdravljenju s pembrolizumabom 86 % in pri zdravljenju
samo s kemoterapijo 83 %. Varnost pembrolizumaba v kombinaciji z aksitinibom so
ocenili v klinični študiji pri 429 bolnikih z napredovalim rakom ledvičnih celic, ki so
prejemali 200 mg pembrolizumaba na 3 tedne in 5 mg aksitiniba dvakrat na dan. V tej
populaciji bolnikov so bili najpogostejši neželeni učinki diareja (54 %), hipertenzija (45 %),
utrujenost (38 %), hipotiroidizem (35 %), zmanjšan apetit (30 %), sindrom palmarnoplantarne eritrodisestezije (28 %), navzea (28 %), zvišanje vrednosti ALT (27 %), zvišanje
vrednosti AST (26 %), disfonija (25 %), kašelj (21 %) in zaprtost (21 %). Pojavnost neželenih
učinkov 3. do 5. stopnje je bila med kombiniranim zdravljenjem s pembrolizumabom 76
% in pri zdravljenju s sunitinibom samim 71 %. Za celoten seznam neželenih učinkov,
prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Način in režim izdaje
zdravila: H – Predpisovanje in izdaja zdravila je le na recept, zdravilo se uporablja samo v
bolnišnicah. Imetnik dovoljenja za promet z zdravilom: Merck Sharp & Dohme B.V. ,
Waarderweg 39, 2031 BN Haarlem, Nizozemska.
Merck Sharp & Dohme inovativna zdravila d.o.o.,
Ameriška ulica 2, 1000 Ljubljana,
tel: +386 1/ 520 42 01, fax: +386 1/ 520 43 50;
Pripravljeno v Sloveniji, julij 2021; SI-KEY-00304 EXP: 07/2023
Samo za strokovno javnost.
H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo
v bolnišnicah. Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih
značilnosti zdravila Keytruda, ki je na voljo pri naših strokovnih sodelavcih ali na
lokalnem sedežu družbe.

Zdravilo KEYTRUDA®

(pembrolizumab, MSD)

OMOGOČA VEČ ČASA
Q6W - samo 9 infuzij letno*

ODMERJANJE NA 6 TEDNOV:
MANJ INFUZIJ ZA VAŠE BOLNIKE, VEČ ČASA ZA VAS!

* Priporočeni odmerek zdravila KEYTRUDA pri odraslih je bodisi 200 mg na 3 tedne ali 400 mg na 6 tednov,
apliciran z intravensko infuzijo v 30 minutah.
Q3W = vsake 3 tedne; Q6W = vsakih 6 tednov. Referenca: 1. Keytruda EU SmPC
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti
zdravila!
Ime zdravila: KEYTRUDA 25 mg/ml koncentrat za raztopino za infundiranje vsebuje
pembrolizumab. Terapevtske indikacije: Zdravilo KEYTRUDA je kot samostojno
zdravljenje indicirano za zdravljenje: napredovalega (neoperabilnega ali metastatskega)
melanoma pri odraslih; za adjuvantno zdravljenje odraslih z melanomom v stadiju III, ki se
je razširil na bezgavke, po popolni kirurški odstranitvi; metastatskega nedrobnoceličnega
pljučnega raka (NSCLC) v prvi liniji zdravljenja pri odraslih, ki imajo tumorje z ≥ 50 %
izraženostjo PD-L1 (TPS) in brez pozitivnih tumorskih mutacij EGFR ali ALK; lokalno
napredovalega ali metastatskega NSCLC pri odraslih, ki imajo tumorje z ≥ 1 % izraženostjo
PD-L1 (TPS) in so bili predhodno zdravljeni z vsaj eno shemo kemoterapije, bolniki s
pozitivnimi tumorskimi mutacijami EGFR ali ALK so pred prejemom zdravila KEYTRUDA
morali prejeti tudi tarčno zdravljenje; odraslih in pediatričnih bolnikov, starih 3 leta ali več,
s ponovljenim ali neodzivnim klasičnim Hodgkinovim limfomom (cHL), pri katerih
avtologna presaditev matičnih celic (ASCT) ni bila uspešna, ali po najmanj dveh
predhodnih zdravljenjih kadar ASCT ne pride v poštev kot možnost zdravljenja; lokalno
napredovalega ali metastatskega urotelijskega raka pri odraslih, predhodno zdravljenih s
kemoterapijo, ki je vključevala platino; lokalno napredovalega ali metastatskega
urotelijskega raka pri odraslih, ki niso primerni za zdravljenje s kemoterapijo, ki vsebuje
cisplatin in imajo tumorje z izraženostjo PD-L1 ≥ 10, ocenjeno s kombinirano pozitivno
oceno (CPS); ponovljenega ali metastatskega ploščatoceličnega raka glave in vratu
(HNSCC) pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS), in pri katerih je
bolezen napredovala med zdravljenjem ali po zdravljenju s kemoterapijo, ki je vključevala
platino in za prvo linijo zdravljenja metastatskega kolorektalnega raka z visoko
mikrosatelitsko nestabilnostjo (MSI-H – microsatellite instability-high) ali s pomanjkljivim
popravljanjem neujemanja pri podvojevanju DNA (dMMR - mismatch repair deficient) pri
odraslih. Zdravilo KEYTRUDA je kot samostojno zdravljenje ali v kombinaciji s
kemoterapijo s platino in 5-fluorouracilom (5-FU) indicirano za prvo linijo zdravljenja
metastatskega ali neoperabilnega ponovljenega ploščatoceličnega raka glave in vratu pri
odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1. Zdravilo KEYTRUDA je v
kombinaciji s pemetreksedom in kemoterapijo na osnovi platine indicirano za prvo linijo
zdravljenja metastatskega neploščatoceličnega NSCLC pri odraslih, pri katerih tumorji
nimajo pozitivnih mutacij EGFR ali ALK; v kombinaciji s karboplatinom in bodisi
paklitakselom bodisi nab-paklitakselom je indicirano za prvo linijo zdravljenja
metastatskega ploščatoceličnega NSCLC pri odraslih; v kombinaciji z aksitinibom je
indicirano za prvo linijo zdravljenja napredovalega raka ledvičnih celic (RCC) pri odraslih;
v kombinaciji s kemoterapijo s platino in fluoropirimidinom indicirano za prvo linijo
zdravljenja lokalno napredovalega neoperabilnega ali metastatskega raka požiralnika ali
HER-2 negativnega adenokarcinoma gastroezofagealnega prehoda pri odraslih, ki imajo
tumorje z izraženostjo PD-L1 s CPS ≥ 10. Odmerjanje in način uporabe: Testiranje PD-L1:
Če je navedeno v indikaciji, je treba izbiro bolnika za zdravljenje z zdravilom KEYTRUDA
na podlagi izraženosti PD-L1 tumorja potrditi z validirano preiskavo. Testiranje MSI-H/
dMMR pri bolnikih s CRC: Za samostojno zdravljenje z zdravilom KEYTRUDA je
priporočljivo opraviti testiranje MSI-H/dMMR statusa tumorja z validirano preiskavo, da se
izbere bolnike s CRC. Odmerjanje: Priporočeni odmerek zdravila KEYTRUDA pri odraslih je
bodisi 200 mg na 3 tedne ali 400 mg na 6 tednov, apliciran z intravensko infuzijo v 30
minutah. Priporočeni odmerek zdravila KEYTRUDA za samostojno zdravljenje pri
pediatričnih bolnikih s cHL, starih 3 leta ali več, je 2 mg/kg telesne mase (do največ 200
mg) na 3 tedne, apliciran z intravensko infuzijo v 30 minutah. Za uporabo v kombinaciji
glejte povzetke glavnih značilnosti sočasno uporabljenih zdravil. Če se uporablja kot del
kombiniranega zdravljenja skupaj z intravensko kemoterapijo, je treba zdravilo
KEYTRUDA aplicirati prvo. Bolnike je treba zdraviti do napredovanja bolezni ali
nesprejemljivih toksičnih učinkov. Pri adjuvantnem zdravljenju melanoma je treba
zdravilo uporabljati do ponovitve bolezni, pojava nesprejemljivih toksičnih učinkov
oziroma mora zdravljenje trajati do enega leta. Če je aksitinib uporabljen v kombinaciji s
pembrolizumabom, se lahko razmisli o povečanju odmerka aksitiniba nad začetnih 5 mg
v presledkih šest tednov ali več. Pri bolnikih starih ≥ 65 let, bolnikih z blago do zmerno
okvaro ledvic, bolnikih z blago okvaro jeter prilagoditev odmerka ni potrebna. Odložitev
odmerka ali ukinitev zdravljenja: Zmanjšanje odmerka zdravila KEYTRUDA ni priporočljivo.
Za obvladovanje neželenih učinkov je treba uporabo zdravila KEYTRUDA zadržati ali
ukiniti, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Kontraindikacije:
Preobčutljivost na učinkovino ali katero koli pomožno snov. Povzetek posebnih
opozoril, previdnostnih ukrepov, interakcij in neželenih učinkov: Imunsko pogojeni
neželeni učinki (pnevmonitis, kolitis, hepatitis, nefritis, endokrinopatije, neželeni učinki

na kožo in drugi): Pri bolnikih, ki so prejemali pembrolizumab, so se pojavili imunsko
pogojeni neželeni učinki, vključno s hudimi in smrtnimi primeri. Večina imunsko
pogojenih neželenih učinkov, ki so se pojavili med zdravljenjem s pembrolizumabom, je
bila reverzibilnih in so jih obvladali s prekinitvami uporabe pembrolizumaba, uporabo
kortikosteroidov in/ali podporno oskrbo. Pojavijo se lahko tudi po zadnjem odmerku
pembrolizumaba in hkrati prizadanejo več organskih sistemov. V primeru suma na
imunsko pogojene neželene učinke je treba poskrbeti za ustrezno oceno za potrditev
etiologije oziroma izključitev drugih vzrokov. Glede na izrazitost neželenega učinka je
treba zadržati uporabo pembrolizumaba in uporabiti kortikosteroide – za natančna
navodila, prosimo, glejte Povzetek glavnih značilnosti zdravila Keytruda. Zdravljenje s
pembrolizumabom lahko poveča tveganje za zavrnitev pri prejemnikih presadkov čvrstih
organov. Pri bolnikih, ki so prejemali pembrolizumab, so poročali o hudih z infuzijo
povezanih reakcijah, vključno s preobčutljivostjo in anafilaksijo. Pembrolizumab se iz
obtoka odstrani s katabolizmom, zato presnovnih medsebojnih delovanj zdravil ni
pričakovati. Uporabi sistemskih kortikosteroidov ali imunosupresivov pred uvedbo
pembrolizumaba se je treba izogibati, ker lahko vplivajo na farmakodinamično aktivnost
in učinkovitost pembrolizumaba. Vendar pa je kortikosteroide ali druge imunosupresive
mogoče uporabiti za zdravljenje imunsko pogojenih neželenih učinkov. Kortikosteroide
je mogoče uporabiti tudi kot premedikacijo, če je pembrolizumab uporabljen v
kombinaciji s kemoterapijo, kot antiemetično profilakso in/ali za ublažitev neželenih
učinkov, povezanih s kemoterapijo. Ženske v rodni dobi morajo med zdravljenjem s
pembrolizumabom in vsaj še 4 mesece po zadnjem odmerku pembrolizumaba
uporabljati učinkovito kontracepcijo, med nosečnostjo in dojenjem se ga ne sme
uporabljati. Varnost pembrolizumaba pri samostojnem zdravljenju so v kliničnih študijah
ocenili pri 6.185 bolnikih z napredovalim melanomom, kirurško odstranjenim
melanomom v stadiju III (adjuvantno zdravljenje), NSCLC, cHL, urotelijskim rakom, HNSCC
ali CRC s štirimi odmerki (2 mg/kg telesne mase na 3 tedne, 200 mg na 3 tedne in 10 mg/
kg telesne mase na 2 ali 3 tedne). V tej populaciji bolnikov je mediani čas opazovanja
znašal 7,6 mesece (v razponu od 1 dneva do 47 mesecev), najpogostejši neželeni učinki
zdravljenja s pembrolizumabom so bili utrujenost (32 %), navzea (21 %) in diareja (21 %).
Večina poročanih neželenih učinkov pri samostojnem zdravljenju je bila po izrazitosti 1.
ali 2. stopnje. Najresnejši neželeni učinki so bili imunsko pogojeni neželeni učinki in hude
z infuzijo povezane reakcije. Varnost pembrolizumaba pri kombiniranem zdravljenju s
kemoterapijo so ocenili pri 1.437 bolnikih NSCLC, HNSCC ali rakom požiralnika, ki so v
kliničnih študijah prejemali pembrolizumab v odmerkih 200 mg, 2 mg/kg telesne mase ali
10 mg/kg telesne mase na vsake 3 tedne. V tej populaciji bolnikov so bili najpogostejši
neželeni učinki naslednji: navzea (55 %), anemija (51 %), utrujenost (39 %), zaprtost (37
%), zmanjšanje apetita (34 %), diareja (33 %), nevtropenija (29 %) in bruhanje (28 %).
Pojavnost neželenih učinkov 3. do 5. stopnje je pri bolnikih z NSCLC pri kombiniranem
zdravljenju s pembrolizumabom znašala 67 % in pri zdravljenju samo s kemoterapijo 66
%, pri bolnikih s HNSCC pri kombiniranem zdravljenju s pembrolizumabom 85 % in pri
zdravljenju s kemoterapijo v kombinaciji s cetuksimabom 84 %, ter pri bolnikih z rakom
požiralnika pri kombiniranem zdravljenju s pembrolizumabom 86 % in pri zdravljenju
samo s kemoterapijo 83 %. Varnost pembrolizumaba v kombinaciji z aksitinibom so
ocenili v klinični študiji pri 429 bolnikih z napredovalim rakom ledvičnih celic, ki so
prejemali 200 mg pembrolizumaba na 3 tedne in 5 mg aksitiniba dvakrat na dan. V tej
populaciji bolnikov so bili najpogostejši neželeni učinki diareja (54 %), hipertenzija (45 %),
utrujenost (38 %), hipotiroidizem (35 %), zmanjšan apetit (30 %), sindrom palmarnoplantarne eritrodisestezije (28 %), navzea (28 %), zvišanje vrednosti ALT (27 %), zvišanje
vrednosti AST (26 %), disfonija (25 %), kašelj (21 %) in zaprtost (21 %). Pojavnost neželenih
učinkov 3. do 5. stopnje je bila med kombiniranim zdravljenjem s pembrolizumabom 76
% in pri zdravljenju s sunitinibom samim 71 %. Za celoten seznam neželenih učinkov,
prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Način in režim izdaje
zdravila: H – Predpisovanje in izdaja zdravila je le na recept, zdravilo se uporablja samo v
bolnišnicah. Imetnik dovoljenja za promet z zdravilom: Merck Sharp & Dohme B.V. ,
Waarderweg 39, 2031 BN Haarlem, Nizozemska.
Merck Sharp & Dohme inovativna zdravila d.o.o.,
Ameriška ulica 2, 1000 Ljubljana,
tel: +386 1/ 520 42 01, fax: +386 1/ 520 43 50;
Pripravljeno v Sloveniji, julij 2021; SI-KEY-00305 EXP: 07/2023
Samo za strokovno javnost.
H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo
v bolnišnicah. Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih
značilnosti zdravila Keytruda, ki je na voljo pri naših strokovnih sodelavcih ali na
lokalnem sedežu družbe.

