o Onkološki Inštitut Institute of Oncology Ljubljana O/^v iet Q^J years KATEDRA ZA ONKOLOGIJO SEKCIJA ZA INTERNISTIČNO ONKOLOGIJO j Slovensko j Zdravniško Društvo SCHOOL IN MEDICAL ONCOLOGY Part 1 - Tuesday (3.9.) & Wednesday (4.9.) LJUBLJANA 3-6. SEPTEMBER 2019 Strokovni odbor: izr. prof. dr. Janja Ocvirk, dr.med. doc. dr. Martina Reberšek, dr.med. dr. Tanja Mesti, dr.med. Marko Boc, dr.med. Organizacijski odbor: izr. prof. dr. Janja Ocvirk, dr.med. doc. dr. Martina Reberšek, dr.med. dr. Tanja Mesti, dr.med. Marko Boc, dr.med. ga. Lidija Kristan Uredniki zbornika: Marko Boc, dr.med. doc. dr. Martina Reberšek, dr.med. izr. prof. dr. Janja Ocvirk, dr.med. dr. Tanja Mesti, dr.med. Organizator in izdajatelj (založnik): Onkološki inštitut Ljubljana Sekcija za internistično onkologijo Katedra za onkologijo Ljubljana, september 2019 AGENDA & INDEX Tuesday, September 3 10:30-11:00 Registration of participants Part 1 Moderators: dr. Dobrila, dr. Boc 11:00-11:30 Neoadjuvant and Adjuvant treatment strategies for gastric cancer (dr. Boc) 11:30-12:15 Systemic treatment of metastatic gastric cancer (dr. Dobrila) 12:15-12:35 Neoadjuvant and Adjuvant treatment strategies for pancreatic cancer (dr. Mesti) 12:35-13:15 Systemic treatment of metastatic pancreatic cancer (dr. Mesti) 13:15-13:30 Discussion 13:30-14:30 Lunch break Part 2 Moderators: dr. Plestina, dr. Hlebania 14:30-14:50 Satellite symposium 14:50-15:20 Systemic treatment of biliary tract cancer (dr. Rebersek) 15:20-15:40 Systemic treatment strategies for HCC (dr. Mesti) 15:40-16:10 Adjuvant treatment strategies for colorectal cancer (dr. Ignjatovic, dr. Ocvirk) 16:10-16:55 Systemic treatment of metastatic colorectal cancer (dr. Plestina) 16:55-17:10 Discussion Wednesday, September 4 Part 1 Moderators: dr. Radosavljevic, dr. Grasic Kuhar 8:30-9:15 Neoadjuvant and Adjuvant treatment strategies for lung cancer (dr. Radosavljevic) 9:15-10:00 Systemic treatment of metastatic lung cancer (dr. Zaric) 10:00-10:45 Systemic treatment of head and neck cancer (dr. Grasic Kuhar) 10:45-11:00 Break 11:00-11:30 Systemic treatment of patients with unknown primary tumor (dr. Matos) 11:30-11:45 Systemic treatment of germinal tumors (dr. Skrbinc) 11:45-12:15 Discussion 12:15-12:45 Satellite symposium (Roche) 12:45-13:45 "First line treatment of metastatic NSCLC" (dr. Maximilian J. Hochmair ) 13:45-14:30 Lunch break Part 2 Moderators: dr. Belev, dr. Seruga 14:30-15:15 Systemic treatment of prostate cancer (dr. Belev) 15:15-16:00 Systemic treatment of RCC (dr. Seruga) 16:00-16:15 Break 16:15-16:45 The systemic treatment of the bladder cancer (dr. Mencinger) 16:45-17:15 The palliative care - when to start and how to lead the patient and the patients family through the process (dr. Ebert Moltara) 17:15-18:15 Interesting cases from audience PERI-OPERATIVE TREATMENT OF GASTRIC CANCER Marko Boc, dr.med. Sector of medical oncology Institute of Oncology Ljubljana SLOVENIA Ljubljana, 3-6. september 2019 Summary • Peri-operative chemotherapy (pre- and post-operative) is standard of care for unmetastatic resectable gastric cancer > Stage IB (ESMO: I,A): • Peri-operative chemotherapy comprises a platinum compaund and a fluoropyrimidine, • Addition of epirubicine is optional (toxicity), strongest evidence for cisplatin/fluorouracil ± epirubicine, • Taxanes improve peri-operative chemoterapy response and improve survival outcomes trough better response. • For patients > Stage IB gastric cancer who have undergone surgery without administration of pre-operative chemotherapy or postoperative CRT, adjuvant chemotherapy is recommended (ESMO: I,A): • S-1 (1,A) and XELOX in Asian pupulation • 6% absolute benefit for 5-FU based chemotherapy, [HR 0.82 (0.76-0.90), p< 0001] (ESMO: 1,A). Summary • Post-operative CTX intensification did not improve outcomes! • Since capecitabine avoids the need for an central venous access device, and is non-inferior to 5-FU in the advanced disease setting, capecitabine-containing regimens can also be suggested in the peri-operative setting (ESMO: IV,C). • For patients with >Stage IB gastric cancer who have undergone surgery without administration of preoperative chemotherapy, postoperative chemoradiotherapy (CRT) (ESMO: I,A). • For patients having undergone preoperative chemotherapy, the addition of postoperative radiotherapy (RT) has no added benefit. 1 SYSTEMIC TREATMENT FOR METASTATIC DISEASE Gemcitabine CONCLUSIONS • Initially CT th/abd • CA 1 9-9 • Multidisciplinary approach • Treatment according to the guidelines • Pts preferences, tumour burden, comorbidities Systemic treatment of biliary tract cancers 1st Summer school in medical oncology - standards and open questions ASSIST.PROF.MARTINA REBERSEK, MD DEPARTMENT OF MEDICAL ONCOLOGY INSTITUTE OF ONCOLOGY LJUBLJANA J. W. Valle, et al. On behalf of the ESMO Guidelines Committee Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up- 2016 Annals of Oncology 27 (Supplement 5): v28-v37, 2016 doi:10.1093/annonc/mdw324 NCCN: Gallbladder cancer Comprehensive NCCN Guidelines Version 3.2019 Gallbladder Cancer POSTOPERATIVE WORKUP3 Incidental finding at surgery | Incidental finding on • Intraoperative staging • Frozen section Multiphasic abdominal/pelvic CT/MRI of resected * with IV contrast. gallbladder + suspicious lymph chest CT +/■ contrast node (MSI) and/ or mismatch repair (MMR) PRIMARY TREATMENT • Cholecystectomy13^ + en bloc hepatic resection + lymphadenectomy + bile duct excision for malignant involvement Options:® • Gemcitabine/cisplatin combination therapy' (category 1) • Fluoropyrimidine-based or other gemcitabine-based chemotherapy regimenf • EBRT with concurrent fluoropyrimidine9,h • Radiation therapy11 • Clinical trial • Best supportive care • Pembrolizumab' (only for MSI-H/dMMR tumors) I comprehensive NCCN Guidelines Version 3.2019 I NetwSïk* Gallbladder Cancer PRESENTATION WORKUP H&P LFTs Chest CT+/- contrast3 Multiphasic abdominal/ pelvic CT/MRI with IV contrast3 Cholangiography"1 Surgical consultation" Consider CEA1 Consider CA19-91 Consider staging iaparoscopy Metastatic disease - 3See Principles of Imaging (GALL-A). ^See Principles of Surgery and Pathology (GALL-B). clf there is evidence of locoregionally advanced disease (big m. Consider neoadjuvant Fluoropyrimidine- gemcitabine-based chemotherapy regimen Clinical trial ; invading liver and/or nodal PRIMARY TREATMENT • Consider preoperative biliary drainage • Cholecystectomy15 + en bloc hepatic resection + lymphadenectomy + bile duct excision Options:e •Biliary drainage0 • Gemcitabine/cisplatin combination therapy' (category 1) • Other gemcitabine-based or fluoropyrimidine-based chemotherapy regimen • EBRT with concurrent fluoropyrimidine^" • Radiation therapy" • Clinical trial • Best supportive, care • Pembrolizumab' (only for MSI-H/dMMR tumors) Options:e •Biliary drainage0 • Gemcitabine/cisplatin combination therapy'(category 1) • Other gemcitabine-based or fluoropyrimidine-based chemotherapy regimen' • Clinical trial •Bestsupportive care • Pembrolizumab' (only for MSI-H/dMMR tumors) NCCN: Intrahepatic cholangiocarcinoma I Comprehensive NCCN Guidelines Version 3.2019 NCCN Guidelines Index Table of Contents Discussion Isolated intrahepatic mass3 (imaging characteristics consistent with malignancy but not consistent with Multiphasic al CT/MRI with I' Surgical consultation" Unresectable • MSI/MMR testing • Consider molecular testing I Metastatic • MSI/MMR • Consider molecular aSee Principles ot Surgery (INTRA-A). DSee Principles of Imaging (HCC-A). CCEA and CA19-9 are baseline tests and should not be done to confirm diagnosis. ! comprehensive NCCN Guidelines Version 3.2019 Cancer I Network™ NCCN Guidelines Index Intrahepatic Cholangiocarcinoma PRIMARY TREATMENT I- Consider staging laparoscopye| , • Resection3 ► Consider lymphadenectomy I for accurate staging ! "ptions:f Gemcitabine/cisplatin combination therapy® (category 1) Clinical trial Fluoropyrimidine-based or other gemcitabine-based chemotherapy regimen^ EBRT with concurrent fluoropyrimidine1' Consider locoregiopa! therapy™ ► Arterialiy directed therapiesk Best supportive care Pembrolizumab1 (only for MSI-H/dMMR tumors) Gemcitabine/cisplatin combination therapyS (category 1) Clinical trial Fluoropyrimidine-based or other gemcitabine-based chemotherapy regimen^ Consider locoregionai therapyk,h Radiation therapy) ► Arterialiy directed therapies" Pembrolizumab1 (only for MSI-H/dMMR tumors) Post resection K status No residua! local disease '|(R0 resection) Microscopic margins (R1) Positive regional nodes Residual i local disease0 |(R2 resection) TREATMENT"1 Options:* • Observe • Clinical trial • Fluoropyrimidine-based or gemcitabine-based chemotherapy11 Options^ • Fluoropyrimidine-based or gemcitabine-based chemotherapy" 4 Fluoropyrimidine-based chemoradiation1-' • Fluoropyrimidine-based or gemcitabine-based chemotherapy11 followed by fluoropyrimidine-based chemoradiationi-0 • Fluoropyrimidine-based chemoradiation1^ followed by fluoropyrimidine-based or gemcitabine-based chemotherapy11 < Clinical trial • See treatment for unresectable disease (INTRA-1) SURVEILLANCE13 Consider multiphasic abdominal/pelvic CT/MRI with IV contrast" and chest CT+/-contrast13 every 6 mo for 2 y If clinically indicated, then annually up to 5 years NCCN: Extrahepatic cholangiocarcinoma Conclusions(l) - rare cancers - poor prognosis - important diagnostic procedures - surgical treatment first Conclusions (2)- systemic treatment • Neo- adjuvant therapy: no standards • Adjuvant therapy: - capecitabine monotherapy - role of radiation therapy in combination with systemic treatment-the need of prospective randomized clinical phase III trials • Metastatic disease: - 1st line: gemcitabine + cisplatin (PS ECOG 0-1), gemcitabine mono (PS ECOG 2) - 2nd line: no standard therapy -targeted therapy: no standards - Immunotherapy: MSI- H HCC - systemic treatment strategies TANJA MESTI, MD, PHD INSTITUTE OF ONCOLOGY LJUBLJANA Key Takeaways ► Sorafenib and regorafenib are the only agents approved for advanced HCC ■ Both are rnultikinase inhibitors with prominent ant [angiogenic effects ■ Sorafenib is approved for first-line treatment * Regorafenib is approved for second-tine treatment after sorafenib failure or intolerance » In a head-to-head phase III trial, lenvatinib was shown to be noninferior to sorafenib and may be considered an alternative to sorafenib, particularly in patients with intolerance » Important to recognize the class-wide side effects of these agents (eg, hand-foot skin reaction, hypertension, diarrhea, weight loss) and employ timely interventions to optimize treatment outcomes Health * Landscape-Second line therapy for HCC I Total N PFS benefit I OS benefit I RR i CHECKMATE040 (SINGLE ARM) Nivolumab* 154 NA NA median OS = 15 mo* 14% RESOURCE Regorafenib* v placebo 573 (2:1) +1.6 mo HRO-46 (0.37-0.56); p<0-0001 »2.8 mo HR 0.63 (0.50-0.79) p<0.0001| 11« CELESTIAL** Cabozantinib v placebo 707 (2:1) +3.3 mo HR=0.44 [0.36-0.52]; P < O.OOI +2.2 mo HR=0.76 (0.63-0.92) P - 0.0049 4« REACH1 Ramucirumab v placebo 565 +0.7mo HR 0.63 [0.52-0.75]; p400) Ramucirumab v placebo 292 (2:1) + 1.2 mo HR 0.452 (0.339, 0.G03) p< 0.0001 + 1.2 mo HR 0.71 (0.531,0.949); p=0.0199 4.6% Pooled REACH 1 / 2 (AFP>400 subgroup) Ramucirumab v placebo 5 42 NA +3.1 mo HR 0.694 (0.571, 0.842) P=0.0002 NA „„„,„„ 2018 ASCO *FDA approved annual meeting »* included 2nd arid 3rd line; 2nd line update: Kelley, et al. Abstr #4088 ASCO 2018 O' Onkološki Inštitut ) Institute of Oncology Ljubljana ADJUVANT TREATMENT STRATEGIES FOR COLORECTAL CANCER 1st Summer School in Medical Oncology 3. - 6. September, Ljubljana, Slovenia_ Marija Ignjatovic/MD ADJ.ChT IN CRC □ Start 4 to 8 weeks after operation □ Stage II S Can not be considered as a SOC for all patients S HR, pMMR: capecitabine or5FU for 6 months S HR, dMMR: just for very selected patients, XELOX for 3 months or FOLFOX for 6 months □ Stage III S SOC S LR, XELOX for 3 months S HR, XELOX/FOLFOX for 6 months O Neoadjuvant and adjuvant treatment strategies for lung cancer Davorin Radosavljevic Institute for Oncology and Radiology of Serbia Belgrade „1st Summer School in Medical Oncology - Standards and Open Question", September 3-6th 2019, Ljubljana, Institute of Oncology conclusions • adjuvant chemotherapy is established for stage II and III resected NSCLC with sustained benefit • the regimen with most evidence is cisplatin vinorelbine although the accepted schedule differs from JBR.10 and ANITA trials • stage IB tumours can be considered for adjuvant chemotherapy if >/= 4cm although evidence is from unplanned, retrospective analyses (CALGB 9633 and JBR.10) • selected older patients (70+) tolerate chemotherapy with acceptable toxicity but limited evidence for elderly and very elderly (75+, 80+) • further major improvements with chemotherapy alone are unlikely (pemetrexed?) • research will be focused on better discrimination of high versus low risk patients, predictive factors and more targeted therapies Conclusions The local/regionally advanced setting is rapidly evolving with the addition of immunotherapy The new standard of care in patients with unresectable disease: concurrent chemoradiation, followed by one year of durvalumab Future studies, exploring the role of replacing chemotherapy with immunotherapy in unresectable disease and adding adjuvant or neoadjuvant immunotherapy in resectable disease, may further reshape our standard practice Institute for Pulmonary Diseases of Vojvodina Faculty of Medicine, University of Novi Sad Serbia Systemic treatment of metastatic lung cancer Assist. Prof dr Bojan Zaric, MD, PhD Head, Department for diagnostics and treatment of lung cancer Head, Clinical Trials Unit bojan.zaric@institut.rs Oncogene driven lung cancer treatment in first line Oncogene driven lung cancer treatment beyond first line • Based on molecular profiling and determination of resistance mechanism, • Should be tailored to target secondary mutation (if any), otherwise RCT or standard platinum based doublet, • Adequate sequencing remains to be determined. Treatment of metastatic lung cancer without driver mutations in first line • TPS > 50% (>1%) - pembrolizumab monotherapy, • High TMB - Nivolumab/Ipilimumab, • Any expression of PD-L1 - lO/Chemo combo, standard platinum based therapy. Treatment of metastatic lung cancer without driver mutations beyond first line Immunotherapy if not given in first line (regardless of PD-L1 expression, RCT, Docetaxel mono or any other available (platinum) based chemotherapy. Systemic treatment of head and neck tumors Assist. Prof. Cvetka Grašič Kuhar, MD, PhD Institute of Oncology Ljubljana, Department of Medical Oncology lip, oral cavity, oropharynx, larynx, hypopharynx Accessed 15.8.2019 Estimated age-standardized incidence rates (World) in 2018, both sexes, all ages Incidence: 640 000/year Deaths: 355 000/year All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever Data source: GLOBOCAN 2018 on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area Graph production: 1ARC or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for (http://gco.iarc.fr/today) which there may not yet be full agreement. World Health Organization World Health y Organization C International Agency for Research on Cancer 2018 Etiology, risk factors Tobacco Alcohol HPV EBV Chewingof betel leafs UV-exposure (lips) Poor oral/dental hygiene/mechanical irritation Occupational hazards: wood dust, leather industry, nickel, azbestos Gastroesophageal refluxdisease Genetic syndrome (i.e. Fanconi anemia) 3 HPV+ HPV- Localisation Tonsil, Base of toungue All localizations HPV+ vs. Histology nonkeratinizing, basaloid, high grade keratinising HPV- Age 53-57 years 57-64 years, Soc econ status Good Lower oropharynge Performance status Better Lower al carcinoma Gender 3:1 for men 3:1 for men T stage Low T (Tx, T1-2) High T stage N stage high N stage, cystic cervical nodes High N stage, noncystic Molecular char. PI3KCA mutated p53 mutated PD-L1 overexpression 49-70% 29-34°% DNA metilation more less Risk factors Sexual behaviour, associated with HIV Tobacco, alcohol in anogenital HPV, less tobacco 3-year risk for metastases 9-11 % 14-15 % 3- and 8-year OS of stage III, 82 and 71 % 57 and 30 % IV 4 HPV is a prognostic factor HPV-positive HPV-negative Hazard ratio for death, 0.38 (0.26-0.55); PcO.OOl Years since Randomization No. at Risk HPV-positive 206 HPV-negatrve 117 193 89 179 76 165 65 151 51 73 22 Number at risk HPV-negative 22 HPV-positive 64 Recurrence Overall Survival After Recurrence by HPV tumor status i____- 20 40 Months 14 62 2 20 -----HPV-negative HPV-positive Ang et al. (2010) New England Journal of Medicine, 3fi3(1), 24-35. Joseph et al Head S Neck 2016:28 (suppl 1), E1501-9.. 5 Treatment of early stage (stage I, -one modality only -depend on tumor localisation, patient preferences Surgery or Radiotherapy http ://m edia-cache- ec0.pinimg.com/originals/b0/b1/11/b0b11177ebfa9dc7ae99bcce8df9bc0c.jpg Therapy of stage III, IVa,b J POSTOPERATIVE • Operable disease: ^^^^^ SURGERY (CHEMO)RADIOTHERAPY • Operable disease, but intention for organ preservation (LARINX, PHARYNX, BASE OF TOUNGUE): Inoperable disease: Induction chemotherapy 7 Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update Jean-Pierre Pignon3 ', Aurélie le MaîtreEmilie MaillardJean Bourhisb, on behalf of the MACH-NC Rjdiolhrapy Mid Oncology 92 (2009) 4 14 (a) Hazard ratio of death. Timing No. Deaths I No. Entered LRTVCT LRT HR |9S% CI] Concomitant 3171/4824 3369/4791 -3264 1587.7 B i 0.8110 780 .86] Induction 1877/2740 1813/2S71 -40.0 900.7 ■ ! 0.96(0.901.02] Adjuvant 631/1244 661/1323 17.8 317.4 1.06 |D.9S:1.18] Total 5679/8808 5863,9685 •348.5 2805.8 < 0.88 [0.85; 0.92] Tea for heterogeneity Xa -179.8 p<0.0001 ic? Test for interaction: X' -2660 p <0.0001 P"41* LKT+CT betw | LRT belter LRT.CT effect p < 0 0001 16485 pts 87 trials 8 Concomitant CTRT has an effect on LOCAL FAILURE and DISTANT FAILURE (a) All trials e a « 0 1 Qcnoyrtait Chemotherapy Incbctkm Oerxaherapy Control 46.5* Absolute dfference al 5 years i id -4 J ± 1.5 % 17.1%^ 125% 1234567 28 Time from randomisation (Years) 28 Time from randomisation (Years) 9 Treatment of R/M SCHNC Relapse<6 months after platine CRT /oiumab Reccurence>6 months after platine 5FU/platine/cetux Unfit for platine Cht Individual Cht/best supportive care Individual Cht Nivolumab or pembrolizumab Nivolumab or pembrolizumab Near future reatment of R/M SCHNC Treatment of nasopharyngeal carcinoma: very chemo- and radiosensitive tumor Surgery is not the option ! • Stage I: RT only • Stage II, III, IVA: • Concurrent CT/RT > ACT (category 2) (ACT: 5FU/cis) • CT/RT (category 2a) • ICT > CT/RT (category 2b) (ICT: TPF, gem/cis??) • multimodality clinical trial Primary metastatic or recurrent salivary carcinoma (local/regional/distant metastases) • Trial • CT/RT • CT > CT/RT or RT or Observation • RT/surgery in selected pts with oligometastatic disease • Salvage curative surgery (neck, local) • Salvage RT (carbon or proton IMRT) • CT (gem/cis better than 5FU/cis) • Other active drugs: Taxanes, IFO, FU, capecitabine, vinorelbine, gemcitabine, MTX, EDX, cetuximab (11%) • Non active drugs: TKI • Immunotherapy: CTL, to disrupt EBV cell latency (azacitidine..), Nivo: 20% RR, PFS at 1yr 19%_ Androgen receptors in salivary gland ca. - antiandrogen therapy Advanced disease •AR high expressing cases, independently from histology (mostly SDC; AD, NOS; HG-MEC) •Female? •Which type of HT? > bicalutamide 50 mg/die plus LHRH agonist q4wks? > bicalutamide 150 mg? How long? ' y. .: " -v .V .. « AR negative CANCER OF UNKNOWN PRIMARY SITE (CUP) 4th September 2019 Erika MATOS 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 (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. m Incidence of CUP Rare disease? CUP accounts for 3-5% of all human cancers. CUP is considered the 8th most frequent malignant tumor. During the last two decades we have evidence that the incidence is decreasing (EU and USA). Why is it decreasing? • Improved diagnostics. • better immunohistochemistry, • better imaging technology and • molecular analyses (gene expression profiling tests and comprehensive genomic profiling) • which may enable us to detect the primary site more often. • Better smoking control. • Although the etiology and risk factors for CUP are poorly defined. • Smoking is one of the risk factors: RR 3.6 for current smokers, RR 5.1 for a heavy smokers. Cancer medicine 2018; 7:4814-24. Cancer Causes Control 2014; 25:747-57. 