CILJI ZDRAVLJENJA bolnic z napredovalim
HR+/HER2- rakom dojk

ESMO-MCBS
†

TOČK

ASCO
2021

5

RAZLIKA JE!
1,2*
NAJDALJŠE CELOKUPNO PREŽIVETJE in
3,4
IZBOLJŠANA ALI OHRANJENA KVALITETA ŽIVLJENJA

KISQALI + zaviralec aromataze + goserelin, 1. red zdravljenja: mOS = 58,7 meseca

*

KISQALI + fulvestrant, 1. in 2. red zdravljenja: mOS = 53,7 meseca

#

KISQALI je edini zaviralec CDK4/6, ki dokazano podaljša življenje v različnih kombinacijah
1-6
(zaviralec aromataze ali fulvestrant) in redih zdravljenja ter hkrati izboljša ali ohranja kvaliteto življenja

HR+ hormonsko odvisen rak dojk, HER2- rak dojk, negativen na receptorje humanega epidermalnega rastnega faktorja 2, Overall Survival, OS Celokupno preživetje, mediani OS, mOS mediana celokupnega preživetja. ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale: ESMO lestvica obsega klinične koristi.† Zdravilo KISQALI je po ESMO-MCBS lestvici za študijo MONALEESA-7 prejelo največje možno število točk (5 točk)5.
* MONALEESA-7 je bila randomizirana, dvojno slepa, s placebom nadzorovana multicentrična klinična študija faze III zdravljenja premenopavznih in perimenopavznih žensk z napredovalim HR+ HER2- rakom dojk, ki so poleg endokrinega zdravljenja prejemale še zdravilo Kisqali ali placebo. V raziskavo je bilo vključenih 672 bolnic, zdravilo Kisqali. je prejemalo 335 bolnic. V študiji je bil dosežen sekundarni cilj, dokazana je bila statistično značilna razlika med obema skupinama v dolžini preživetja bolnic1,6,7. Relativno znižanje tveganja za smrt je bilo 24% (razmerje ogroženosti = 0,76: 95%
IZ [0,608; 0,956])1. V skupini bolnic, ki so prejemale kombinacijo zdravila KISQALI + zaviralec aromataze je bilo doseženo najdaljše mediano celokupno preživetje med vsemi raziskavami faze III v katere so bile vključene bolnice s HR+ HER2- napredovalim rakom dojk: 58,7 meseca1.
# MONALEESA- 3 je bila randomizirana, dvojno slepa, s placebom nadzorovana multicentrična klinična študija faze III zdravljenja pomenopavznih žensk z napredovalim HR+ HER2- rakom dojk, ki so poleg fulvestranta prejemale še zdravilo Kisqali ali placebo v prvi ali drugi liniji zdravljenja. V študijo je bilo vključenih 726 bolnic, zdravilo Kisqali je prejemalo 484 bolnic. V študiji je bil dosežen sekundarni cilj, dokazana je bila statistično značilna razlika med obema skupinama v dolžini preživetja bolnic2,6,8. Relativno znižanje tveganja za smrt je bilo 28% (razmerje ogroženosti = 0,72: 95% IZ
[0,568; 0,924])8. Podatki do presečnega datuma 30. oktober 2020 za skupino bolnic, ki so prejemale kombinacijo zdravila Kisqali in fulvestranta kažejo mediano celokupno preživetje, 53,7 meseca (razmerje ogroženosti 0,73: 95% IZ [0,59; 0,90]).2
Reference: 1. Tripathy D, Im S-A, Colleoni M, in sod. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2–) advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Predstavljeno na: San Antonio Breast Cancer Symposium; 8-12. december 2020, 2020; San Antonio, Texas. Poster PD2-04. 2. Slamon D, Neven P, Chia S, in sod. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant ± placebo. Predstavljeno na kongresu American Society of Clinical Oncology (ASCO) 2021, 4-8. junij 2021, virtualni kongres. 3. Harbeck N, Vazquez RV, Franke F, in sod. Ribociclib+ tamoxifen or a non-steroidal aromatase inhibitor in premenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESA-7 patient-reported outcomes. Predstavljeno na: European Society for Medical Oncology Congress; 19- 23 oktober 2018; Munchen, Nemčija. 4.
Fasching PA, Esteva FJ, Pivot X, in sod. Patient-reported outcomes in advanced breast cancer treated with ribociclib + fulvestrant: results from MONALEESA-3. Predstavljeno na: European Society for Medical Oncology Congress; 19-23. oktober, Munchen, Nemčija. 5. Cardoso F, Paluch-Shimon S, Senkus E, in sod. 5th ESOESMO international consensus guidelines for advanced breast cancer (ABC5) 2020; 31 (12): 1623-1649. 6. Povzetek glavnih značilnosti zdravila Kisqali. Oktober 2020. 7. Im SA, Lu YS, Bardia A, in sod. Overall Survival with Ribociclib plus Endocrine Therapy in Breast
Cancer. N Engl J Med 2019; 381:307-16. 8. Slamon DJ, Neven P, Chia S, in sod. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382:514-524.

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA KISQALI®
Za to zdravilo se izvaja dodatno spremljanje varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8 povzetka glavnih značilnosti zdravila, kako poročati o neželenih učinkih.
Ime zdravila: Kisqali 200 mg filmsko obložene tablete. Sestava: Ena tableta vsebuje ribociklibijev sukcinat v količini, ki ustreza 200 mg ribocikliba. Indikacija: Zdravilo Kisqali je v kombinaciji z zaviralcem aromataze ali fulvestrantom indicirano za zdravljenje žensk z lokalno napredovalim ali metastatskim rakom dojk, ki je hormonsko odvisen (HR pozitiven) in negativen na receptorje humanega epidermalnega rastnega faktorja 2 (HER2 negativen), in sicer kot začetno hormonsko zdravljenje ali pri ženskah, ki so predhodno že prejemale
hormonsko zdravljenje. Pri ženskah pred menopavzo ali v perimenopavzi je treba hormonsko zdravljenje uporabljati skupaj z agonistom gonadoliberina (LHRH-luteinizing hormone releasing hormone). Odmerjanje in način uporabe: Zdravljenje mora uvesti zdravnik, ki ima izkušnje z uporabo zdravil proti raku. Priporočeni odmerek je 600 mg (tri 200‑miligramske tablete) ribocikliba 1x/dan 21 dni zaporedoma, čemur sledi 7 dni brez zdravljenja, tako da celotni ciklus traja 28 dni. Zdravljenje je treba nadaljevati, dokler ima bolnik od zdravljenja
klinično korist oz. do pojava nesprejemljivih toksičnih učinkov. Kisqali je treba uporabljati skupaj z 2,5 mg letrozola ali drugim zaviralcem aromataze ali s 500 mg fulvestranta. Zaviralec aromataze je treba jemati peroralno 1x/dan neprekinjeno vseh 28 dni ciklusa. Fulvestrant je treba odmerjati intramuskularno 1., 15. in 29. dan ciklusa, nato pa 1x/mesec. Za več podatkov glejte povzetek glavnih značilnosti zdravila za zaviralec aromataze oz. fulvestrant. Ženske pred menopavzo ali v perimenopavzi morajo prejemati tudi katerega od agonistov
gonadoliberina v skladu z lokalno klinično prakso. Kisqali je treba jemati peroralno 1x/dan skupaj s hrano ali brez nje. Bolniki naj vzamejo odmerek zdravila vsak dan ob približno istem času, najbolje zjutraj. Tablete je treba pogoltniti cele in se jih pred zaužitjem ne sme gristi, drobiti ali lomiti. Tablet, ki so razlomljene, zdrobljene ali kako drugače poškodovane, se ne sme zaužiti. Če bolnik po zaužitju odmerka bruha ali pozabi vzeti odmerek, na ta dan ne sme vzeti dodatnega odmerka. Naslednji predpisani odmerek mora vzeti ob običajnem času.
Prilagajanje odmerkov: Obvladovanje hudih ali nesprejemljivih neželenih dogodkov zdravila lahko vključuje prekinitev jemanja zdravila, znižanje odmerka ali ukinitev zdravila Kisqali. Ob prvem zmanjšanju odmerek zmanjšamo na 400 mg/dan (dve 200‑miligramski tableti), ob drugem zmanjšanju pa na 200 mg/dan (ena 200‑miligramska tableta). Če bi bilo treba odmerek zmanjšati na manj kot 200 mg/dan, je treba zdravljenje ukiniti. Za priporočila glede prekinitve jemanja zdravila, zmanjšanje odmerka ali ukinitev zdravljenja v primerih, ko je
to potrebno za obvladovanje določenih neželenih dogodkov zdravila, prosimo glejte povzetek glavnih značilnosti zdravila. Za prilagajanje odmerkov in druge pomembne podatke v primeru toksičnega delovanja glejte povzetek glavnih značilnosti zdravila za sočasno uporabljeni zaviralec aromataze, fulvestrant oz. agonist gonadoliberina. Okvara ledvic: Pri bolnikih z blago ali zmerno okvaro ledvic prilagajanje odmerka ni potrebno. Pri bolnikih s hudo okvaro ledvic (aGFR 15 do < 30 ml/min) je priporočen začetni odmerek 200 mg. Okvara jeter:
Bolnikom z blago okvaro jeter (Child‑Pugh razreda A) odmerka ni potrebno prilagajati. Pri bolnikih z zmerno (Child‑Pugh razreda B) ali hudo okvaro jeter (Child‑Pugh razreda C) je priporočeni začetni odmerek zdravila Kisqali 400 mg 1x/dan. Pediatrična populacija: Varnost in učinkovitost zdravila pri otrocih in mladostnikih, starih manj kot 18 let, nista bili dokazani. Starostniki: Pri bolnikih, ki so stari več kot 65 let, prilagajanje odmerka ni potrebno. Kontraindikacije: Preobčutljivost na učinkovino, arašide, sojo ali katero koli pomožno snov.
Posebna opozorila in previdnostni ukrepi: Kritična visceralna bolezen: Učinkovitosti in varnosti ribocikliba pri bolnikih s kritično visceralno boleznijo niso proučevali. Nevtropenija in hepatobiliarna toksičnost: Pregled celotne krvne slike in vrednosti jetrnih testov je treba opraviti pred začetkom zdravljenja, nato v prvih 2 ciklusih vsaka 2 tedna, v naslednjih 4 ciklusih na začetku vsakega ciklusa, nato pa kot je klinično indicirano. Če pride do nenormalnih vrednosti jetrnih testov stopnje ≥ 2, so priporočene pogostejše meritve jetrnih testov. Za
bolnike z zvišanjem vrednosti AST/ALT stopnje ≥3 ob izhodišču priporočila za odmerjanje niso dognana. Glede na to, kako močno je izražena nevtropenija ali zvišane vrednosti aminotransferaz, je morda treba odmerjanje zdravila Kisqali prekiniti, zmanjšati odmerek ali zdravljenje ukiniti. Podaljšanje intervala QT: Pred začetkom zdravljenja je treba posneti EKG. Zdravljenje je mogoče začeti samo pri bolnikih s trajanjem intervala QTcF manj kot 450 ms. EKG je treba ponovno posneti približno 14. dan prvega ciklusa in na začetku drugega ciklusa,
nato pa kot je klinično indicirano. V primeru, da v času zdravljenja pride do podaljšanja intervala QTcF, je priporočeno pogostejše snemanje EKG. Ustrezno spremljanje koncentracij elektrolitov v serumu (vključno s koncentracijami kalija, kalcija, fosforja in magnezija) je treba izvajati pred začetkom zdravljenja, nato na začetku prvih 6 ciklusov in kasneje kot je klinično indicirano. Kakršnekoli nepravilnosti je treba odpraviti pred začetkom oz. med potekom zdravljenja z zdravilom Kisqali. Uporabi zdravila Kisqali se je treba izogibati pri bolnikih s
prisotnim podaljšanjem intervala QTc ali s povečanim tveganjem za podaljšanje intervala QTc. To vključuje bolnike s sindromom podaljšanega intervala QT, z neurejenim ali pomembnim srčnim obolenjem, kar vključuje nedaven miokardni infarkt, kongestivno popuščanje srca, nestabilno angino pektoris in bradiaritmije ter bolnike z elektrolitskimi nepravilnostmi. Izogibati se je treba sočasni uporabi zdravila Kisqali z zdravili, za katera je znano, da lahko podaljšajo interval QT, kot so antiaritmiki (med drugim amiodaron, dizopiramid, prokainamid,
kinidin in sotalol) ter druga zdravila, za katera je znano, da podaljšujejo interval QT (med drugim klorokin, halofantrin, klaritromicin, ciprofloksacin, levofloksacin, azitromicin, haloperidol, metadon, moksifloksacin, bepridil, pimozid in intravenski ondansetron). Zdravila Kisqali prav tako ni priporočeno uporabljati v kombinaciji s tamoksifenom. Če se zdravljenju z močnim zaviralcem CYP3A4 ni mogoče izogniti, je treba odmerek zdravila Kisqali zmanjšati na 400 mg 1x/dan. Glede na izmerjeno podaljšanje intervala QT v času zdravljenja je morda
treba odmerjanje zdravila Kisqali prekiniti, zmanjšati odmerek ali zdravljenje ukiniti. Hude kožne reakcije: Poročali so o pojavu toksične epidermalne nekrolize (TEN). Če se pojavijo znaki in simptomi, ki lahko pomenijo, da gre za hudo kožno reakcijo (na primer progresiven generaliziran kožni izpuščaj, pogosto z mehurji, ali lezijami sluznice), je treba zdravljenje takoj prekiniti. Intersticijska pljučna bolezen/pnevmonitis: Glede na izraženost intersticijske pljučne bolezni/pnevmonitisa, ki se lahko končata tudi s smrtjo bolnika, bo v skladu s
priporočilom v povzetku glavnih značilnosti zdravila morda potrebno odmerjanje zdravila Kisqali prekiniti, zmanjšati odmerek ali zdravljenje ukiniti. Bolnike je treba spremljati glede pljučnih simptomov, ki bi lahko nakazovali na intersticijsko pljučno bolezen/pnevmonitis, in lahko vključujejo hipoksijo, kašelj in dispnejo. Zvišanje kreatinina: Če v času zdravljenja pride do zvišanja vrednosti kreatinina v krvi, je priporočeno izvesti dodatno oceno ledvične funkcije za izključitev okvare ledvic. Okvara ledvic: Pri začetnem odmerku 200 mg pri bolnikih
s hudo okvaro ledvic so ocenili, da je izpostavljenost za približno 45 % nižja kot pri standardnem začetnem odmerku pri bolnikih z normalnim delovanjem ledvic. Učinkovitosti pri tem začetnem odmerku niso preučevali. Pri bolnikih s hudo okvaro ledvic je potrebna previdnost s skrbnim spremljanjem glede znakov toksičnega delovanja. Sojin lecitin: Zdravilo vsebuje sojin lecitin. Bolniki s preobčutljivostjo na arašide ali sojo ne smejo jemati zdravila Kisqali. Plodnost, nosečnost in dojenje: Pred začetkom zdravljenja je treba preveriti status
nosečnosti. Ženskam v rodni dobi je treba svetovati, naj v času zdravljenja z zdravilom Kisqali in še najmanj 21 dni po prejemu zadnjega odmerka uporabljajo učinkovito kontracepcijsko metodo. Bolnice, ki jemljejo zdravilo Kisqali, ne smejo dojiti še najmanj 21 dni po prejemu zadnjega odmerka. Glede na ugotovitve študij pri živalih lahko zdravilo Kisqali zmanjša plodnost pri reproduktivno sposobnih moških. Vpliv na sposobnost vožnje in upravljanja strojev: Zdravilo ima lahko blag vpliv na sposobnost vožnje in upravljanja strojev. Bolnike
je treba opozoriti, naj bodo pri vožnji in upravljanju strojev previdni, če imajo v času zdravljenja težave z utrujenostjo, omotičnostjo ali vrtoglavico. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Snovi, ki lahko zvišajo koncentracijo ribocikliba v plazmi: Izogibati se je treba sočasni uporabi močnih zaviralcev CYP3A4, med drugim klaritromicinu, indinavirju, itrakonazolu, ketokonazolu, lopinavirju, ritonavirju, nefazodonu, nelfinavirju, posakonazolu, sakvinavirju, telaprevirju, telitromicinu, verapamilu in vorikonazolu. Za
sočasno uporabo je treba razmisliti o izbiri drugih zdravil z manjšim potencialom za zaviranje CYP3A4, bolnike pa je treba spremljati glede neželenih dogodkov v povezavi z ribociklibom. Če mora bolnik sočasno z ribociklibom prejemati močan zaviralec CYP3A4, je treba odmerek zdravila Kisqali zmanjšati na 400 mg 1x/dan. Pri bolnikih, pri katerih je odmerek že zmanjšan na 400 mg/dan, je treba odmerek zmanjšati na 200 mg, pri bolnikih, pri katerih je odmerek ribocikliba že zmanjšan na 200 mg dnevno, pa je treba zdravljenje z zdravilom
Kisqali prekiniti. Zaradi interindividualne variabilnosti priporočeno prilagajanje odmerjanja morda ni najboljše za vse bolnike, zato je priporočeno skrbno spremljanje bolnikov glede znakov toksičnega delovanja. Če bolnik preneha jemati zdravilo, ki je močan zaviralec, je treba odmerek zdravila Kisqali prilagoditi in po najmanj 5 razpolovnih dobah močnega zaviralca CYP3A4 spet začeti z odmerkom zdravila Kisqali, ki ga je bolnik prejemal pred začetkom uporabe močnega zaviralca CYP3A4. Po začetku sočasne uporabe šibkih ali zmernih
zaviralcev CYP3A4 odmerka ribocikliba ni treba prilagajati, priporočeno pa je spremljanje bolnikov glede neželenih dogodkov v povezavi z ribociklibom. Bolnikom je treba naročiti, naj se izogibajo uživanju grenivk in njihovega soka, ker lahko povečajo izpostavljenost ribociklibu. Snovi, ki lahko znižajo koncentracijo ribocikliba v plazmi: Sočasna uporaba močnih induktorjev CYP3A4 lahko zmanjša izpostavljenost zdravilu, to pa lahko predstavlja tveganje za manjšo učinkovitost zdravila. Izogibati se je treba sočasni uporabi močnih induktorjev
CYP3A4, med drugim fenitoina, rifampicina, karbamazepina in šentjanževke (Hypericum perforatum). Za sočasno uporabo je treba razmisliti o izbiri drugega zdravila, ki ne inducira oziroma ima manjši potencial za indukcijo CYP3A4. Učinka zmernega induktorja CYP3A4 na izpostavljenost ribociklibu niso proučevali. Sočasna uporaba zmernega induktorja CYP3A4 lahko privede do zmanjšane izpostavljenosti ribociklibu, to pa lahko predstavlja tveganje za manjšo učinkovitost, še posebej pri bolnikih, ki se zdravijo z ribociklibom v odmerku 400 mg
ali 200 mg 1x/dan. Snovi, na katerih koncentracijo v plazmi lahko vpliva zdravilo Kisqali: Ribociklib je zmeren do močan zaviralec CYP3A4, zato lahko pride do interakcij z zdravili, ki so substrati oz. jih presnavlja CYP3A4, kar lahko povzroči zvišanje koncentracij sočasno uporabljenih zdravil v serumu. Pri sočasnem odmerjanju ribocikliba z drugimi zdravili je praviloma treba pregledati povzetek glavnih značilnosti drugega zdravila in poiskati priporočila za sočasno odmerjanje z zaviralci CYP3A4. Pri sočasni uporabi z občutljivimi substrati CYP3A4,
ki imajo nizek terapevtski indeks, je priporočena previdnost. Pri teh substratih, med drugim pri alfentanilu, ciklosporinu, everolimusu, fentanilu, sirolimusu in takrolimusu, je v nekaterih primerih treba zmanjšati njihov odmerek, saj ribociklib lahko poveča izpostavljenost tem snovem. Izogibati se je treba sočasni uporabi ribocikliba v odmerku 600 mg skupaj z naslednjimi substrati CYP3A4: alfuzosin, amiodaron, cisaprid, pimozid, kinidin, ergotamin, dihidroergotamin, kvetiapin, lovastatin, simvastatin, sildenafil, midazolam in triazolam. Pri uporabi
klinično ustreznega odmerka 600 mg je mogoče pričakovati le šibak zaviralni učinek ribocikliba na substrate CYP1A2 (< 2‑kratno povečanje AUC). Snovi, ki so substrati prenašalcev: Vrednotenje podatkov in vitro raziskav kaže, da ima ribociklib potencial za zaviranje aktivnosti prenašalcev P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 in BSEP. Pri sočasnem zdravljenju s snovmi, ki so občutljivi substrati teh prenašalcev in imajo nizek terapevtski indeks, med drugim z digoksinom, pitavastatinom, pravastatinom, rosuvastatinom in metforminom,
je priporočena previdnost in spremljanje bolnikov glede toksičnega delovanja. Zdravila, ki zvišujejo pH v želodcu: Pri populacijski farmakokinetični analizi in nekompartmentalni farmakokinetični analizi pri sočasni uporabi niso opažali sprememb v absorpciji ribocikliba. Medsebojno delovanje med ribociklibom in letrozolom oz. anastrozolom oz. fulvestrantom oz. tamoksifenom: Med ribociklibom in letrozolom oz. med ribociklibom in anastrozolom ne prihaja do medsebojnega delovanja pri sočasnem odmerjanju obeh zdravil. Po podatkih iz
klinične študije fulvestrant nima klinično pomembnega vpliva na izpostavljenost ribociklibu pri sočasnem odmerjanju, po sočasnem odmerjanju ribocikliba in tamoksifena pa se je izpostavljenost tamoksifenu povečala na približno 2‑kratno vrednost. Neželeni učinki: Zelo pogosti (≥ 1/10): okužbe, nevtropenija, levkopenija, anemija, limfopenija, zmanjšan apetit, glavobol, omotičnost, dispneja, kašelj, navzea, diareja, bruhanje, obstipacija, stomatitis, bolečine v trebuhu, dispepsija, alopecija, izpuščaj, pruritus, bolečine v hrbtu, utrujenost, periferni
edemi, astenija, zvišana telesna temperatura, nenormalne vrednosti jetrnih testov. Pogosti (≥ 1/100 do < 1/10): trombocitopenija, febrilna nevtropenija, hipokalciemija, hipokaliemija, hipofosfatemija, vrtoglavica, močnejše solzenje, suhe oči, sinkopa, motnje okušanja, hepatotoksičnost, eritem, suha koža, vitiligo, suha usta, orofaringealna bolečina, zvišana vrednost kreatinina v krvi, podaljšan interval QT v elektrokardiogramu. Neznana pogostnost: toksična epidermalna nekroliza (TEN). Imetnik dovoljenja za promet z zdravilom: Novartis
Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Irska. Dodatne informacije in literatura: Novartis Pharma Services Inc., Podružnica v Sloveniji, Verovškova ulica 57, 1000 Ljubljana. Način/režim izdajanja zdravila: Rp/Spec. Pred predpisovanjem natančno preberite zadnji odobreni povzetek glavnih značilnosti zdravila. Datum zadnje revizije skrajšanega povzetka glavnih značilnosti zdravila: november 2020.