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. m m Additional diagnostic-work-up in CUP (1) m Additional procedures should be sign-, symptom-, lab. abnormalities guided. m Breast MRI: in patients with isolated axillary lymph node metastases and suspected occult primary breast carcinoma after negative mammography and sonography results. m Broader use of MRI in CUP diagnostics is questionable. m Endoscopy: if the patient has symptoms or relevant signs. m FDG-PET imaging in CUP diagnostics: in patients with cervical lymphadenopathy of primarily squamous histological subtype. PET-CT is useful (not been prospectively studied): m m m patients presenting with solitary metastatic disease who are candidates for curative loco-regional treatment in purpose to exclude occult metastases before extensive surgery, m patients with known severe iodine dye allergy m patients with predominant bone disease who would otherwise require either multiple MRIs or bone scans to evaluate response to therapy. Abeloff's Clinical Oncology (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. Additional diagnostic-work-up in CUP (2) m Serum tumor markers have no proven prognostic, predictive or diagnostic assistance. m Increased values of some tumor markers may help in guiding further diagnostics: m Beta human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP): m in patients with midline tumor masses with undifferentiated histology. m Prostate Specific Antigen (PSA): m in men with adenocarcinoma and predominantly bone disease. Unfortunately, most tumor markers (CEA, CA125, CA19-9 and CA15-3) are not specific and thus are not helpful in searching for the site of primary tumor. Abeloff's Clinical Oncology (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. 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 theirs' 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. How can pathologist help? (1) » Challenging work! Direct communication between clinician and pathologist is crucial. » Core biopsy is preferred over fine needle aspirate specimen. » Light microscopy: the tissue specimen (paraffin sections stained with eosine and hematoxyilin) » 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 tumor lineage by using peroxidase-labelled antibodies against specific tumor 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. Again, the method has a limitation, no pattern is 100% specific. Primary markers | CK 7-/CK 20+1 | CK 7+/CK 2QT| — I CK 7+/CK 20+ I —■ Colorectal and Mcrkel Additional markers CEA and CDX-2 Lung, breast, lhyniid, endometrial, cervical, and pancreatic carcinoma and el lolangiocarc i nonm TTF-l, ER, PR, GCDFP-15, and CK 19 Urothelial, ovarian, and purHTCalic CaitCCi and choiangiocarcinoma Hepatocellular, renal cell, prostate, squamous cell Urothelin and WT-1 Hep Par-1 and PSA 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 (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. How can pathologist help? (3) • Novel molecular studies in CUP evaluation? • There are two main approaches: • Gene expression profiling tests (GEP) to identify the tissue of origin (ToO): • Methodology: RT-PCR evaluating the expression od different genes • Several assays on the market (evaluating from 10 to 92 and more genes) • Comprehensive genomic profiling tests (CGP) to find treatable genomic aberrations (GA): • methodology: NGS Abeloff's Clinical Oncology (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. Is there a clinical benefit of identifying ToO by GEP? GEP: * Has the potential to predict the origin of tumor tissue. * It is based on the finding that metastases have molecular signatures that may resemble to ToO. * The strategy has been validated in metastatic tumors with known primary site with an accuracy of 80% to 90%. Survival of patients who received tissue-specific therapy did not differ significantly to historical cohorts, treated with empiric chemotherapy. Abeloff's Clinical Oncology (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. Is there a clinical benefit of identifying ToO by GEP? (3) « ASCO 201 9: _ Conclusion: Site-directed therapy based on microarray profiling does not improve OS or PFS compared to empirical treatment. . Hayashi H et al. JCO 2019; 37:570-9. * prospective phase II randomized study * 130 patients included * Randomization: site-specific therapy or empiric paclitaxel and carboplatin * GEP was used to successfully predict a tissue of origin in all patients. * The results were disappointing. » mOS: 9,8 mos for he site-specific therapy and 12,5 mos for empiric treatment (p=0,896). » mPFS: 5,1 mos vs 4,8 mos (p=0,55). m Current clinical role of comprehensive gene profiling (CGP) in CUP? » The trend across all cancer types is personalized medicine (CUP seem ideal candidate). » Aim of tumor CGP (methodology is NGS): to find aberrations that can be targeted therapeutically: » FoundationOne™ assay » is FDA-approved for solid tumors. It is based on 324 genes. All four types of genetic aberrations can be identified (substitutions, insertion, deletion and copy number alterations, as well as MSI and TMB) using paraffin embedded tumor sample. PDL1 testing can be added. » MI Transcriptome™ assay. » provides information on 592 genes, detects gene fusions and can differentiate fusions from other rearrangements in solid tumors. The assay is supposed to get FDA approval in late 2019. Abeloff's Clinical Oncology (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. Do we have effective drugs for CUP patients? a responsive subset: favourable prognostic subset an unresponsive subset: poor prognostic subset about 20% of CUP patients should be treated with primary-specific therapy corresponding to most likely primary site about 80% of CUP patients m m m Int J Cancer 2014; 135, 2475-81. Abeloff's Clinical Oncology (6th Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. 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 tumors 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 (611 Edition) 2020; Cancer of Undefined Site of Origin 1 694-702. Unfavourable prognostic subset (1) Sensitivity to chemotherapy is modest. GEP could identify ToO in majority of these patients. • If identified tissue specific therapy or inclusion into clinical trial (if available) is the best option. • If not-identified, the option is either clinical trial or CGP in terms to identify potentially treatable GA • 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. m m m m 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. m m NCCN guidelines Conclusions m 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. Especially for patients with widespread disease and poor PS BSC is the best option. Novel approaches are promising, present a fundamental shift in the paradigm of treatment of cancer patients from tissue-specific to individual, patient customized treatment, directed according to tumor specific GAs. m m m m m m m Systemic treatment of prostate cancer Borislav Belev Clinical Hospital Center Zagreb School of Medicine Zagreb 1st Summer School in medical oncology -Ljubljana, 3.-6. September 2019 Prostate cancer - possible scenarios Localized prostate cancer Local treatment/RT Active surveillence Approved therapies for CRPC ADT=androgen-deprivation therapy; mCRPC=metastatic castration-resistant prostate cancer. Time to events in the COU-AA-302 and PREVAIL studies Abiraterone or Docetaxel? Directly randomised data from the STAMPEDE: 566 pts KM OS: all raían»' KM Ifl-ft ahrafarcnu D. 1Ï Si M 46 Trtf ton mrttamlsslm imnltral hunter plwitetw*1*! SflMBtP lift (1) in ffl 175 JRl US (7) 15fl (7) Hi «I IM |I0| tIS |î| 7n SOT MB J77 (1) .171 00 3® llfl) ÏID (;7| JJft (HJ iS7('-li 77A (11 ?1il ll?| IM KW FFS; BtlrSBrcm w ÔÏWBSI TJnftlrom ranmnpjttf.r. jmcntisi kxmimp in» mi i?a(i?] iki(13)hs (Sj m m; aiiini vi BOMAP nT7|ll| 9H|JI| SM pi) Mil IpOj M» |9J ¡WI17IMI KM SPC »intmnew®««»! ra (6 w fu (B) 3JS.;iß)l» Urna luira miran-mato (mirths) (i 15 Sd as dû Í fire hin rairtamlsalin iranltis} Nafta ni Mint* il patenUifivtrb) iilsrls JimHilt} sccicoj t»(ii)iîs{â9)i«iM)iai fi-r; i»is) » ft m .üi v ;si no SûCiCwP i» ci <7a is;, ic? is;, tsc (4| us pi tar ¡g¡- ia» io; » SCCiAAP 377(16}3» ;ST)31í |35| 5S5|-1¡ 27tir>}25C ,7.l 2« (51 all |7| !4t SOClMP 3^7 |"| 965 111! 347(15)324(10) »1 Maw |C; SES (S) & Cause-specific survival Favours SQC+AAP Failure-free survival Progression-free survival Melaslalic progression-free survival Symptomatic skeletal j events Favours SOC+DocP 0.5 1.0 Hazard ratio Sydes et al. Annals of Oncology 29:1235-1248,2018 The NEW ENGLAND JOURNAL of MEDICINE U12 fUNh ZK, 201« VOL m HO- M Enzaliitamide in Men with Nan metastatic, Castration-Resistant Prostate Cancer Ulhi HmJi-. M 0. Inn for. M.D, Pt.0, f«d Slid, «.