Novartis Pharma Services Inc., Podružnica v Sloveniji
Verovškova ulica 57, 1000 Ljubljana, tel.: 01 300 75 50

Datum priprave materiala: junij 2021

Samo za strokovno javnost.

SI-2021-KIS-099

Prva terapija
za zdravljenje odraslih bolnikov
z metastatskim ali lokalno
napredovalim ploščatoceličnim
karcinomom kože (PCKK), ki
niso kandidati za kurativni
kirurški poseg ali kurativno
obsevanje. 1,2
Zaviralec PD-1:
spodbuja bolnikov imunski p rotitumorski
odziv za izboljšanje rezultatov zdravljenja 3
PD-1, receptor programirane celične smrti 1

Pred predpisovanjem prosimo preberite celoten povzetek glavnih značilnosti zdravila.
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
▼Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila.
Ime zdravila: LIBTAYO 350 mg koncentrat za raztopino za infundiranje. Sestava: En mililiter koncentrata vsebuje 50 mg cemiplimaba. Ena viala vsebuje 350 mg cemiplimaba v 7 ml raztopine. Terapevtske indikacije: Ploščatocelični karcinom kože: Zdravilo
LIBTAYO je kot samostojno zdravljenje (monoterapija) indicirano za zdravljenje odraslih bolnikov z metastatskim ali lokalno napredovalim ploščatoceličnim karcinomom kože (mPCKK ali lnPCKK), ki niso kandidati za kurativni kirurški poseg ali kurativno
obsevanje. Bazalnocelični karcinom: Zdravilo LIBTAYO je kot samostojno zdravljenje (monoterapija) indicirano za zdravljenje odraslih bolnikov z lokalno napredovalim ali metastatskim bazalnoceličnim karcinomom (1aBCK ali mBCK), pri katerih je bolezen
napredovala kljub uporabi zaviralca signalne poti Hedgehog (HHI) ali ga ne prenašajo. Nedrobnocelični pljučni rak: Zdravilo LIBTAYO je kot samostojno zdravljenje (monoterapija) indicirano za prvo linijo zdravljenja odraslih bolnikov z nedrobnoceličnim pljučnim
rakom (NSCLC – Non-Small Cell Lung Cancer), katerih tumorji izražajo PD-L1 (v ≥ 50 % tumorskih celic) brez aberacij EGFR, ALK ali ROSI z: lokalno napredovalim NSCLC, ki niso primerni za definitivno kemoradiacijo, ali metastatskim NSCLC. Odmerjanje in
način uporabe: Zdravljenje mora uvesti in nadzorovati zdravnik, izkušen na področju zdravljenja raka. Testiranje PD-L1 pri bolnikih z NSCLC: Za zdravljenje s cemiplimabom kot monoterapijo je treba bolnike izbrati na podlagi validiranega testa izražanja PD-L1
v tumorju. Priporočeni odmerek: Priporočeni odmerek cemiplimaba je 350 mg na 3 tedne v 30 minutni intravenski infuziji. Zdravljenje se sme nadaljevati do napredovanja bolezni ali nesprejemljivih toksičnih učinkov. Prilagoditve odmerka: Zmanjšanja odmerka
niso priporočena. Glede na varnost in prenašanje pri posameznem bolniku je lahko potrebna odložitev odmerka ali prenehanje uporabe. Za priporočene prilagoditve za obvladovanje neželenih učinkov glejte celoten Povzetek glavnih značilnosti zdravila. Posebne
populacije: Pediatrična populacija: Varnost in učinkovitost zdravila LIBTAYO pri otrocih in mladostnikih, mlajših od 18 let, nista ugotovljeni. Starejše osebe, okvara ledvic, okvara jeter: odmerka ni treba prilagoditi. Način uporabe: Zdravilo LIBTAYO je namenjeno
intravenski uporabi. Daje se v intravenski infuziji v obdobju 30 minut po intravenski liniji, ki vsebuje sterilen, nepirogen filter (v sami liniji ali kot dodatek), ki malo veže beljakovine (velikost por od 0,2 do 5 mikronov). Po isti infuzijski liniji se ne sme istočasno
dajati drugih zdravil. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Sledljivost: Z namenom izboljšanja sledljivosti bioloških zdravil je treba jasno zabeležiti ime in številko serije
uporabljenega zdravila. Imunsko pogojeni neželeni učinki: Med uporabo cemiplimaba so opažali hude imunsko pogojene neželene učinke, tudi s smrtnim izidom. Pri bolnikih, zdravljenih s cemiplimabom ali drugimi zaviralci PD-1/PD-L1, se lahko sočasno pojavijo
imunski neželeni učinki, ki vplivajo na več telesnih sistemov, na primer miozitis in miokarditis ali miastenija gravis. Za obvladanje imunsko pogojenih neželenih učinkov je treba prilagoditi odmerek cemiplimaba, nadomestno hormonsko zdravljenje (če je klinično
indicirano) in kortkosteroide. Odvisno od izrazitosti neželenega učinka je treba uporabo cemiplimaba začasno prekiniti ali za stalno prenehati. Imunsko pogojeni pnevmonitis: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojeni pnevmonitis,
opredeljen s potrebo po uporabi kortikosteroidov in brez jasne alternativne etiologije, vključno s primeri s smrtnim izidom. Imunsko pogojeni kolitis: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojeno drisko ali kolitis, opredeljena s potrebo
po uporabi kortikosteroidov in brez jasne alternativne etiologije. Imunsko pogojeni hepatitis: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojeni hepatitis, opredeljen s potrebo po uporabi kortikosteroidov in brez jasne alternativne etiologije,
vključno s primeri s smrtnim izidom. Imunsko pogojene endokrinopatije: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojene endokrinopatije, opredeljene kot med zdravljenjem nastale endokrinopatije brez jasne alternativne etiologije. Motnje v
delovanju ščitnice (hipotiroidizem/hipertiroidizem/tiroiditis): Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojene motnje v delovanju ščitnice. Tiroiditis se lahko pojavi s spremembo testov delovanja ščitnice ali brez nje. Hipertiroidizmu lahko sledi
hipotiroidizem. Hipofizitis: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojeni hipofizitis. Nadledvična insuficienca: Pri bolnikih, ki so prejemali cemiplimab, so opažali nadledvično insuficienco. Sladkorna bolezen tipa 1: Pri bolnikih, ki so prejemali
cemiplimab, so opažali imunsko pogojeno sladkorno bolezen tipa 1, vključno z diabetično ketoacidozo. Imunsko pogojeni neželeni učinki na kožo: Med zdravljenjem s cemiplimabom so poročali o imunsko pogojenih neželenih učinkih na kožo, opredeljenih s potrebo
po uporabi sistemskih kortikosteroidov in brez jasne alternativne etiologije; med njimi so bili hudi neželeni učinki na kožo, na primer Stevens-Johnsonov sindrom (SJS) in toksična epidermalna nekroliza (TEN) (v nekaterih primerih s smrtnim izidom), in druge
kožne reakcije, na primer izpuščaj, multiformni eritem in pemfigoid. Imunsko pogojeni nefritis: Pri bolnikih, ki so prejemali cemiplimab, so opažali imunsko pogojeni nefritis, opredeljen s potrebo po uporabi kortikosteroidov in brez jasne alternativne etiologije.
Drugi imunsko pogojeni neželeni učinki: Pri bolnikih, ki so prejemali cemiplimab, so opažali še druge življenjsko nevarne in smrtne imunsko pogojene neželene učinke, med njimi paraneoplastični encefalomielitis, meningitis in miozitis. Zdravljenje s
cemiplimabom lahko pri prejemnikih presadkov parenhimskih organov poveča tveganje za zavrnitev. V obdobju po prihodu na trg so pri bolnikih, ki so prejemali druge zaviralce PD-1/PD-L1 obenem z alogensko presaditvijo hematopoetskih matičnih celic, poročali
o primerih bolezni presadka proti gostitelju. Z infundiranjem povezane reakcije: Cemiplimab lahko povzroči resne ali življenjsko nevarne z infundiranjem povezane reakcije. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Uporabi
sistemskih kortikosteroidov ali imunosupresivov pred uvedbo cemiplimaba se je treba izogibati, razen fizioloških odmerkov sistemskih kortikosteroidov (≤ 10 mg/dan prednizolona ali enakovredno), ker lahko motijo farmakodinamično aktivnost in učinkovitost
cemiplimaba. Vendar pa je kortikosteroide ali druge imunosupresive mogoče uporabiti po začetku zdravljenja s cemiplimabom za zdravljenje imunsko pogojenih neželenih učinkov. Plodnost, nosečnost in dojenje: Ženske v rodni dobi morajo med zdravljenjem
s cemiplimabom in vsaj še 4 mesece po zadnjem odmerku cemiplimaba uporabljati učinkovito kontracepcijo. Cemiplimab ni priporočljiv med nosečnostjo in za ženske v rodni dobi, ki ne uporabljajo učinkovite kontracepcije, razen če klinična korist odtehta možno
tveganje. Če se ženska odloči za zdravljenje s cemiplimabom, ji je treba svetovati, da med zdravljenjem s cemiplimabom in vsaj še 4 mesece po zadnjem odmerku ne sme dojiti. Vpliv na sposobnost vožnje in upravljanja strojev: Po zdravljenju s
cemiplimabom so poročali o utrujenosti. Neželeni učinki: Zelo pogosti: okužba zgornjih dihal, anemija, zmanjšan apetit, kašelj, slabost, driska, zaprtje, izpuščaj, pruritus, mišično-skeletna bolečina, utrujenost. Pogosti: okužba sečil, z infundiranjem povezane
reakcije, hipotiroidizem, hipertiroidizem, glavobol, periferna nevropatija, hipertenzija, dispneja, pnevmonitis, bolečina v trebuhu, bruhanje, stomatitis, kolitis, hepatitis, artritis, nefritis, zvišana aspartat-aminotransferaza, zvišana alanin-aminotransferaza, zvišana
alkalna fosfataza v krvi, zvišan kreatinin v krvi. Občasni: sjögrenov sindrom, imunsko pogojena trombocitopenična purpura, nadledvična insuficienca, tiroiditis, sladkorna bolezen tipa 1, hipofizitis, meningitis, encefalitis, miastenija gravis, praneoplastični
encefalomielitis, kronična vnetna demielinizirajoča poliradikulonevropatija, keratitis, miokarditis, perikarditis, šibkost mišic, miozitis, revmatska polimialgija, zvišan ščitnični hormon v krvi, zvišane transaminase, zvišan bilirubin v krvi, znižan ščitnični hormon
v krvi. Preveliko odmerjanje: V primeru prevelikega odmerjanja naj se bolnike natančno kontrolira glede znakov in simptomov neželenih učinkov in uvede ustrezno simptomatsko zdravljenje. Način in režim izdaje zdravila: H-Predpisovanje in izdaja zdravila
je le na recept, zdravilo pa se uporablja samo v bolnišnicah. Imetnik dovoljenja za promet z zdravilom: Regeneron Ireland Designated Activity Company (DAC), One Warrington Place, Dublin 2, D02 HH27, Irska. Datum zadnje revizije besedila: 21.06.2021

SAMO ZA STROKOVNO JAVNOST

MAT-SI-2000079-5.0-09/2021
1. Libtayo (cemiplimab) Povzetek glavnih značilnosti zdravila, www.ema.europa.com, datum zadnjega podaljšanja 08.03.2021
2. www.nice.org.uk, technology appraisal guidance TA592. dostop 07.08.2019. 3. www.cancer.gov/publications/dictionaries/cancer-terms/def/pd-1, dostop 07.08.2019

ZAUPANJE,
ZGRAJENO
NA MOČI

Za zdravljenje lokalno
napredovalega ali
metastatskega
HR+/HER2- raka dojk:
•

v kombinaciji z zaviralcem aromataze,

•

v kombinaciji s fulvestrantom pri
ženskah, ki so prejele
predhodno endokrino zdravljenje.

Pri ženskah v pred- in perimenopavzi je
treba endokrino zdravljenje kombinirati
z agonistom gonadoliberina (LHRH –
Luteinizing Hormone–Releasing Hormone).
BISTVENI PODATKI IZ POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA
IIBRANCE 75 mg, 100 mg, 125 mg trde kapsule(1)
IBRANCE 75 mg, 100 mg, 125 mg filmsko obložene tablete(2)
Sestava in oblika zdravila: (1) Ena trda kapsula vsebuje 75 mg, 100 mg ali 125 mg palbocikliba in 56 mg, 74 mg ali 93 mg laktoze (v obliki monohidrata). (2) Ena filmsko obložena tableta
vsebuje 75 mg, 100 mg ali 125 mg palbocikliba. Indikacije: Zdravljenje lokalno napredovalega ali metastatskega na hormonske receptorje (HR – Hormone Receptors) pozitivnega in na
receptorje humanega epidermalnega rastnega faktorja 2 (HER2 – Human Epidermal growth factor Receptor 2) negativnega raka dojk: v kombinaciji z zaviralcem aromataze ali v kombinaciji
s fulvestrantom pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina.
Odmerjanje in način uporabe: Zdravljenje mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil za zdravljenje rakavih bolezni. Priporočeni odmerek je 125 mg enkrat na dan
21 zaporednih dni, sledi 7 dni brez zdravljenja (shema 3/1), celotni cikel traja 28 dni. Zdravljenje je treba nadaljevati, dokler ima bolnik od zdravljenja klinično korist ali dokler se ne pojavi
nesprejemljiva toksičnost. Pri sočasnem dajanju s palbociklibom je treba zaviralec aromataze dajati v skladu s shemo odmerjanja, ki je navedena v Povzetku glavnih značilnosti zdravila
(PGZZ). Pri sočasnem dajanju s palbociklibom je priporočeni odmerek fulvestranta 500 mg intramuskularno 1., 15. in 29. dan ter nato enkrat na mesec, glejte PGZZ za fulvestrant. Prilagajanja
odmerkov: Za prilagajanja odmerkov zaradi hematološke toksičnosti glejte preglednico 2, zaradi nehematološke toksičnosti pa preglednico 3 v PGZZ‑ju. Pri bolnikih s hudo intersticijsko
boleznijo pljuč (ILD)/pnevmonitisom je treba zdravljenje trajno prekiniti. Posebne skupine bolnikov: Starejši: Prilagajanje odmerka ni potrebno. Okvara jeter ali ledvic: Pri bolnikih z blago
ali zmerno okvaro jeter ali blago, zmerno ali hudo okvaro ledvic prilagajanje odmerka ni potrebno. Pri bolnikih s hudo okvaro jeter je priporočeni odmerek 75 mg enkrat na dan po shemi
3/1. Pediatrična populacija: Varnost in učinkovitost pri otrocih in mladostnikih, starih < 18 let, nista bili dokazani. Način uporabe: Peroralna uporaba. (1) Jemanje s hrano, priporočljivo z
obrokom. (2) Tablete se lahko jemlje s hrano ali brez nje. (1, 2) Ne smemo jemati z grenivko ali grenivkinim sokom. Kapsule oz. tablete zdravila je treba pogoltniti cele. Kontraindikacije:
Preobčutljivost na učinkovino ali katerokoli pomožno snov. Uporaba pripravkov s šentjanževko. Posebna opozorila in previdnostni ukrepi: Ženske v pred- in perimenopavzi: Kadar
zdravilo uporabljamo v kombinaciji z zaviralcem aromataze je obvezna ovarijska ablacija ali supresija z agonistom gonadoliberina. Hematološke bolezni: Pri nevtropeniji stopnje 3 ali 4 je
priporočljiva prekinitev odmerjanja, zmanjšanje odmerka ali odložitev začetka ciklov zdravljenja, bolnike pa je treba ustrezno spremljati. ILD/pnevmonitis: Pri bolnikih se lahko pojavita huda,
življenjsko ogrožajoča ali smrtna ILD in/ali pnevmonitis, kadar zdravilo jemljejo v kombinaciji z endokrinim zdravljenjem. Bolnike je treba spremljati glede pljučnih simptomov, ki kažejo
na ILD/pnevmonitis (npr. hipoksija, kašelj, dispneja), in pri pojavu novih ali poslabšanju respiratornih simptomov oz. sumu na ILD/pnevmonitis zdravljenje prekiniti. Okužbe: Zdravilo lahko
poveča nagnjenost k okužbam, zato je bolnike treba spremljati glede znakov in simptomov okužbe ter jih ustrezno zdraviti. Okvara jeter ali ledvic: Pri bolnikih z zmerno ali hudo okvaro
jeter ali ledvic je treba zdravilo uporabljati previdno in skrbno spremljati znake toksičnosti. (1) Laktoza: Vsebuje laktozo. Bolniki z redko dedno intoleranco za galaktozo, odsotnostjo encima
laktaze ali malabsorpcijo glukoze-galaktoze ne smejo jemati tega zdravila. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Učinki drugih zdravil na farmakokinetiko
palbocikliba: Zaviralci CYP3A: Sočasni uporabi močnih zaviralcev CYP3A, med drugim klaritromicina, indinavirja, itrakonazola, ketokonazola, lopinavirja/ritonavirja, nefazodona, nelfinavirja,
posakonazola, sakvinavirja, telaprevirja, telitromicina, vorikonazola in grenivke ali grenivkinega soka, se je treba izogibati. Induktorji CYP3A: Sočasni uporabi močnih induktorjev CYP3A,
med drugim karbamazepina, enzalutamida, fenitoina, rifampicina in šentjanževke, se je treba izogibati. Učinek zdravil za zmanjševanje kisline: (1) Če palbociklib zaužijemo s hrano, klinično
pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. (2) Klinično pomembnega učinka na izpostavljenost palbociklibu ni pričakovati. Učinki palbocikliba na farmakokinetiko
drugih zdravil: Pri sočasni uporabi bo morda treba zmanjšati odmerek občutljivih substratov CYP3A z ozkim terapevtskim indeksom (npr. alfentanil, ciklosporin, dihidroergotamin,
ergotamin, everolimus, fentanil, pimozid, kinidin, sirolimus in takrolimus), saj IBRANCE lahko poveča izpostavljenost tem zdravilom. Študije in vitro s prenašalci: Palbociklib lahko zavira
prenos, posredovan s P-gp v prebavilih in beljakovino odpornosti pri raku dojk (BCRP). Uporaba palbocikliba z zdravili, ki so substrati P-gp (npr. digoksin, dabigatran, kolhicin) ali BCRP
(npr. pravastatin, rosuvastatin, sulfasalazin) lahko poveča njihov terapevtski učinek in neželene učinke. Palbociklib lahko zavira privzemni prenašalec organskih kationov OCT1. Plodnost,
nosečnost in dojenje: Med zdravljenjem in vsaj 3 tedne (ženske) oziroma 14 tednov (moški) po koncu zdravljenja je treba uporabljati ustrezne kontracepcijske metode. Zdravila ne
uporabljajte pri nosečnicah in ženskah v rodni dobi, ki ne uporabljajo kontracepcije. Bolnice, ki prejemajo palbociklib, ne smejo dojiti. Zdravljenje s palbociklibom lahko ogrozi plodnost
pri moških. Pred začetkom zdravljenja naj moški zato razmislijo o hrambi sperme. Vpliv na sposobnost vožnje in upravljanja s stroji: Ima blag vpliv na sposobnost vožnje in upravljanja
strojev. Potrebna je previdnost. Neželeni učinki: Zelo pogosti: okužbe, nevtropenija, levkopenija, anemija, trombocitopenija, pomanjkanje teka, stomatitis, navzea, diareja, bruhanje, izpuščaj,
alopecija, suha koža, utrujenost, astenija, pireksija, povečane vrednosti ALT/AST. Način in režim izdaje: Rp/Spec - Predpisovanje in izdaja zdravila je le na recept zdravnika specialista
ustreznega področja medicine ali od njega pooblaščenega zdravnika. Imetnik dovoljenja za promet: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgija. Datum zadnje
revizije besedila: 16.07.2021
Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila.
PP-IBR-EEP-0236 Datum priprave: avgust 2021. Samo za strokovno javnost.
HR+/HER2- = pozitiven na hormonske receptorje in negativen na receptorje humanega epidermalnega rastnega faktorja 2.
Literatura: Povzetek glavnih značilnosti zdravila Ibrance, 16.7.2021.

Pfizer Luxembourg SARL, GRAND DUCHY OF LUXEMBOURG,
51, Avenue J. F. Kennedy, L-1855
Pfizer, podružnica Ljubljana, Letališka cesta 29a, Ljubljana

Revolucije
zahtevajo strast.

M-SI-00000051(v2.0)

Več kot stoletje postavljamo nove standarde v diagnostiki in zdravljenju
številnih bolezni. Danes nam novi viri podatkov in napredna analitika
omogočajo, da zagotovimo pravo zdravljenje za pravega bolnika ob pravem
času. Zato se povezujemo s tistimi, ki stremijo k istemu cilju in razumejo, da
nova znanja služijo ne samo znanosti, temveč predvsem človeštvu.

Informacija pripravljena: september 2020.
DODATNE INFORMACIJE SO NA VOLJO PRI: Roche farmacevtska družba d.o.o., Stegne 13g, 1000 Ljubljana.