[>. n> laM>| M 0, M Short. WD. Uhlfalara Frdcjra. M.J Ph.D., Petra Ivasliclillm, M.D., tlin Dem.rhari, Ph.D., KilliriM ModeWa, W D. Prr.D. He WiUilj. B S.. Andrew Kilvokhlk. M.C. -l\Q and Cfiri N SltrJrihrr^. MO. HKW ■ 1u Mt) JO LI :; : n.r M t nn. i v K ORÎûlWM. ARTICLÜ OR KilNAL ARTICLE Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer Matthew».Smith,M.D., Ph.D., FredSaad M.D,, Simon OiDwdhury, M.B., B.S., Ph.D., Stiphne Qudard, M.D., Ph.D., Ml«, Htdnctt, M.D., JulieN. Graff, M.D, David Olmos, M.D.. Ph.D, Paul N. Mair.waring. M.B., B.5., M,D..Ji Youl Lee. M.D., Hiroji Uemura, M.D,, Ph.D.. Angela Ijopez-Gitlili, M.D, Giratyn C. Trudal, Ph.D., M, Espinn, 6.S., Youyi Shu, Ph. D, Voun C. Park, Ph.D, Wayne R. Backoff, M.D, Margamt K, Vu, M.D., and Eric j. Small, M.D.. for Ihe SPARTAN Inresligalors-1 Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer Kaiim I'izazi, M.D, heal 5liore, M.J.. fejvo.L Tamirtflla, M.D, Ph.D, Albsrtai U lys. M.D, Lgjls Vjaters, ',' D Sergey Pdyakov, M -Mirtdau^iSjievallas, M.D, I.1!.'b.ui, M,D„ BorisAtekseev, M.D,, ImKuss, M.D, Chiiitan r^ppiler. Ph.D., Am:r Snapir. W.D., Ph.D, Tuhi Saraptjhja, M.Sr. and MsBlisn R. Smilll, M.D,, Ph.D.. for Ihe ARAMIS Inveslijslprs* Take home messages Optimal sequence of treatment is not defined, since prostate cancer is heterogenous disease Treatment paradigm is changing dynamicaly, there are many new agents evolving in the last decade Androgen deprivation therapy is still fundamental Understanding of pathophysiology of disease determined new strategies, recognizing AR-pathway as still very important even in castrate situation Focus of treatment strategy is shifted toward earlier phases of disease, providing more benefitial outcomes Enzalutamide produces good therapy effect in mCRPC, abiraterone-acetat in mCRPC and mCSPC Docetaxel is valid option in mPC Cabazitaxel, mitoxantron and carboplatine are the options in mCRPC Apalutamide and enzalutamide are good option in mOCRPC New area of diagnostics - tumor genetic analysis - provides more individua-tailored treatment approach Topics ■ Role of surgery in advanced RCC ■ Targeted Therapy for Advanced RCC ■ Immune Checkpoint Inhibitors for Advanced RCC ■ Combination Therapy: Current and Future Opportunities ■ Optimal Sequencing of Systemic Therapy in Advanced RCC ■ Nuances in Treating Patients: Adjuvant Therapy, Treating Brain Metastases, Managing Adverse Events Univerza v Ljubljani ONKOLOS* uifXpo Advances in treatment of u — renal cell carcinoma Bostjan Seruga, MD, PhD Division of Medical Oncology Institute of Oncology Ljubljana and University in Ljubljana Ljubljana, September 4, 2019 Take-home Messages 2 ■ Small molecule targeted agents dramatically improved the outcome of patients with metastatic RCC ■ Sequencing of small targeted agents should be based on the currently available evidence ■ In the era of checkpoint inhibitors small molecule targeted agents remain important therapeutic strategy for patients with metastatic RCC Take-home Messages 1 ■ The key for cytoreductive nephrectomy is patient selection - Cytoreductive nephrectomy should no longer be considered standard of care in intermediate- and poor-risk groups of metastatic RCC at least when medical treatment is required Radical metastasectomy followed by observation is commonly used strategy in selected patients with oligometastatic disease. There is no role of trageted agents in patients who underwent radical metastasectomy Take-home Messages 4 ■ Most immune-related AEs are reversible with immunosuppression through steroid treatment - Typically start with high-dose IV and then taper over 1-3 mos - Exception: adrenal insufficiency and hypothyroid need replacement hydrocortisone and levothyroxine, respectively, without use of steroids ■ No evidence that intervening with steroids curtails antitumor efficacy of agent Take-home Messages 3 ■ Anti-PD-1 based therapy is active in treatment-naive patients including favorable-risk patients ■ Much, but not all, of the activity of nivo/ipi is likely from the anti-PD-1 component ■ Anti-PD-1 monotherapy with nivo/ipi salvage might be a reasonable strategy when one is concerned about the toxicity of nivo/ipi ■ A trial of nivo/ipi vs nivo in frontline RCC is indicated lO-Non-IO Combinations ■ IO is different than tumor-directed therapy because of its ability to produce Treatment-Free Survival (TFS) ■ Combinations that improve median PFS or median OS without producing TFS may sacrifice the potential of IO while contributing toxicity, inconvenience, and tremendous extra cost ■ Not only must A+B > A followed by B (or B followed by A), but TFS must be maintained in order for such combos to be fully embraced ■ Clinical trials with IO agents need to use IO endpoints Take-home Messages 5 ■ Adjuvant VEGF therapy, when adequately dosed, can offer very modest benefit balanced against toxicity ■ The goal of a patient with newly metastatic RCC is potential cure; therefore, regimens with the highest chance of cure/durable response, balanced against acceptable toxicity/time off of treatment, should be prioritized ■ Immunotherapy-based regimens offer the best chance of achieving patient goals - Whether immunotherapies in combination with one another or with VEGF therapies most effectively achieves these goals is as yet undefined O Onkološki Inštitut Institute of Oncology Ljubljana Systemic treatment of bladder cancer Marina Mencinger MD , PhD International School for Medical Oncology Ljubljana Sept 2019 Tumours of the urothelial tract Cancer that starts in the urothelium is called urothelial (or transitional cell) cancer. By definition, urothelial carcinoma with divergent differentiation refers to tumours arising within the urothelial tract, in which some percentage of "usual type" urothelial carcinoma is present along with other morphologies Histological type (1) Urothelial carcinoma 90-95% Squamous-cell 3% ca rcinoma Adenoca rcinoma 2% Small-cell carcinoma <1% Bladder Cancer (2) Superficial pTa, pTis, pT1 75-85% Muscle-invasive pT2, pT3, pT4 10-15% Metastatic N+, M+ 5% O 1. Humphrey, European Urology 2016, 2. MatulayJ, F1000Res. 2018; Molecular characterisation of bladder c. The TCGA (The Cancer Genome Atlas) study confirmed the existence of luminal (KRT20+, GATA3+, FOXA1+) and basal (KRT5,6,14+, GATA3-, FOXA1-) transcriptional sub-types, and neuronal subtypes-1. The subtypes were associated with overall survival (retrospectively)-2. Luminal-best OS, basal-most improvement in OS with NAC, claudine low-poor OS. o Using a novel singlepatient subtype classifier based on The Cancer Genome Atlas identified 11 patients with a neuronal subtype, with 72% response rate to atezolizumab.-3 Rodriguez V Cancer Treat Res 2018; Seiler, Eur Urology 2017; Kim, Europ Urol., 2019 Muscular invasive bladder carcinoma has bad prognosis in comparison to muscular noninvasive clasification Stadium at diagnosis Percentage of patients 5 year OS1 Risk for relaps in 5 years Muscular noninvasive noninvasive (Ta, Tis ,T1) 51-75%1-4 96% 50-90%2'4 Muscular Localised (T2-4, N0) 35%1 30%4 7%1 69% ~50%6 invasive Localy advanced (Tx, N1) 34% metastatic (Tx, Nx, M1) 4%1'5 6%% NA O 1. Howlader N, et al. (eds). SEER Cancer Statistics Review, 1975-2011. 2. NCCN Guidelines - Bladder cancer v1.2015. 3. Sharma S, et al. Am Fam Physician 2009. 4. Kaufman DS, et al. Lancet 2009. 5. American Cancer Society 2014: Bladder Cancer. 6. de Vos FY and de Wit R. Ther Adv Med Oncol 2010. RATIONALE FOR NAC-prolonged OS: T2-4a, No, Mo: Neoadjuvant CT with platinum Trial n Neoadj. CT + surgery vs. surgery alone Meta-analysis 11 trials1 3.005 Statistically significant prolonged OS (HR=0,86; 95% CI: 0,770,95; p=0.003) • 5% absolute improvment 5 - y OS (from 45% na 50%)2 Statistically significant prolonged survival without disease (HR=0,78; 95% CI: 0,71-0,86; p<0,0001) • 9% absolute improvement in 5 - y survival without disease Recommended CT schemes by NCCN-2 3-4 cycles dd-MVAC : dose-dense metotreksat, vinblastin, doksorubicin in cisplatin) 4 cycles gemcitabin in cisplatin 3 cycles CMV (cisplatin, metotreksat, vinblastin) o 1- Advanced Bladder Cancer Meta-analysis Eur Urol 2005 2-National Comprehensive Cancer Network. Bladder Cancer (Version 1.2019). Rationale ACT: T3/4, N+, Mx: adjuvant CT | trial n Surgery + adjuv. CT vs surgery alone Meta-analysis of 9 trials (1) Statistically significant prolongation of OS (HR=0,77; 95% CI: 0,59-0,99; p=0,049) 945 Statistically significant prolongation of survival withouth disease (HRr0 fifi- Randomised trials of adjuvant therapy ¡are incomplete or underpowered. EORTC (2) PFS was longer with immediate versus deferred adjuvant 284 chemotherapy [Hazard ratio (HR): 0.54; p < 0.001], but no diferences in OS were observed (HR 0.78; p = 0.13) o 1-Leow JJ, Eur Urol 2014; 2-Sternberg, Lancet Oncol 2015 Bladder sparing treatments : T2, No, Mo Who are optimal candidates for bladder preservation? Optimal candidates for bladder preservation with chemoradiotherapy include patients with tumors that present without hydronephrosis, are without concurrent extensive or multifocal Tis. and are <6 cm. Ideally, tumors should allow a visually complete or maximally debulking TURBT. 3'ee Principles of Radiation 1. TURBT + Concurrent chemoradiotherapy 2. Radiotherapy _ 3. TURB plus BCG Reasses tumor status after 2-3 m Tumor present O * • CT • CT+RT • Paliative TURBT/salvage cystectomi • BSC Morales R, Clin Transl Oncol. 