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA ZA ZDRAVILI TAFINLAR IN MEKINIST

KO PRI VAŠIH BOLNIKIH Z
MELANOMOM STADIJA III ALI
IV UGOTOVITE PRISOTNOST
MUTACIJE BRAF

ODGOVORITE S
PREIZKUŠENIM
OROŽJEM
Dosežite podaljšano preživetje pri
bolnikih z BRAF+ melanomom stadija IV
ali možnost ozdravitve pri bolnikih s
stadijem III s kombinacijo zdravil
3, 4 #
TAFINLAR + MEKINIST. * †

* V študiji COMBI-AD je bila po medianem času spremljanja 60 mesecev (dabrafenib in

trametinib), oz. 58 mesecev (placebo) ocenjena stopnja ozdravitve 52 % (95-% IZ, 48 %-58 %;
dabrafenib in trametinib), in 36 % (95-% IZ, 32 %-41 %; placebo).
V združeni populaciji bolnikov iz študij COMBI-d in COMBI-v je bila stopnja celokupnega preživetja bolnikov
v skupini zdravljeni s kombinacijo zdravil dabrafenib in trametinib po 5 letih 34 % (95-% IZ, 30 %-38 %)
v primerjavi s 27% (dabrafenib+placebo) in 23 % (vemurafenib).
† Zdravili TAFINLAR in MEKINIST sta v kombinaciji indicirani za zdravljenje odraslih bolnikov z inoperabilnim ali metastatskim
melanomom z mutacijo BRAF V600 in adjuvantno zdravljenje odraslih bolnikov po totalni resekciji melanoma stadija III
z mutacijo BRAF V600.1,2

Imena zdravil: Tafinlar 50 mg trde kapsule, Tafinlar 75 mg trde kapsule, Mekinist 0,5 mg filmsko obložene tablete, Mekinist 2 mg filmsko obložene tablete. Sestava: Ena trda kapsula zdravila Tafinlar
vsebuje dabrafenibijev mesilat, ki ustreza 50 mg dabrafeniba ali 75 mg dabrafeniba. Ena filmsko obložena tableta zdravila Mekinist vsebuje 0,5 mg trametiniba ali 2 mg trametiniba v obliki
trametinibijevega dimetilsulfoksida. Indikacija: Melanom: Dabrafenib in trametinib sta v kombinaciji indicirana za zdravljenje odraslih bolnikov z inoperabilnim ali metastatskim melanomom
z mutacijo BRAF V600. Dabrafenib in trametinib sta oba tudi v monoterapiji indicirana za zdravljenje odraslih bolnikov z inoperabilnim ali metastatskim melanomom z mutacijo BRAF V600. Trametinib
v monoterapiji ni izkazal klinične aktivnosti pri bolnikih, ki jim je bolezen napredovala med predhodnim zdravljenjem z zaviralcem BRAF. Adjuvantno zdravljenje melanoma: Dabrafenib in trametinib
sta v kombinaciji indicirana za adjuvantno zdravljenje odraslih bolnikov po totalni resekciji melanoma stadija III z mutacijo BRAF V600. Nedrobnocelični pljučni rak (NDCPR): Dabrafenib
in trametinib sta v kombinaciji indicirana za zdravljenje odraslih bolnikov z napredovalim nedrobnoceličnim pljučnim rakom z mutacijo BRAF V600. Odmerjanje: Zdravljenje mora uvesti in
nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil proti raku. Pred uporabo dabrafeniba in/ali trametiniba mora biti z validirano preiskavo potrjeno, da ima bolnik mutacijo BRAF V600. Kombinirano
zdravljenje: 150 mg dabrafeniba 2x/dan in 2 mg trametiniba 1x/dan. Dabrafenib v monoterapiji (melanom): 150 mg dabrafeniba 2x/dan. Trametinib v monoterapiji (melanom): 2 mg trametiniba 1x/dan.
Če bolnik pozabi vzeti odmerek trametiniba, naj ga vzame samo, če je do naslednjega rednega odmerka več kot 12 ur, pozabljenega odmerka dabrafeniba ne sme vzeti, če je do naslednjega odmerka
po razporedu manj kot 6 ur. Zdravljenje je priporočljivo nadaljevati, dokler bolniku koristi oz. do pojava nesprejemljivih toksičnih učinkov. Pri adjuvantnem zdravljenju melanoma je treba bolnike zdraviti
12 mesecev, razen če pride do ponovitve bolezni ali nesprejemljivih toksičnih učinkov. Obvladovanje neželenih učinkov lahko zahteva znižanje odmerka, prekinitev zdravljenja ali prenehanje zdravljenja.
Prilagoditve odmerka ali prekinitve zdravljenja niso priporočljive v primeru neželenih učinkov ploščatoceličnega karcinoma kože ali novega primarnega melanoma. Če pri uporabi kombinacije
dabrafeniba in trametiniba pride do toksičnih učinkov zdravljenja, je treba sočasno znižati odmerek obeh zdravil oz. sočasno začasno prekiniti ali dokončno ukiniti obe zdravljenji. Izjeme, pri katerih je
treba odmerek prilagajati samo pri enem od obeh zdravil, so pojav zvišane telesne temperature (dabrafenib), uveitisa (dabrafenib), nekožnih malignomov z mutacijo RAS (dabrafenib), zmanjšanja
iztisnega deleža levega prekata (LVEF) (trametinib), zapore mrežnične vene (RVO) ali odstopa mrežničnega pigmentnega epitelija (RPED) (trametinib) in intersticijske bolezni pljuč (IBP)/pnevmonitisa
(trametinib). Za natančnejša navodila glede prilagajanja odmerkov glejte povzetka glavnih značilnosti zdravil Tafinlar in Mekinist. Bolnikom z blago ali zmerno okvaro ledvic ali z blago okvaro jeter
odmerkov dabrafeniba in trametiniba ni treba prilagoditi. Pri bolnikih s hudo okvaro ledvic ali z zmerno ali hudo okvaro jeter je treba dabrafenib in trametinib, bodisi v monoterapiji ali v kombinaciji,
uporabljati previdno. Bolnikom, starim > 65 let, začetnega odmerka dabrafeniba in trametiniba ni treba prilagoditi, je pa pri teh bolnikih lahko potrebno pogostejše prilagajanje odmerka trametiniba. Pri
bolnikih azijske rase ni potrebno prilagajati odmerkov dabrafeniba. Varnost in učinkovitost trametiniba nista ugotovljeni pri bolnikih, ki niso belci. Varnost in učinkovitost dabrafeniba in trametiniba pri
otrocih in mladostnikih (< 18 let) nista bili dokazani. Način uporabe: Zdravilo Tafinlar: Kapsule je treba zaužiti cele z vodo najmanj 1 uro pred jedjo oz. najmanj 2 uri po jedi. Ne sme se jih zgristi ali
odpreti. Če bolnik po zaužitju dabrafeniba ali trametiniba bruha, odmerka ne sme vzeti ponovno, temveč mora vzeti naslednji odmerek ob običajnem času. Zdravilo Mekinist: Tablete je treba zaužiti s
polnim kozarcem vode vsaj 1 uro pred jedjo ali vsaj 2 uri po jedi. Ne sme se jih gristi ali drobiti. Kontraindikacije: Preobčutljivost na učinkovini ali katero koli pomožno snov. Posebna opozorila in
previdnostni ukrepi: Dabrafeniba se ne sme uporabljati pri bolnikih z melanomom in pri bolnikih z NDCPR z divjim tipom BRAF. O uporabi kombinacije dabrafeniba in trametiniba pri bolnikih z
melanomom, pri katerih je bolezen napredovala med predhodnim zdravljenjem z zaviralcem BRAF, je na voljo malo podatkov, ki pa kažejo, da je učinkovitost kombinacije pri teh bolnikih manjša.
Ploščatocelični karcinom kože (dabrafenib ali kombinirano zdravljenje): Opisani so primeri ploščatoceličnega karcinoma kože. Priporočljivo je opraviti pregled kože pred uvedbo dabrafeniba, vsak mesec
med zdravljenjem in še do 6 mesecev po zdravljenju ploščatoceličnega karcinoma kože. Bolnika se mora spremljati še 6 mesecev po prenehanju zdravljenja z dabrafenibom ali do uvedbe drugega
antineoplastičnega zdravljenja. Primere ploščatoceličnega karcinoma kože je treba zdraviti z dermatološko ekscizijo, z dabrafenibom oz. kombinacijo pa nadaljevati brez prilagoditve odmerka. Bolnikom
je treba naročiti, naj nemudoma obvestijo zdravnika, če se jim pojavi kakšna nova sprememba. Nov primarni melanom (dabrafenib ali kombinirano zdravljenje): Bolnika je mogoče zdraviti z ekscizijo,
spremembe v zdravljenju niso potrebne. Nadzor kot pri ploščatoceličnem karcinomu kože. Nekožni malignomi (dabrafenib ali kombinirano zdravljenje): Dabrafenib lahko poveča tveganje za razvoj
nekožnih malignomov, če so prisotne mutacije RAS. Bolnikom je treba pred uvedbo zdravljenja pregledati glavo in vrat (najmanj ogled ustne sluznice in palpacijo bezgavk), opraviti morajo CT prsnega
koša/trebuha. Med zdravljenjem jih je treba nadzirati, kot je klinično primerno; to lahko vključuje pregled glave in vratu na 3 mesece in CT prsnega koša/trebuha na 6 mesecev. Pred zdravljenjem in na
koncu zdravljenja (ter kadar koli je klinično indicirano) sta priporočljiva analni in ginekološki pregled. Opraviti je treba pregled celotne krvne slike in biokemične preiskave krvi, kot je klinično indicirano.
Krvavitev (trametinib ali kombinirano zdravljenje): Prihajalo je do krvavitev, med katerimi so bile tudi večje krvavitve in krvavitve, zaradi katerih so bolniki umrli. Tveganje se lahko poveča v primeru
sočasne uporabe antiagregacijskih ali antikoagulantnih zdravil. Če pride do krvavitve, je treba bolnika zdraviti v skladu s kliničnimi indikacijami. LVEF (trametinib ali kombinirano zdravljenje): Poročali
so, da trametinib zmanjša LVEF. Vsem bolnikom je treba LVEF oceniti pred uvedbo trametiniba, 1 mesec po uvedbi in nato na približno 3 mesece med zdravljenjem. Pri jemanju trametiniba v kombinaciji
z dabrafenibom, so poročali o akutni hudi disfunkciji levega prekata zaradi miokarditisa. Zdravniki naj bodo pozorni na možnost miokarditisa pri bolnikih, pri katerih se znaki ali simptomi težav s srcem
pojavijo na novo oziroma se poslabšajo. Zvišana telesna temperatura (dabrafenib, trametinib ali kombinirano zdravljenje): Poročali so o zvišanju telesne temperature. Pri kombiniranem zdravljenju sta
pogostnost in izraženost večji. Zdravljenje z dabrafenibom je treba prekiniti, če je bolnikova telesna temperatura ≥ 38,5 °C in bolnike oceniti glede znakov in simptomov okužbe. Ko mine, je mogoče
zdravljenje z dabrafenibom znova začeti ob ustrezni profilaksi z uporabo nesteroidnih protivnetnih zdravil ali paracetamola. Če antipiretiki ne zadoščajo, je treba razmisliti o uporabi peroralnih
kortikosteroidov. Če je zvišana telesna temperatura povezana z drugimi hudimi znaki ali simptomi, je treba zdravljenje z dabrafenibom znova začeti z nižjim odmerkom, ko zvišana telesna temperatura
mine in kot je klinično primerno. Hipertenzija (trametinib ali kombinirano zdravljenje): Opisana so zvišanja krvnega tlaka tako pri bolnikih, ki so že prej imeli hipertenzijo, kot pri tistih, ki je prej niso imeli.
Krvni tlak je treba izmeriti izhodiščno in med zdravljenjem; hipertenzijo je treba obvladovati s standardnim zdravljenjem. IBP (trametinib ali kombinirano zdravljenje): V primeru suma na IBP ali
pnevmonitis je treba zdravljenje s trametinibom prekiniti; tudi pri bolnikih z novonastalimi ali napredujočimi pljučnimi simptomi ali izvidi, vključno s kašljem, dispnejo, hipoksijo, plevralnim izlivom ali
infiltrati, dokler niso opravljene klinične preiskave. Pri bolnikih, ki imajo diagnosticirano z zdravljenjem povezano IBP ali pnevmonitis, je treba zdravljenje s trametinibom trajno končati. Okvara vida
(trametinib ali kombinirano zdravljenje): Lahko pride do težav, povezanih z motnjami vida, vključno z RPED in RVO. Uporaba trametiniba ni priporočljiva pri bolnikih, ki so v preteklosti že imeli RVO. Če
se pojavijo novonastale motnje vida, npr. poslabšanje centralnega vida, zamegljen vid ali izguba vida, je priporočljiva takojšnja oftalmološka ocena. Pri bolnikih z diagnozo RVO, je treba trametinib trajno
ukiniti. Okvara vida (dabrafenib ali kombinirano zdravljenje): Opisovali so oftalmološke reakcije, vključno z uveitisom, iridociklitisom in/ali iritisom. Bolnike je treba redno kontrolirati glede znakov in
simptomov s strani vida (npr. sprememb vida, fotofobije in bolečin v očesu). Prilagajanje odmerka ni potrebno, dokler je očesno vnetje mogoče obvladati z učinkovitimi lokalnimi zdravili. Če se uveitis
ne odziva na lokalna očesna zdravila, je treba zdravljenje z dabrafenibom prekiniti, dokler očesno vnetje ni odpravljeno, nato pa ga ponovno uvesti v odmerku, ki je za eno odmerno raven nižji. Odpoved
ledvic (dabrafenib ali kombinirano zdravljenje): Med zdravljenjem je treba rutinsko določati vrednost kreatinina v serumu. Če se vrednost zviša, je morda treba začasno prekiniti uporabo dabrafeniba,
če je to klinično primerno. Uporabe dabrafeniba niso preučili pri bolnikih z insuficienco ledvic (kreatinin > 1,5 x ZMN), zato ga je treba v takšnih okoliščinah uporabljati previdno. Pankreatitis (dabrafenib
ali kombinirano zdravljenje): Poročali so o primerih pankreatitisa. Nepojasnjene bolečine v trebuhu je treba nemudoma raziskati, vključno z meritvijo amilaze in lipaze v serumu. Ob ponovnem začetku
uporabe dabrafeniba po pankreatitisu je treba bolnike skrbno kontrolirati. Jetrni dogodki (trametinib ali kombinirano zdravljenje): Prvih 6 mesecev po začetku zdravljenja s trametinibom je delovanje
jeter priporočljivo kontrolirati na 4 tedne in nato kot je klinično indicirano. Globoka venska tromboza/pljučna embolija (trametinib ali kombinirano zdravljenje): Če se pri bolniku pojavijo znaki pljučne
embolije ali globoke venske tromboze, kot so zadihanost, bolečine v prsnem košu ali zatekanje rok ali nog, mora takoj poiskati zdravniško pomoč. Če gre za življenjsko nevarno pljučno embolijo, je treba
bolniku dokončno ukiniti zdravljenje s trametinibom in dabrafenibom. Hude kožne neželene reakcije: Pred uvedbo zdravljenja je treba bolnike opozoriti na znake in simptome kožnih reakcij in jih skrbno
spremljati. Če se pojavijo znaki in simptomi, ki lahko pomenijo, da gre za hudo kožno neželeno reakcijo, mora bolnik prekiniti zdravljenje z dabrafenibom in trametinibom. Bolezni prebavil (trametinib
ali kombinirano zdravljenje): Poročali so o kolitisu in perforaciji prebavil, vključno s primeri, ki so se končali s smrtjo. Previdnost je potrebna pri uporabi trametiniba pri bolnikih z dejavniki tveganja za
perforacijo prebavil, kot so divertikulitis v anamnezi, metastaze v prebavnem traktu ali sočasna uporaba zdravil z znanim tveganjem za perforacijo prebavil. Sarkoidoza: Ob diagnozi sarkoidoze je treba
razmisliti o ustreznem zdravljenju. Pomembno je, da se sarkoidoza ne interpretira kot napredovanje bolezni. Plodnost, nosečnost in dojenje: Ženske v rodni dobi morajo uporabljati učinkovite
kontracepcijske metode med zdravljenjem in še 2 tedna po prenehanju zdravljenja z dabrafenibom ter še 16 tednov po zadnjem odmerku trametiniba. Dabrafenib lahko zmanjša učinkovitost peroralnih
oz. katerihkoli hormonskih kontraceptivov, zato je treba uporabiti drug učinkovit način kontracepcije. Trenutno ni znano, ali trametinib vpliva na hormonske kontraceptive. Za preprečitev nosečnosti se
bolnicam, ki jemljejo hormonske kontraceptive svetuje, da uporabijo dodaten ali drug način kontracepcije med zdravljenjem in še 16 tednov po prekinitvi zdravljenja s trametinibom. Nosečnice in doječe
matere ne smejo dobivati trametiniba. Nosečnice naj ne bi prejemale dabrafeniba, razen če možna korist za mater odtehta možno tveganje za plod. Odločiti se je treba bodisi za prenehanje dojenja
bodisi za prenehanje zdravljenja z dabrafenibom, upoštevaje koristi dojenja za otroka in koristi zdravljenja za žensko. Dabrafenib in trametinib lahko prizadeneta plodnost moških in žensk. Moške
bolnike, ki jemljejo dabrafenib in/ali trametinib, je treba seznaniti z možnim tveganjem za motnje spermatogeneze, ki so lahko ireverzibilne. Dabrafenib in trametinib imata blag vpliv na sposobnost
vožnje in upravljanja strojev. Bolnika je treba seznaniti z možnostjo za utrujenost, omotico in težave z očmi, ki lahko vplivajo na takšne dejavnosti. Medsebojno delovanje z drugimi zdravili: Zdravilo
Tafinlar: Verjetno je, da zdravila, ki močno zavirajo ali inducirajo CYP2C8 ali CYP3A4, povečajo oz. zmanjšajo koncentracijo dabrafeniba. Če je mogoče, je treba med uporabo dabrafeniba uporabiti druga
zdravila. V primeru uporabe dabrafeniba z močnimi zaviralci (npr. ketokonazolom, gemfibrozilom, nefazodonom, klaritromicinom, ritonavirjem, sakvinavirjem, telitromicinom, itrakonazolom,
vorikonazolom, posakonazolom, atazanavirjem) je potrebna previdnost. Izogibajte se sočasni uporabi dabrafeniba z močnimi induktorji (npr. rifampicinom, fenitoinom, karbamazepinom, fenobarbitalom
ali šentjanževko (Hypericum perforatum)) CYP2C8 ali CYP3A4. Ne pričakuje se, da bi zdravila, ki spreminjajo pH zgornjega gastrointestinalnega trakta (npr. zaviralci protonske črpalke, antagonisti
histaminskih receptorjev H2, antacidi), zmanjšala biološko uporabnost dabrafeniba. Dabrafenib je induktor encimov in poveča sintezo encimov, ki presnavljajo zdravila. Posledica je manjša plazemska
koncentracija zdravil, ki se presnavljajo s temi encimi, kar lahko povzroči izgubo ali zmanjšanje kliničnega učinka teh zdravil. Pričakovati je mogoče medsebojna delovanja s številnimi zdravili, ki se
izločajo s presnavljanjem ali aktivnim transportom, a velikost medsebojnega delovanja se razlikuje. To lahko velja za, vendar ni omejeno na naštete skupine zdravil: analgetiki (npr. fentanil, metadon),
antibiotiki (npr. klaritromicin, doksiciklin), zdravila proti raku (npr. kabazitaksel), antikoagulansi (npr. acenokumarol, varfarin), antiepileptiki (npr. karbamazepin, fenitoin, primidon, valprojska kislina),
antipsihotiki (npr. haloperidol), zaviralci kalcijevih kanalčkov (npr. diltiazem, felodipin, nikardipin, nifedipin, verapamil), srčni glikozidi (npr. digoksin), kortikosteroidi (npr. deksametazon, metilprednizolon),
protivirusna zdravila proti HIV (npr. amprenavir, atazanavir, darunavir, delavirdin, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, sakvinavir, tipranavir), hormonski kontraceptivi, hipnotiki (npr.
diazepam, midazolam, zolpidem), imunosupresivi (npr. ciklosporin, takrolimus, sirolimus), statini, ki se presnavljajo s CYP3A4 (npr. atorvastatin, simvastatin). Če je njihov terapevtski učinek za bolnika
zelo pomemben in če odmerka ni mogoče zlahka prilagoditi glede na kontrolo učinkovitosti ali koncentracije v plazmi, se je tem zdravilom treba izogniti ali jih je treba uporabljati previdno. Tveganje za
okvaro jeter po uporabi paracetamola je domnevno večje pri bolnikih, ki sočasno prejemajo induktorje encimov. Pojav indukcije je verjeten po 3 dneh ponavljajočega se odmerjanja dabrafeniba. Po
prenehanju uporabe dabrafeniba indukcija mine postopoma. Bolnike je treba spremljati glede toksičnih učinkov; potrebna je lahko prilagoditev odmerjanja navedenih zdravil. Zdravilo Mekinist: Zaradi
možnosti zvišanja koncentracije trametiniba, je priporočena previdnost pri sočasnem odmerjanju trametiniba in zdravil, ki so močni zaviralci P‑gp (na primer verapamila, ciklosporina, ritonavirja,
kinidina, itrakonazola). Trametinib lahko povzroči prehodno zavrtje substratov BCRP (npr. pitavastatina) v črevesu; to je mogoče omejiti na najmanjšo mero tako, da se ta zdravila in trametinib uporablja
z medsebojnim zamikom (zamik 2 ur). Neželeni učinki: Dabrafenib v monoterapiji: Zelo pogosti (≥ 1/10): papilom, zmanjšan apetit, glavobol, kašelj, navzea, bruhanje, driska, hiperkeratoza, alopecija,
izpuščaj, sindrom palmarno-plantarne eritrodisestezije, artralgija, mialgija, bolečine v okončini, pireksija, utrujenost, mrzlica, astenija. Pogosti (≥ 1/100 do < 1/10): ploščatocelični karcinom kože,
seboroična keratoza, akrohordon (kožni izrastki), bazalnocelični karcinom, hipofosfatemija, hiperglikemija, zaprtost, suha koža, srbenje, aktinična keratoza, kožne lezije, eritem, fotosenzitivnost, gripi
podobna bolezen. Občasni (≥ 1/1.000 do < 1/100): nov primarni melanom, preobčutljivost, uveitis, pankreatitis, panikulitis, odpoved ledvic, akutna odpoved ledvic, nefritis. Trametinib v monoterapiji:
Zelo pogosti: hipertenzija, krvavitev, kašelj, dispneja, driska, navzea, bruhanje, zaprtost, bolečine v trebuhu, suha usta, izpuščaj, akneiformni dermatitis, suha koža, srbenje, alopecija, utrujenost, periferni
edemi, zvišana telesna temperatura, zvišana aspartat-aminotransferaza. Pogosti: folikulitis, paronihija, celulitis, pustulozen izpuščaj, anemija, preobčutljivost, dehidracija, zamegljen vid, periorbitalni
edem, okvara vida, disfunkcija levega prekata, zmanjšanje iztisnega deleža, bradikardija, limfedem, pnevmonitis, stomatitis, eritem, sindrom palmarno-plantarne eritrodisestezije, fisure na koži,
razpokana koža, edem obraza, vnetje sluznice, astenija, zvišana alanin-aminotransferaza, zvišana alkalna fosfataza v krvi, zvišana kreatin-fosfokinaza v krvi. Občasni: horioretinopatija, papiledem,
odstop mrežnice, zapora mrežnične vene, srčno popuščanje, intersticijska bolezen pljuč, perforacija prebavil, kolitis, rabdomioliza. Kombinirano zdravljenje z dabrafenibom in trametinibom: Zelo
pogosti:nazofaringitis, zmanjšan apetit, glavobol, omotica, hipertenzija, krvavitev, kašelj, bolečine v trebuhu, zaprtost, diareja, navzea, bruhanje, suha koža, srbenje, izpuščaj, eritem, artralgija, mialgija,
bolečine v okončini, mišični krči, utrujenost, mrzlica, astenija, periferni edemi, zvišana telesna temperatura, gripi podobna bolezen, zvišana vrednost alanin aminotransferaze, zvišana vrednost aspartat
aminotransferaze. Pogosti: okužba sečil, celulitis, folikulitis, paronihija, pustulozen izpuščaj, ploščatocelični karcinom kože, papilom, seboroična keratoza, nevtropenija, anemija, trombocitopenija,
levkopenija, dehidracija, hiponatriemija, hipofosfatemija, hiperglikemija, zamegljen vid, okvara vida, uveitis, zmanjšanje iztisnega deleža, limfedem, hipotenzija, dispneja, suha usta, stomatitis,
akneiformni dermatitis, aktinična keratoza, nočno znojenje, hiperkeratoza, alopecija, sindrom palmarno-plantarne eritrodisestezije, kožne spremembe, čezmerno znojenje, panikulitis, fisure na koži,
fotosenzitivnost, vnetje sluznice, edem obraza, zvišana vrednost alkalne fosfataze v krvi, zvišana vrednost gama-glutamiltransferaze, zvišana vrednost kreatin-fosfokinaze v krvi. Občasni: nov primarni
melanom, akrohordon (pecljati fibrom), preobčutljivost, sarkoidoza, horioretinopatija, odstop mrežnice, periorbitalni edem, bradikardija, pnevmonitis, pankreatitis, kolitis, odpoved ledvic, nefritis. Redki:
perforacija prebavil. Neznana pogostnost: miokarditis, Stevens‑Johnsonov sindrom, reakcija na zdravilo z eozinofilijo in sistemskimi simptomi (DRESS sindrom), generaliziran eksfoliativni dermatitis.
Imetnik dovoljenja za promet z zdravilom: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Irska Dodatne informacije in literatura: Novartis Pharma Services Inc.,
Podružnica v Sloveniji, Verovškova ulica 57, 1000 Ljubljana. Način/režim izdajanja zdravil Tafinlar in Mekinist: Rp/Spec. Pred predpisovanjem natančno preberite zadnji odobreni povzetek
glavnih značilnosti zdravila. Datum zadnje revizije skrajšanega povzetka glavnih značilnosti zdravila: januar 2021.
Viri in literatura: 1. Povzetek glavnih značilnosti zdravila Tafinlar. Januar 2021. 2. Povzetek glavnih značilnosti zdravila Mekinist. Januar 2021. 3. Dummer R, Hauschild A, Santinami M, et al.
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med 2020;383:1139-48. 4. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib
plus Trametinib in Metastatic Melanoma. N Engl J Med 2019;381:626-36.