2011; NCCN guidelines 2019 1. Line treatment-cisplatin fit The standard of care for first-line (1L) metastatic urothelial carcinoma (mUC) is cisplatin-based combination chemotherapy (NCCN V2.2019). Not eligible for cisplatin Eligibility for Cis NAC 10 the ratio of PD-L1-expressing tumor-infiltrating immune cells relative to the total number of tumor cells ATEZOLIZUMAB: Clone: SP142 staining on tumor-infiltrating immune cells covering at least > 5% Second line phase III trials with PDL-1 inhibitors (atezolizumab, pembrolizumab)-study design _SECOND LINE PHASE III_ KEYNOTE-045 Study Design (NCT02256436) o Urothelial Progression or recurrence of urothelial cancer following a first-line platinum-containing No more than 2 prior I ir*es of systemic chemotherapy. Paclitaxel, Docetaxel or IMvigor211 Study Design (NCT02302807) • Urothelial cancer Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen. E)Uw*t«d iintlbw EiUituuil completion Nov2017 SOC: Docetaxel, Paclitaxel or Vînfiunine Bellmunt 2017, NEJM, Powels Lancet 2018 2.Line: Pembrolizumab vs CT: mOS and duration of response Duration of response mOS A Overall Survival Longer follow up 27 m, HR=0,7 Hazard ratio for ntath, 0,73 (S5%.CI, 0.59-0.91.) P=0.002 3 4 6 g JÖ u i4 Months No. at Risk PembröliZinnat 2/1; Vi-4 194 Iii 147 131 S7 54 27 Ii Chgmoiheraßy 272 232 171 IM 10S S9 55 27 14 i o Time to Response and Duration of Response in Patients with a Confirmed Objective Response. Bellmunt, NEJM, 2017 2. Line : Atezolizumab vs CT PDL1 positive patient group mOS Duration of response Üvirafl iuhwivil Evesils/ Median aveill 12 month overall numbef survival survival rat* ol patients (months; 9SK CIJ {Ml O) - AtMfllliumab 72/llS 111 (Sfr-lSSj 4&:4K(J23-5SE) - ChennihHapy EtyilB 10 6(34-12-2] 412% 012-ia-3J Stratified rti D-E7, 3SH □ 0-63-1 21; o=a-41 HR=0,87 p=0,42 "-t—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i—i-0 L 7 q A q S 7 3 1 10 U 13 n II K li D ll H UumbctniKk AtMcJTmmjb litujujc ÜB US Si 77 73 71 £3. SB. 55 SI |7 39 as 2J- 19 is I Cbmulliraiiv Tliimil» a 51 is Si Ä /1 B tl mi <1 2 i! ¡H 11 li 11 o & i 15.9m (Atezo) vs 8.3 m (CT) rTTSTTT ¿t. M K K Ä Figure 2j Efficacy___ tumour-infittratsna in patients with programmed death- liqa nd-1 expression on 5% o e cells iüC2,'i no ou tat ion! Powles, Lancet, 2018 Summary of Treatment in bladder cancer FIRST LINE (MANDATORY PD-L1 TESTING) SECOND LINE (NO PD-L1 TESTING) Cisplatin ineligible Cisplatin ineligible (PD-L1) (PD-L1 high) low) CT-ineligible Cisplatin-based CT Carboplatin based PD-1/PD-L1 blockade CT o O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana 1st SUMMER SCHOOL IN MEDICAL ONCOLOGY PALLIATIVE CARE When to start and how to lead Maja Ebert Moltara, MD mebert@onko-i.si Head of a Department for Acute Palliative Care Department of Medical Oncology i;;, ^ ES« 3-6 September 2019, Ljubljana, Slovenia 6 BASIC QUESTIONS: WHAT? For WHO? WHO provides? WHERE? WHEN? WHY? Onkološki Institute A ^ EM) I j Inštitut of Oncology m. f oaigfwedcmt™ V^/ Ljubljana Ljubljana 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, physicalpsychosocial and spiritual. o Onkoloski Institut Ljubljana institute of Oncology Ljubljana COMPREHENSIVE PALLIATIVE CARE O Onkoloski Institut Ljubljana institute of oncology Ljubljana COMPREHENSIVE PALLIATIVE CARE O Onkološki Inštttut Ljubljana institute of Oncology Ljubljana d ES 0 Designated Centers 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 O Onkološki Institute Inštttut of Oncology Ljubljana Ljubljana O ES 0 CONTINOUS PALLIATIVE CARE For WHO? Death Time Murray, S. A et al. BMJ 2008;336:958-959 O Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana o Onkoloski Institut L)ubl)ana Institute of Oncology Ljubljana O ran Conceptual framework -L- SUPPORTIVE CARE »ALLIATIVE CAR HOSPICE CARE SPECIFIC THERAPY newer term less stigma more hospital based wider range of services lower definitional clarity less volunteer involment older term more stigma more home based more focused services higher definitional clarity more volunteer involment early stage disease (curable) advanced disease (incurable) bereavement Hui, D. etal. 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). O Onkoloski Institut Ljubljana Institute of Oncology Ljubljana WHEN? The NEW ENGLAND JOURNAL ef MEDICINE ORIGINAL ARTICLE Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer Jennifer S. Temel, M.D.Joseph A. Greer, Ph.D.,Alona Muzikansky, M.A., Emily R. Gallagher, R.N., Sonal Admane, M.B., B.S., M.P.H., Vicki A. Jackson. M.D., M.P.H., Constance M. Dahlin, A.P.N., Craig D. Blinderman, M.D., JulietJacobsen, M.D., William F. Pirl, M.D., M.P.H., J. Andrew Billings, M.D., and Thomas J. Lynch, M.D. o Onkoloskj InStttut Ljubliana institute of Oncology Ljubljana o EM) EARLY PALLIATIVE CARE Ferell, J Pain Manag, 2015 Higginson 2015 O Onkoloskj InStttut Liubliana Bakitas, JCO 2013 o™ institute of Oncology Ljubljana Extra: HOW many Onkoloski instftut l|ubl|ana Institute of oncology l|ubljana Global Atlas of Palliative Care at the End of Life, January 2014 Ljublana Institute of Oncology Ljubljana 2. PALLIPHOBIA "He's our new Palliative Specialist!' 3. PALLILALIA 4. PALLIACTIVE Hope is like the sun, which, as we journey toward it, casts the shadow of our burden behind us. Top 10 Things Palliative Care Clinicians Wished Everyone Knew About Palliative Care Jacob J. Strand. MD: Mihir M. Kamdar. MD: and Elise C. Carey. MD 2013 Mayo Foundation for Medical education an Research, Mayo Clin Proc. 2013; 88 (8):859865 O Onkološki Institute 4 tl; Inštitut of Oncology V r. liubiiana uubljana ' 32£S, #1. SUMMER SCHOOL IN MEDICAL ONCOLOGY IS SPONSORED BY: Roche ^MSD ^ MERCK ib NOVARTIS o Onkološki Inštitut Institute of Oncology Ljubljana O/^v iet Q^J years KATEDRA ZA ONKOLOGIJO SEKCIJA ZA INTERNISTIČNO ONKOLOGIJO j Slovensko j Zdravniško Društvo SCHOOL IN MEDICAL ONCOLOGY Part 2 - Thursday (5.9.) & Friday (6.9.) LJUBLJANA 3-6. SEPTEMBER 2019 Strokovni odbor: izr. prof. dr. Janja Ocvirk, dr.med. doc. dr. Martina Reberšek, dr.med. dr. Simona Borštnar, dr.med. doc. dr. Cvetka Grašič, dr.med. dr. Tanja Mesti, dr.med. Marko Boc, dr.med. Organizacijski odbor: izr. prof. dr. Janja Ocvirk, dr.med. doc. dr. Martina Reberšek, dr.med. doc. dr. Cvetka Grašič, dr.med. dr. Tanja Mesti, dr.med. Marko Boc, dr.med. ga. Lidija Kristan Uredniki zbornika: Marko Boc, dr.med. doc. dr. Martina Reberšek, dr.med. izr. prof. dr. Janja Ocvirk, dr.med. dr. Tanja Mesti, dr.med. Organizator in izdajatelj (založnik): Onkološki inštitut Ljubljana Sekcija za internistično onkologijo Katedra za onkologijo Ljubljana, september 2019 AGENDA & INDEX Thursday, September 5 Part 1 Moderator: dr. Borstnar 8:30-10:00 Early and locally advanced Breast cancer (dr. Borstnar, dr. Ribnikar, dr. Beslija) Introduction (20-30 min) (Dr. Borstnar) Case 1: HR+HER2- luminal A BC (dr. Gersak, dr. Borstnar) Case 2: HR+HER2- luminal B BC (dr. Prepeluh, dr. Borstnar) Case 3: Early TNBC (dr. Gersak, dr. Borstnar) Case 4: First-line ribociclib in primary metastatic hormone receptor-positive breast cancer (dr. Rugelj, dr. Borstnar) 10:00-10:15 Break 10:15-11:45 Metastatic breast cancer (dr. Borstnar, dr. Ribnikar, dr. Beslija) Introduction (20-30 min) (Dr. Ribnikar) Case 5: Metastatic HR+ BC with visceral crisis (dr. Dobovisek, dr. Borstnar) Case 6: Primary metastatic HER2+, HR+ BC (dr. Dobovisek, dr. Borstnar) Case 7: Metastatic TNBC (dr. Dobovisek, dr. Borstnar) 11:45-12:00 Discussion 12:00-12:30 Systemic treatment of sarcomas (dr. Unk) 12:30-13:20 Lunch break Part 2 Moderators: dr. Kandolf Sekulovic, dr. Ocvirk 13:20-14:00 Satellite symposium (MSD) 14:00-14:30 Adjuvant treatment strategies for malignant melanoma (dr. Herceg) 14:30-15:15 Melanoma 2020 Standards of care and unmet needs (dr. Kandolf Sekulovic) 15:15-15:30 Discussion 15:30-15:40 Break 15:40-16:10 Systemic treatment of non melanoma skin cancers (dr. Ocvirk) 16:10-17:10 Interesting cases from audience Case 1: Skin toxicity of immunotherapy (dr. Vermiglio, dr. Mesti) 17:10-17:40 Satellite symposium Friday, September 6 Moderators: dr. Rebersek, dr. Ebert Moltara 8:30-9:30 Interesting cases from audience 9:30-10:00 Systemic treatment of ovarian cancer (dr. Skof) 10:00-11:00 How to manage patients with renal insufficiency (dr. Milanez) 11:00-11:30 Side effects of immunotherapy and the management (dr. Hribernik, dr. Rebersek) 11:30-11:40 Break 11:40-12:30 Side effects of chemotherapy (including extravasation) and TKI and the management (dr. Ovcaricek, dr. Bokal) 12:30-13:00 Discussion and conclusions O' Onkološki Inštitut | Institute of Oncology Ljubljana Treatment of early and locally advanced breast cancer Simona Borstnar 1st Summer School of Medical oncology, September 2019, Ljubljana Multidisciplinary approach in treatment of breast cancer Features for selection of treatment Distribution of patients by stage Tumor characteristics nodal status Division into subtypes and treatment decision HR-HER2-(Triple negative) HR-HER2 + (HER2 positive) * HR+HER2-(Luminal A) Endocrine therapy (ET) Chemotherapy (CT) anti HER2 therapy (TT) Gene signatures in ER+ subtype HUMAN GENOM: ~25 000 genes ❖MammaPrint (70 genes) ♦♦♦Oncotype (21 genes) GENES RELATED TO PROLIFERATION AND INVASION OF BREAST CANCER: 231 genes J The 70-gene and the 21-gene signatures identify patients who may not require adjuvant chemotherapy. Oncotype DX Mammaprint EARLY BREAST CANCER Anti HER2 therapy 1 year Endocrine therapy 5-10 years Adjuvant therapy of triple negative BC □ CT in all pts, except ductal, TiaNo ■ CT with anthracyclines and taxanes (dose dense AC followed by paclitaxel every 2 weeks, dose dense AC followed by weekly paclitaxel, TC, FEC folowed by docetaxel etc.); TC, TAC, CMF □In pts with Stage II in III neoadjuvant treatment is recommended Adjuvant treatment of HER2+ breast cancer CT +anti-HER2 therapy (+ ET in HR+) □ CT should contain anthracyclines and taxanes; • a possible but not preferred choice is a combination without anthracyclines TCH (docetaxel + carboplatin + trastuzumab) • For pT1b,c N0, paclitaxel weekly x 12 is sufficient • For stage II and III, neoadjuvant CT is recommended □Anti-HER2 treatment • Trastuzumab +/- pertuzumab (addition of pertuzumab if positive limphnodes or negative HR • infusions or subcutaneous applications every 3 weeks; ^duration: 1 year □ In pts with HR+ tumors , ET after completion of CT, selection by age and menopausal status Adjuvant therapy of HR+ (luminal) breast cancer LUMINAL B CT followed by ET □ Premenopausal: CT and then AI+ OS or tamoxifen ± OS; prolongation of ET to 10 or 15 years depending on side effects □ Postmenopausal: CT and then AI ± bisphosphonates; prolongation of ET to 10 or 15 years based on side effects. LUMINAL A ET only □Premenopausal: tamoxifen 5 years □Postmenopausal: tamoxifen or aromatase inhibitors (AI), or both in sequence up to 5 years Adjuvant therapy in INTERMEDIATE (HR+) BC CT in majority of pts, ET in all pts □Premenopausal: ^ Tamoxifen ± OS or AI + OS in No and intermediate characteristics (gradus, proliferation, gene signature) ^ CT and then AI + OS or tamoxifen ± OS in N + and intermediate / poor characteristics (gradus, proliferation, gene signature); prolongation of HT to 10 or 15 years depending on side effects □Pomenopausal: ^ AI in NO and intermediate characteristics (gradus, proliferation, gene signature) ± bisphosphonates ^ CT and AI in N + and intermediate / poor characteristics (gradus, proliferation, gene signature) ± bisphosphonates; prolongation of HT to 10 or 15 years depending on side effects LOCALLY ADVANCED OR TNBC/ HER2 positive, stage II or III BC Endocrine therapy 5-10 years Indications for neoadjuvant CT □Inflammatory breast cancer □Triple-negative or HER2-positive stages II and III □ Luminal B with intention to deescalate surgical treatment Diagnostic procedure before neoadjuvant CT □Core biopsy is mandatory to determine tumor characteristics □CT of the neck, chest and abdomen, bone scan □ Insertion of a marker clip into the tumor before the onset of neoadjuvant CT □ Breast MRI before and after neoadjuvant CT Choice of neoadjuvant systemic therapy □polychemotherapy: a combination of anthracyclines and taxanes is preferred(dose dense AC followed by paclitaxel every 2 weeks; dose dense AC followed by weekly paclitaxel , FEC followed by docetaxel) □ trastuzumab + pertuzumab in HER2 positive patients □capecitabine (8 cycles) is recommended in patients with triple-negative cancer where a complete response is not obtained after neoadjuvant CT, □ET in elderly patients with hormone-dependent cancer and / or contraindications for CT; 5-8 months or until the best response Literature □ Cardoso F , Kyriakides S , Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S and Senkus E, on behalf of the ESMO Guidelines Committee. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 201Q;30: 1194-1220. □ Waks AG, Winer EP. Breast Cancer Treatment. : A Review. JAMA 20l9;32l(3):288-300. □ Burstein HJ et al: Estimating the Benefits of Therapy for Early Stage Breast Cancer The St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019. Ann Oncol. 2019 Aug 2. pii: mdz235. doi: 10.1093/annonc/mdz235. [Epub ahead of print] □ https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Version 2.2019; 07/02/2019 o O Onkološki Inštitut Institute of Oncology Ljubljana Case i: Bilateral breast cancer luminal A + luminal B (HER2+) Author: Klara Geršak, MD Mentor: Simona Borštnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA H National NCCN Guidelines Version 1.2018 HH^H Comprehensive Genetic/Familial High-Risk Assessment: Breast an d Ovarian IBKMMkI Cancer ■ Network" Increased risk of BC Screening: Annual mammogram with consideration of tomosynthesis and consider breast MRI with contrast age 40 y (c,d) Risk-reducing mastectomy: Evidence insufficient, manage based on family history c May be modified based on family history (typically beginning screening 5-10 years earlier than the youngest diagnosis in the family but not later than stated in the table) or specific gene mutation. d For women with mutations who are treated for breast cancer and have not had bilateral mastectomy, screening should continue as described O 27.9.1967 F amily history: Mother bilateral breast cancer at age 50 and 52 Aunt(mother) breast cancer at age 39 Aunt(father) breast cancer Medical history: Healthy Gynecological history: Menarche at age 13 Menstrual periods not regular No oral contraceptives One child - at age 31 0 Year 2004 "«hi Two suspicious breast lesions on mammography l Core needle biopsy: LCIS and atypical ductal hyperplasia 1 ROLL bilateral l O Histology results: fibroadenoma Year 2002 '"la High risk for developing breast cancer CHEK2 mutation Regular follow ups Mammography, breast US, MRI of the breast & visit at Medical oncologist every 6 months 0 Year 2014 Right breast: IDC 8mm (T1 N0 M0) I t Mastectomybilaterally& sentinel node biopsy bilaterally; with immediate reconstruction I I Histology results: Right: IDC, grade III, 10mm, ER 100%, PR 100%, MIB-1 25%, HER2 +, N 0/8 Left: ILC, grade II, 6mm, ER 100%, PR 100%, MIB-1 5%, HER2 - O voting Following treatment: Right: IDC, grade III, 10mm, ER 100%, PR 100%, HER2 +, MIB-1 25%, N 0/8 A ET + trastuzumab B ChT + trastuzumab Left: ILC, grade II, 6mm, ER 100%, PR 100%, HER2 -, MIB- 1 5% C ChT + trastuzumab + ET D ChT + trastuzumab + ET + RT 0 Ovarian cyst -* laparoscopic adnexectomy bilaterally Side effects of hormonal therapy: Muscle pain in arms and legs, severe joint pain, small foot joint s tiffn ess, ankle pain, tiredness, lower physical capacity, hot flashes, occasional headaches O voting Which ChT: Right: IDC, grade III, 10mm, ER 100%, PR 100%, HER2 +, MIB-1 25%, N 0/8 A anthracylines B taxanes Left: ILC, grade II, 6mm, ER 100%, PR 100%, HER2 -, MIB-1 5% C anthracylines + taxanes D capecitabine 0 voting Extended Adjuvant Endocrine Therapy: A YES B NO Right: IDC, grade III, 10mm, ER 100%, PR 100%, HER2 +, MIB-1 25%, N 0/8 Left: ILC, grade II, 6mm, ER 100%, PR 100%, HER2 -, MIB-1 5% O Year 2014 3X FEC-100 (5-fluorouracil,epirubicin, cyclophosphamide) +3x docetaxel + trastuzumab (July 2014 - July 2015) + tamoxifen (from September 2014) 0 Year 2019 END of adjuvant HT (start: september 2014) Follow-ups once a year Regular US of the heart Lab tests repeatedly ok Tumor marker (CA 15-3): negative O Follow ups: A LAB + tumor marker CA 15-3 B Mammography/breast US C Clinical exam DA+B+C o O Onkološki Inštitut Institute of Oncology Ljubljana Case 2: HR+HER2+ luminal B breast cancer Nina Prepeluh Simona Borstnar, PhD., MD. Institute of Oncology Ljubljana Clinical presentation • 43- years old female • history: lump in left breast for 6 months, otherwise healthy • family history: cousin had uterine cancer • gynecological history: regular menses, 4x partus, no use of contraceptive pills • smoker (25 years, a pack a day) o Diagnostic work-up • mammography (June 2018) - tumor formation in upper inner quadrant of left breast, 5 cm in diameter with microcalcinations; MRI- tumor formation 27x22 mm, one pathological lymph node • core needle biopsy: IDC, grade 3, ER 100%, PgR 0%, Ki-67 15%, HER-2 positive (3+) • staging: CT of the thorax & abdomen + bone scan -no metastases detected o TABLE 1 Criteria for staging breast tumors according to the American Joint Committee on Cancer's TNM classification4 Primary tumor (T)* Carcinoma in situ Tumor < 2 cm+ No evidence of primary tumor Tumor < 2 cm+ Tumor > 2 cm but < 5 cm lumor > L cm but < 5 cm Regional lymph node status (N) No evidence of cancer in nearby nodes No evidence of cancer in nearby nodes Metastasis to 1-3 nodes Metastasis to 1-3 nodes No evidence of cancer in nearby nodes Metastasis to 1-3 nodes Stage NIC Stage IV Tumor > 5 cm No evidence of primary tumor Tumor < 2 cm+ Tumor > 2 cm but < 5 cm Tumor > 5 cm Tumor > 5 cm Tumor of any size with direct extension to chest wall or skin Tumor of any size with direct extension to chest wall or skin Tumor of any size with direct extension to chest wall or skin Any tumor designation Any tumor designation ce ot cancer in nearby nodes Metastasis to 4-10 nodes Metastasis to 4-10 nodes Metastasis to 4-10 nodes Metastasis to 1-3 nodes Metastasis to 4-10 nodes No evidence of cancer in nearby nodes Metastasis to 1-3 nodes Metastasis to 4-10 nodes Metastasis to > 10 nodes Any lymph node designation O What treatment regimen would you recommend to start with? A. neoadjuvant chemotherapy (anthracydines + taxanes) + neoadjuvant antiHER-2 therapy (trastuzumab) B. neoadjuvant chemotherapy (anthracyclines + taxanes) + dual neoadjuvant antiHER-2 therapy (trastuzumab+ pertuzumab) C. surgery followed by adjuvant chemotherapy + adjuvant antiHER-2 therapy D. surgery followed by adjuvant antiHER-2 therapy o Treatment timeline June - November 2018 December 2018 - XTin1T, __ ^^ breast conserving January 2019 - NAChT (4x EC + 4x DOCE+ surgery with ALND trastuzumab) Slnb MRI breast (November 2018): - Tumor formation of the left breast 1 cm - US of the axilla -no suspect nodes Pathological examination after NAChT: - partial response - 10 mm residual tumor, R0 resection - 2/3 positive nodes; 3 mm and 6 mm Pathological examination - regressive changes in 3/22 nodes O Which adjuvant therapy would you recommend? A. anti-HER2 therapy (trastuzumab) to complete 1 year + ET (tamoxifen) + postoperative radiotherapy B. anti-HER2 therapy (trastuzumab) to complete 1 year + ET (goserelin/oophorectomy with AI) + postoperative radiotherapy C. anti-HER2 therapy (trastuzumab) to complete 1 year followed by adjuvant neratinib D. anti-HER2 therapy (trastuzumab) to complete 1 year + ET (tamoxifen) E. dual anti-HER2 therapy (trastuzumab + pertuzumab) to complete 1 year + ET (tamoxifen) + postoperative radiotherapy O Treatment timeline (part 2) February 2019 - started adjuvant ET with tamoxifen and continued with trastuzumab March - May 2019 postoperative radiotherapy: 57 Gy in 25 fractions September 2019 -last trastuzumab administration, continuing treatment with tamoxifen august 2019: - no symptoms or signs of relapse, no mayor AE of the therapy O Clinical trials 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial Profluca Gianni, MO < ■ ProfTadeuszPienkowski.MD • Prof Young-Hyuck Im. MD ■ Ling-Ming Tseng, HD Trastuzumab plu» Pcrtuzumabi trastuzumab, Pertuzumab plus Pertuzumab phis (groupA; n>107) (group B; n-107) (group C; n-107) (groupD;n>g6) O o Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial O There is more to come... O Onkološki Inštitut Institute of Oncology Ljubljana Case 3: Early TNBC Author: Klara Gersak, MD Mentor: Simona Borstnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA Born: 4.11.1990 Family history of cancer: Aunt -cancer of the larynx at age 67 (father's side) Grandfather - breast cancer at age 60 Aunt - breast cancer at age 80 ^ Hashimoto thyroiditis Euthyrox 50 mcg/day ^«W Medical doctor (just started internship), lives with her family o Year 2018: a7«*USoId LEFT breast Self examination Upper quadrants Fine needle aspiration of the breast tumor (US 1.4x1 cm) and lymph node Cytology results: adenocarcinoma and metastasis of the adenocarcinoma n the left axilla (US 7 mm) n the lymph node Core needle biopsy 5.7.2018: IDC, poorly differentiated, high nuclear grade. ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg. 0 Tumor size - clinically: 1.5 x 1 cm Clinically no lymph node in the axilla. VAP Genetic counselling and testing Year 2018: y^s old LEFT breast Self examination Upper quadrants Fine needle aspiration of the breast tumor (US 1.4x1 cm) and lymph node Cytology results: adenocarcinoma and metastasis of the adenocarcinom in the left axilla (US 7 mm) in the lymph node O Core needle biopsy 5.7.2018: IDC, poorly differentiated, high nuclear grade, ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg. Tumor size - clinically: 1.5 x 1 cm Clinically no lymph node in the axilla. BRCA 2 mutation VAP Genetic counselling and testing voting How to treat: A NACT + surgery US 1.4x1 cm B surgery + adjuvant ChT lymph node in the left axilla (US 7 mm) IDC, poorly differentiated, high nuclear grade, ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg 0 voting Which ChT: A dose dense anthracyclines+taxanes (AC+PACLI) B (F)EC+DOCE C capecitabine o US 1.4x1 cm lymph node in the left axilla (US 7 mm) IDC, poorly differentiated, high nuclear grade, ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg NEOADJUVANT SYSTEMIC THERAPY 4x AC (DOXORUBICIN+ CYCLOPH O S PHAMID E) D + S E 4x PAKLITAKSEL D + pegfilgrastim E N S E 0 After 2. Cycles of the therapy: no tumor clinically 16.11.2018 OPERATION 7ye*rsold LEFT: Subcutaneous mastectomy with axillary lymph node dissection + immediate reconstruction RIGHT: prophylactic mastectomy + immediate reconstruction Pathohistological results: 0 Residual IDC and DCIS, partial response to therapy -10-50% residual tumor. No vascular invasion. No perineural invasion. Surgical margins clear. Nodal status 2/24 - 1mm & 5mm - without extracapsular growth. voting Following treatment: partial response to therapy nodal status 2/24 - 1mm & 5mm - without extracapsular A RT growth B capecitabine US 14 x 10 mm C RT + capecitabine lymph node in the left axilla (US 7 mm) IDC, poorly differentiated, high nuclear grade, 0 ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg 28ye^sold Adjuvant RADIATION therapy From 14.1.- 20.2.2019 (+ parasternal lymph nodes) o 28 ye*rsold 25.2.2019 adjuvant CHEMOTHERAPY Capecitabine 2150 mg/12 hours, 14 days + goserelin 3.6 mg sc 6th, 7th and 8th cycle 75% dose - because of hematotoocicity 0 Last visit: 16.8.2019 voting Expected 10-year survival: A More than 90% B 80-89% C 70-79% o US 14 x 10 mm lymph node in the left axilla (US 7 mm) IDC, poorly differentiated, high nuclear grade, ER 0%, PR 0%, MIB-1 around 30%, HER-2 neg partial response to therapy nodal status 2/24 - 1mm & 5mm - without extracapsular growth Overall survival This chart shows the percentage of women surviving 10 years after surgery. _ _ . Survival rate excluding deaths from breast cancer. O • Additional benefit of chemotherapy is 8% at 10 years. • Surgery only survival is 75% at 10 years. O Onkološki Inštitut Institute of Oncology L|UBL|ANA Case 4: First-line ribociclib in primary metastatic hormone receptor-positive breast cancer Author: Urška Rugelj, MD Mentor: Simona Borštnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA Clinical case • 43-year-old premenopausal woman • No comorbidities • Medication: antihistamines due to atopy • Family history negative for malignancy • First visit in June 2017 • Patient presented with a lump 5x4cm lump in the upper inner quadrant of the left breast • No skin or areola abnormalities • No enlarged lymph nodes • ECOG: 0 O Initial assessment • Imaging: • Mammography - structural abnormality in the left breast • Magnetic resonance imaging of the left breast: tumor on the border of upper quadrants 50x35 mm, 2 other foci in the upper and lower inner quadrant 30 and 35 mm, pathological axillary lymph nodes with enlarged capsule - the largest 6 mm in diameter • Bone scan: no signs of osteoblastic lesions • Ultrasound of the abdomen: no signs of metastases • Chest X-ray: no signs of metastases • Cytological puncture of the tumor: adenocarcinoma • Ultrasound guided cytological puncture of the axillary lymph node: metastasis of the adenocarcinoma • Diagnosis: adenocarcinoma of the left breast with positive ipsilateral axillary lymph nodes o Core needle biopsy - pathology report • Biopsy • Core needle biopsy • Histopathology: ILC • Biomarkers • HER2-, PgR 95%, ER 1009 • Gene signature • Not done I Ki67 5-10% 4 • Luminal A like disease 0 Initial treatment and final pathology • Surgery: • Radical mastectomy and axillary lymph node dissection with immediate reconstruction with DIEP flap • Definitive histology • Invasive lobular carcinoma, 50 mm in largest diameter, with foci of lobular carcinoma in situ, grade 2, mitosis 2, lymphovascular invasion present • 25/28 axillary lymph nodes positive, the largest metastasis measuring 18 mm with extension outside of the capsule and infiltrating the surrounding adipose tissue O What additional treatment would you recomend? A. Adjuvant endocrine therapy A. Adjuvant endocrine therapy and radiotherapy A. Adjuvant chemotherapy and endocrine therapy O A. Adjuvant chemotherapy, endocrine therapy and radiotherapy Early breast cancer 1 Invasive lobular carcinoma pT2N3aMx Stage IIIC HR positive, Her-2 negative, grade II, MIB1 10-15% A New symptoms ' Before chemotherapy was started new onset of pain with deterioration of performance status from 0 to 1 was observed » Additional bone scan - September 2018 • No changes from the preoperative scan in June 2018 - most likely degenerative changes in both shoulders and hips » CT of the chest and abdomen - September 2018 • Diffuse osteolytic bone metastases, no signs of metastases elsewhere O What would you do now? A. Continue with the initial treatment plan (ChT, ET, RT) B. Ovarian function suppression and ET with AI C. Ovarian function suppression and ET with tamoxifen D. Ovarian function suppression and ET with AI and CD4/6 inh E. Ovarian function suppression and ET with tamoxifen and CD4/6 inh F. Chemotherapy O First line treatment • Ribociclib 600 mg once daily (OD) for 21 days, then 7 days off • Letrozole 2.5 mg OD continuously • Goserelin 3.6 mg subcutaneously monthly • Denosumab 120 mg subcutaneously monthly • Monitoring strategy • Complete blood count (CBC), liver tests, electrolytes and electrocardiogram - every 14 days for the first 2 or 3 cycles • CBC, liver tests, electrolytes monthly • Supportive treatment: • Analgesia with paracetamol/tramadol combination, later de-escalation to a non-steroidal anti-inflammatory drug • Calcium carbonate, vitamin D due to bone antiresorptive agent O Treatment - cont. • Patient responded well to therapy, no major adverse effects were noted, no treatment delays, the pain improved • Improvement in ECOG from 1 to 0 was noted • Quality of life was improved • The best response is stable disease. The duration of response is currently 20 months Conclusion • Patient started her treatment of an early breast cancer • Bone metastases were found after surgery when new symptoms were present • Treatment plan was changed from adjuvant chemotherapy, followed by endocrinal therapy and radiotherapy to treatment of primary metastatic HR+/HER2- breast cancer with a combination of hormonal therapy and a CDK 4/6 inhibitor O Metastatic breast cancer 1st Summer School in medical oncology -Standards and open questions Domen Ribnikar, MD, Medical Oncology staff Institute of Oncology Ljubljana Department of Medical Oncology Ljubljana, September 5th 2019 Tumor Register Mammakarzinom Prospective German TMK cohort study Overall survival according to subtype 100 90 80 70 60 50 40 30 20 10 0 Events Median OS n (%) months (95% CI) - HR-pos./HER2-neg. 269 (60.7%) 33.8 (30.2 - 40.2) HER2-positive 164 (59.2%) 38.2 (31.3 - 43.0) - Triple negative 90 (76.9%) 16.8 (11.5 - 22.0) 36 48 60 72 Time [months] Number at risk HR-pos./HER2-neg. 443 HER2-positive 277 Triple negative 117 344 226 63 239 163 37 147 111 23 83 74 13 65 46 31 26 3 14 11 1 Fietz, T., Tesch, H., Rauh, J., Boiler, E., Kruggel, L., Janicke, M., Marschner, N., 2017. Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer - Results from the prospective German TMK cohort study. The Breast 34, 122-130, 2017 Prognosis of de novo & recurrent MBC diverges over time dnMBC disease specific survival over time (n=247) .00 5.00 10.00 survival years post rMBC diagnosis (log rank = 5.48. p =.065) m. Mayer, ABC4 Goals of the Treatment in MBC Balancing treatment efficacy and toxicity is the main objective Goals of treatment: - Improve survival (very few agents achieve it!) - Delay disease progression - Prolong duration of response - Palliate symptoms - Improve or maintain quality of life - Transform into a chronic disease Quantity Quality of of Life Life ) TREATMENT TAILORING IN MBC Treatment choice should take into account at least these factors: HR & HER-2 status, previous therapies and their toxicities, disease-free interval, tumor burden (defined as number and site of metastases), biological age, performance status, co-morbidities (including organ dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological factors, available therapies in the patient's country and patient preference! -Jl Tailoring Therapy In Metastatic Breast Cancer TAILOR FOR THE PATIENT TAILOR FOR THE DISEASE both biologically and clinically C* > Target 1 ¥ INDIVIDUALIZED TREATMENT The management of MBC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social workers, nurses and palliative care specialists), is crucial. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women ACCESS EiEeen M Kesson project manager Gwen M AiEardice statistician1 \ vV David George school of medicine honorary professor', Harry J G Bums chief medical officer for Scotland*, David S Morrison director BMJ2m2;344:ezn8 da: 10 113&fcmj.e2?ia (Publish«! 