#

Novartis Pharma Services Inc., Podružnica v Sloveniji
Verovškova ulica 57, 1000 Ljubljana, tel.: 01 300 75 50

Datum priprave materiala: februar 2021

Samo za strokovno javnost

SI-2021-MEK-014

POWERING
TARGETED
THERAPY
Decades of innovation in targeted
therapies is helping people with
lung cancer live longer

© 2020 Amgen Inc. All rights reserved. Amgen zdravila d.o.o., Ameriška ulica 2, Ljubljana
Date of preparation: August 2021. SI-510-0821-00001

vsak dan

abemaciklib

dvakrat na dan

EDINI
zaviralec CDK4 & 6,
ki se jemlje
NEPREKINJENO
VSAK DAN,
NE
2x NA DAN1, 2, 3
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da
poročajo o katerem koli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8, kako poročati o neželenih učinkih.
IME ZDRAVILA: Verzenios 50 mg/100 mg/150 mg filmsko obložene tablete KAKOVOSTNA IN KOLIČINSKA SESTAVA: Ena filmsko obložena tableta vsebuje 50 mg/100 mg/150
mg abemacikliba. Ena filmsko obložena tableta vsebuje 14 mg/28 mg/42 mg laktoze (v obliki monohidrata). Terapevtske indikacije: Zdravilo Verzenios je indicirano za zdravljenje
žensk z lokalno napredovalim ali metastatskim, na hormonske receptorje (HR – Hormone Receptor) pozitivnim in na receptorje humanega epidermalnega rastnega faktorja 2
(HER2 – Human Epidermal Growth Factor Receptor 2) negativnim rakom dojk v kombinaciji z zaviralcem aromataze ali s fulvestrantom kot začetnim endokrinim zdravljenjem
ali pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- in perimenopavzi je treba endokrino zdravljenje kombinirati z agonistom gonadoliberina
(LHRH – Luteinizing Hormone–Releasing Hormone). Odmerjanje in način uporabe: Zdravljenje z zdravilom Verzenios mora uvesti in nadzorovati zdravnik, ki ima izkušnje
z uporabo zdravil za zdravljenje rakavih bolezni. Zdravilo Verzenios v kombinaciji z endokrinim zdravljenjem: Priporočeni odmerek abemacikliba je 150 mg dvakrat na dan,
kadar se uporablja v kombinaciji z endokrinim zdravljenjem. Zdravilo Verzenios je treba jemati, dokler ima bolnica od zdravljenja klinično korist ali do pojava nesprejemljive
toksičnosti. Če bolnica bruha ali izpusti odmerek zdravila Verzenios, ji je treba naročiti, da naj naslednji odmerek vzame ob predvidenem času; dodatnega odmerka ne sme
vzeti. Obvladovanje nekaterih neželenih učinkov lahko zahteva prekinitev in/ali zmanjšanje odmerka. Zdravljenje z abemaciklibom prekinite v primeru povišanja vrednosti AST
in/ali ALT >3 x ZMN SKUPAJ s celokupnim bilirubinom > 2,0 x ZMN v odsotnosti holestaze ter pri bolnicah z intersticijsko pljučno boleznijo (ILD)/pnevmonitis stopnje 3 ali 4.
Sočasni uporabi močnih zaviralcev CYP3A4 se je treba izogibati. Če se uporabi močnih zaviralcev CYP3A4 ni mogoče izogniti, je treba odmerek abemacikliba znižati na 100
mg dvakrat na dan. Pri bolnicah, pri katerih je bil odmerek znižan na 100 mg abemacikliba dvakrat na dan in pri katerih se sočasnemu dajanju močnega zaviralca CYP3A4 ni
mogoče izogniti, je treba odmerek abemacikliba dodatno znižati na 50 mg dvakrat na dan. Pri bolnicah, pri katerih je bil odmerek znižan na 50 mg abemacikliba dvakrat na
dan in pri katerih se sočasnemu dajanju močnega zaviralca CYP3A4 ni mogoče izogniti, je mogoče z odmerkom abemacikliba nadaljevati ob natančnem spremljanju znakov
toksičnosti. Alternativno je mogoče odmerek abemacikliba znižati na 50 mg enkrat na dan ali prekiniti dajanje abemacikliba. Če je uporaba zaviralca CYP3A4 prekinjena, je
treba odmerek abemacikliba povečati na odmerek, kakršen je bil pred uvedbo zaviralca CYP3A4 (po 3–5 razpolovnih časih zaviralca CYP3A4). Prilagajanje odmerka glede
na starost in pri bolnicah z blago ali zmerno ledvično okvaro ter z blago (Child Pugh A) ali zmerno (Child Pugh B) jetrno okvaro ni potrebno. Pri dajanju abemacikliba bolnicam
s hudo ledvično okvaro sta potrebna previdnost in skrbno spremljanje glede znakov toksičnosti. Način uporabe: Zdravilo Verzenios je namenjeno za peroralno uporabo. Odmerek se lahko vzame s hrano ali brez nje. Zdravilo se ne sme jemati z grenivko ali grenivkinim sokom. Bolnice naj odmerke vzamejo vsak dan ob približno istem času. Tableto
je treba zaužiti celo (bolnice je pred zaužitjem ne smejo gristi, drobiti ali deliti). Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila
in previdnostni ukrepi: Pri bolnicah, ki so prejemale abemaciklib, so poročali o nevtropeniji, o večji pogostnosti okužb kot pri bolnicah, zdravljenih s placebom in endokrinim
zdravljenjem, o povečanih vrednostih ALT in AST. Pri bolnicah, pri katerih se pojavi nevtropenija stopnje 3 ali 4, je priporočljivo prilagoditi odmerek. Bolnice je treba spremljati
za znake in simptome globoke venske tromboze in pljučne embolije ter jih zdraviti, kot je medicinsko utemeljeno. Glede na povečanje vrednosti ALT ali AST je mogoče potrebna prilagoditev odmerka. Driska je najpogostejši neželeni učinek. Bolnice je treba ob prvem znaku tekočega blata začeti zdraviti z antidiaroiki, kot je loperamid, povečati
vnos peroralnih tekočin in obvestiti zdravnika. Sočasni uporabi induktorjev CYP3A4 se je treba izogibati zaradi tveganja za zmanjšano učinkovitost abemacikliba. Bolnice z
redkimi dednimi motnjami, kot so intoleranca za galaktozo, popolno pomanjkanje laktaze ali malapsorpcija glukoze/galaktoze, tega zdravila ne smejo jemati. Bolnice spremljajte
glede pljučnih simptomov, ki kažejo na ILD/pnevmonitis, in jih ustrezno zdravite. Glede na stopnjo ILD/pnevmonitisa je morda potrebno prilagajanje odmerka abemacikliba.
Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Abemaciklib se primarno presnavlja s CYP3A4. Sočasna uporaba abemacikliba in zaviralcev CYP3A4
lahko poveča plazemsko koncentracijo abemacikliba. Uporabi močnih zaviralcev CYP3A4 sočasno z abemaciklibom se je treba izogibati. Če je močne zaviralce CYP3A4 treba
dajati sočasno, je treba odmerek abemacikliba zmanjšati, nato pa bolnico skrbno spremljati glede toksičnosti. Pri bolnicah, zdravljenih z zmernimi ali šibkimi zaviralci CYP3A4,
ni potrebno prilagajanje odmerka, vendar jih je treba skrbno spremljati za znake toksičnosti. Sočasni uporabi močnih induktorjev CYP3A4 (vključno, vendar ne omejeno na:
karbamazepin, fenitoin, rifampicin in šentjanževko) se je treba izogibati zaradi tveganja za zmanjšano učinkovitost abemacikliba. Abemaciklib in njegovi glavni aktivni presnovki
zavirajo prenašalce v ledvicah, in sicer kationski organski prenašalec 2 (OCT2) ter prenašalca MATE1. In vivo lahko pride do medsebojnega delovanja abemacikliba in klinično
pomembnih substratov teh prenašalcev, kot je dofelitid ali kreatinin. Trenutno ni znano, ali lahko abemaciklib zmanjša učinkovitost sistemskih hormonskih kontraceptivov, zato
se ženskam, ki uporabljajo sistemske hormonske kontraceptive, svetuje, da hkrati uporabljajo tudi mehansko metodo. Neželeni učinki: Najpogostejši neželeni učinki so driska,
okužbe, nevtropenija, anemija, utrujenost, navzea, bruhanje in zmanjšanje apetita. Zelo pogosti: okužbe, nevtropenija, levkopenija, anemija, trombocitopenija, driska, bruhanje,
navzea, zmanjšanje apetita, disgevzija, omotica, alopecija, pruritus, izpuščaj, utrujenost, pireksija, povečana vrednost alanin-aminotransferaze, povečana vrednost aspartat-aminotransferaze Pogosti: limfopenija, povečano solzenje, venska trombembolija, intersticijska pljučna bolezen (ILD)/pnevmonitis, suha koža, mišična šibkost Občasni: febrilna
nevtropenija Rok uporabnosti: 3 leta Posebna navodila za shranjevanje: Za shranjevanje zdravila niso potrebna posebna navodila. Imetnik dovoljenja za promet z zdravilom:
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528BJ, Utrecht, Nizozemska. Datum prve odobritve dovoljenja za promet: 27. september 2018 Datum zadnje revizije
besedila: 19.7.2021 Režim izdaje: Rp/Spec - Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega
zdravnika.
Reference:
1. Povzetek glavnih značilnosti zdravila Verzenios. Datum zadnje revizije besedila: 19.7.2021. 2. Povzetek glavnih značilnosti zdravila Ibrance. Dostop preverjen
10.4.2020. 3. Povzetek glavnih značilnosti zdravila Kisqali. Dostop preverjen 10.4.2020.
Pomembno: Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. Pred
predpisovanjem zdravila Verzenios si preberite zadnji veljavni Povzetek glavnih značilnosti zdravil. Podrobne informacije o zdravilu so objavljene na spletni
strani Evropske agencije za zdravila http://www.ema.europa.eu
Eli Lilly farmacevtska družba, d.o.o., Dunajska cesta 167, 1000 Ljubljana, telefon 01 / 580 00 10, faks 01 / 569 17 05
PP-AL-SI-0110, 23.8.2021, Samo za strokovno javnost.

Bolniki morajo imeti
dostop do zdravil,
ki jih potrebujejo.

podobna biološka
zdravila
brez meja
SKRBIMO ZA VAS

Peter, 42
Slovenija
električar
rak

BIO0492020

Emmanuel, 54
Nigerija
policist
Crohnova bolezen

Mylan Healthcare, farmacevtsko podjetje, d.o.o., Dolenjska cesta 242c, 1000 Ljubljana, www.v iatris.com/sl-si

Družba Viatris po celem svetu
zdravnikom in bolnikom zagotavlja
dostop do visokokakovostnih
bioloških zdravil.
Slednjega zagotavljajo
zavezanost h kontinuiranemu
razvoju, kakovostnim raziskavam,
nadzoru kakovosti in logistični
odličnosti. To je naš svet. Naš
svet je svet, ki mu je mar za vas.

Strokovna knjižnica za

onkologijo

8 čitalniških mest
5.300 knjig
6.000 e-revij

vsak delovni dan od 8. do 15. ure
www.onko-i.si/strokovna_knjiznica

#2 INTERNATIONAL SUMMER SCHOOL SO PODPRLE
NASLEDNJE DRUŽBE:

NOVARTIS – ZLATI SPONZOR
MSD – ZLATI SPONZOR
SERVIER
ELI LILLY
PFIZER
AMGEN
BRISTOL-MYERS SQUIBB
ROCHE
EWOPHARMA
LEK
ABBOTT
JANSSEN
SANOFI GENZYME
PHARMASWISS
TAKEDA
MYLAN
MERCK