2E April 2013} LUMINAL TUMOURS = HETEROGENEOUS GROUP • The principal characteristic of the luminal group is the luminal expression signature, composed of ESR1, GATA3, FOXA1, XBP1, and cMYB — the most frequent mutations in the luminal A subtype are PIK3CA (45%), MAP3K1 (13%), GATA3 (13%), TP53 (12%), and CDH1 (9%) - the most frequent mutations in luminal B tumors are TP53 (29%), PIK3CA (29%), GATA3 (13%), and TTN (12%) • In addition to TP53 mutations, several other events may intervene in other steps of the same pathway, including ATM loss and MDM2 amplification • ESR1 mutations (up to 19%) after AI treatment => resistance Courtesy F. Penault-Llorca Mechanisms of De Novo & Acquired Endocrine Resistance De Novo ET Resistance Acquired ET Resistance • The lost/inactivation of ER/ER pathway • Activation of PI3K/AKT/mTOR pathway • Activation of the growth factor or HER pathway activation 1. Osborne CK, et al. Ann Rev Med. 2011;62:233-247; 2. Arpino G, et al. EndocrRev. 2008;29:217-233; 3. Shou J, et al. J Natl Cancer Inst. 2004;96(12):926-935; 4. Chung YL, et al. IntJ Cancer. 2002;97:306-312; 5. Meng S, et al. Proc Natl Acad Sci USA. 2004;101:9393-9398; 6. Nicholson RI, et al. Endocr RelatCancer. 2004;11:623-641; 7. Gee JM, et al. Endocrinology. 2003;144:5105-5117; 8. Knowlden JM, et al. Endocrinology. 2005;146:4609-4618; 9. Miller W, et al. AARC Special Conference: Targeting PI3K/mTOR Signaling in Cancer; 2011. Abstract A09. HOW TO TACKLE HETEROGENEITY OF LUMINAL-LIKE MBC? Are there ready-to-use (bio)markers to individualize treatment? • None ready for clinical practice yet! • So, how do we choose? HOW TO TREAT ER+/HER-2 neg (LUMINAL) MBC: MAIN QUESTIONS: 1. Do we need Chemotherapy (CT)? 2. If Endocrine Therapy (ET) which agent? 3. Is a targeted agent also necessary or is ET alone sufficient? 4. If CT: combination vs. sequential monotherapy? 5. If CT: which agent(s)? □□SH^j ER POSITIVE / HER-2 NEGATIVE MBC Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. ALL guidelines are in agreement for this recommendation In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium D.J. A. Lobbezoo1-2, R. J. W. van Kampen1, A. C. Voogd1-3, M. W. Dercksen2, F. van den Berkmortel4, T. J. Smilde5, A. J. van de Wouw6, F. P. J. Peters7, J. M. G. H. van Riel8, N. A. J. B. Peters9, M. de Boer1, P. G. M. Peer10 & V. C. G. Tjan-Heijnen1* ET a- Fin- ET '4 May 2015; revised 28 August 2015 and 14 Octt pted 26 October 2015 Starting with ET vs. Starting with CT PFS - Priante Mth initial ctematheisfiy, median PFS 5.3 mcnttifc (MU, Cl J.2-E.2) - Paliems lilli tnitiaû andooina Iterapy, m«f an PFS 13.3 nwnlfie (BSIt a 11.3-15.5) medan OS 16 1 morlhs (S6%Ct13 7-19 7) Patients wifi ntul endocrine Therapy medan OS 36.9 mcnhs (9S% CI 30 6-t3 9) MAIN CHALLENGE: Identify small percentage of "fast progressors" Courtesy Peter Schmid, ESMO 2016, Discussant ER POSITIVE / HER-2 NEGATIVE MBC The addition of a CDK4/6 inhibitor to an aromatase inhibitor, in patients naive or pre-exposed to ET, provided a significant improvement in median PFS (~10 months), with an acceptable toxicity profile, and is therefore one of the preferred treatment options*. Patients relapsing < 12 months from the end of adjuvant AI were not included in the published studies and may not be suitable for this combination. OS results are still awaited. QoL was comparable to that with ET alone. * for pre and peri with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women ESMO-MCBS: 3 1st Line CDK 4/6 INHIBITORS: EFFICACY 2nd Line CDK 4/6 INHIBITORS: EFFICACY OEM —_____,-r—= ' memP" OVERALL SURVIVAL IN PALOMA-3 (ITT) Palbociclib+Fulvestrant (N=347) Median OS=34.9 months 95% CI (28.8-40.0) Placebo+Fulvestrant (N=174) Median OS=28.0 months 95% CI (23.6-34.6) Number of patients at risk PAL+FUL 347 321 PBO+FUL 174 155 Time (Months) Absolute improvement in median OS was 6.9 months BUT NOT STATISTICALLY SIGNIFICANT 115 Cristofanilli et al, ESMO 2018 MANAGEMENT OF LUMINAL MBC F Cardoso et al, Annals of Oncoloav 2018 CLINICAL PRACTICE GUIDELINES Treatment of ER-negative I HER2-positive ABC Note: Include In clinical trials when available ESMO ©2018 ESMO. All rights reserved. esmo.org/Guidelines/ Breast-Cancer/4th-ESO-ESMO-lnternational-Consensus-Guidelines-for-Advanced-Breast-Cancer-ABC-4 CLINICAL PRACTICE GUIDELINES Treatment of ER-positive I HER2-positive ABC Note: Include In clinical trials when available emd Previously untreated with anti-HER2 therapy Previously treated (neo)adjuvantly with anti-HER2 therapy Patients unsuitable for ChT or with long disease-free interval, minimal disease burden and/or strong ER/PgR expression X Stopping antl-HER2 therapy after several years of complete remission may be an option © 2018 ESMO. All rights reserved. esmo.org/Guidelines/ Breast-Cancer/4th-ESO-ESMO-lntematiortal-Consensus-6uideliiies-for-Advanced-Breast-Cancer-ABC-4 CLEOPATRA: Median PFS and OS CAUTION!!!! Only 21% -26% pts had previously received (neo)adjuvant trastuzumab Baselga et al., NEJM 2012., Swain et al., NEJM, 2015. HER-2 POSITIVE MBC: 2nd line and beyond After 1st line trastuzumab-based therapy, T-DM1 provides superior efficacy relative to other HER-2-based therapies in the 2nd line (vs. lapatinib + capecitabine) and beyond (vs. treatment of physician's choice). T-DM1 should be preferred in patients who have progressed through at least 1 line of trastuzumab-based therapy, because it provides an OS benefit. TNBC: CHEMOTHERAPY (general) Both combination and sequential single agent CT are reasonable options. Based on the available data, we recommend sequential monotherapy as the preferred choice for MBC. Combination CT should be reserved for patients with rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease control. ALL guidelines are in agreement for this recommendation Cochrane meta-analysis of Combination vs. Sequential monoCT for MBC Progression-free survival (all trials) Combination Sequential Hazard Ratio Study or Subgroup log[Hazard Ratio] SE Total Total Weight IV, Fixed, 95% CI Alba 2004 0.0296 0.1827 69 75 10.7% 1.03 [0.72,1.47] Baker1974 0.239 0.2295 46 30 6.8% 1.27 [0.81,1.99] Beslija 2006 -0.6033 0.2865 50 50 4.3% 0.55 [0.31, 0.96] Conte 2004 0.0862 0.139 106 92 18.5% 1.09 [0.83.1.43] Fountzilas 2001 0.2151 0.1579 90 93 14.3% 1.24 [0.91,1.69] Park 2010 0.2776 0.2429 41 40 6.0% 1.32 [0.82, 2.12] Sledge 2003 0.2469 0.0962 230 453 38.5% 1.28 [1.06,1.55] Tomova 2010 -0.1625 0.6415 46 53 0.9% 0.85 [0.24, 2.99] Total (95% CI) 67B 886 100.0% 1.16[1.03, 1.311 Heterogeneity: Chi2 = 9.41, df= 7 (P = 0.22); F= 26% Test for overall effect: Z= 2.52 (P = 0.01) Hazard Ralio IV. Fixed. 95% CI Overall survival (all trials) Combination Sequential Hazard Ratio Study or Subgroup log[Hazard Ratio] SE Total Total Weight IV, Fixed, 95% CI Alba 2004 0.2151 0.2634 69 75 4.5% 1.24 [0.74, 2.08] Bakerl 974 0.3716 0.2606 46 30 4.6% 1.45 [0.87, 2.42] Beslija 2006 -0.6387 0.3182 50 50 3.1% 0.53 [0.28, 0.99] Chlebowskl 1989 -0.1054 0.1282 129 93 19.2% 0.90 [0.70,1.16] Conte 2004 0.174 0.2355 106 92 5.7% 1.19 [0.75.1.89] Fountzilas 2001 0.1989 0.1667 90 93 11.3% 1.22 [0.88.1.69] Park 2010 -0.1744 0.235 41 40 5.7% 0.84 [0.53.1.33] Sledge 2003 0.0488 0.0901 230 453 38.8% 1.05 [0.88,1.25] Tomova 2010 0.1989 0.211 46 53 7.1% 1.22 [0.81,1.84] Total (95% CI) 807 979 100.0% 1.04 [0.93, 1.16] Heterogeneity: Chi3 = 1 0.54, df= 8 (P = 0.23); l3 = 24% Test for overall effect: Z = 0.76 (P = 0.45) 0.01 0.1 10 100 Favours combination Favours sequentia Hazard Ratio IV, Fixed, 95% CI Favours combination Favours sequentia Dear RF et al. Combination vs. sequential single agent CT for MBC (Review) 2013 Results: Progression Free Survival Optimal Duration of Chemotherapy? ■ Longer CT duration associated with : ■ significant improvement in PFS (HR 0.64; 95% CI 0.55 - 0.76) ■ significant improvement in OS (HR 0.91; 95% CI 0.84-0.99) Study Coates 1987 Harris 1990 Muss 1991 Ejlertsen 1993 Gregory 1997 Falkson 1998 Bastit 2000 Nooij 2003 Gennari 2006 Majordomo 2009 Alba 2010 Longer better Shorter better %Weight HR 13 0.56 95%CI 0.44-0.71 0.65-2.15 0.16-0.43 0.61-0.83 0.53-0.92 0.31-0.68 0.50-0.84 0.50-0.90 1.01 0.71-1.43 0.77 0.57-1.05 0.53 0.37-0.76 ^0.64^ 0.55-0.76 0.65 0.67 Results: Overall Survival Study Coates 1987 Harris 1990 Ejlertsen 1993 Gregory 1997 Falkson 1998 Bastit 2000 Nooij 2003 Gennari 2006 Majordomo 2009 Alba 2010 Shorter better %Weight HR 95%CI 0.620.570.740.63-0 0.54-' 0.690.7803 0.8312 0.730.6786 0.58- These results provide support to the clinical approach of prolonging 1st line CT in the absence of significant toxicity and disease progression (when CT is the only option...) Role of biologics, HT, metronomic CT !?! Test for heterogeneity, p=0.6S Gennariet al, J Clin Oncol 2011 Heterogeneity of TNBC: Data from the UNC337, NKI1295, MDACC133 databases O Onkološki Inštitut Institute of Oncology Ljubljana Case 5: Metastatic HR+ BC with visceral crisis Authors: Luka Dobovišek, MD; Anja Kovač, MD Mentor: Simona Borštnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA TUMOR BIOMARKERS AND STAGING • Core needle biopsy (left breast): IDC, grade II, ER 100 %, PR 70 %, Ki67 5 %, Her2 negative • Laboratory: • AST 3.06 ukat/l (>5xULN), • ALT 1.24 ukat/l (>2xULN), • AF 11.03 ukat/l (>6xULN), • GGT 30.79 ukat/l (>48xULN), • bilirubin total 75 umol/l (>5xULN), • Ca 15-3 >3000 kU/l, • LDH 3,52 ukat/l. o voting QUESTION 2: WHAT KIND OF CHT WOULD YOU GIVE? A TAXANE B VINORELBINE C ERIBULIN D ANTHRACYCLINE E CAPECITABINE o CLINICAL PRESENTATION • 51-year old female (March 2017) • 2 months history of dry cough, pleuritic and abdominal pain • Other medical conditions: none • Gynecological history: regular menses, lx partus, lx abortus • PS 2, jaundice, palpable mass left breast (5 cm), enlarged liver (reaching the umbilical line) • CT (thorax, abdomen): multiple confluating liver lesions, tumour left breast (35 mm), tumor in the left ovary O voting QUESTION 1: FIRST-LINE TREATMENT? A ENDOCRINE THERAPY B ENDOCRINE THERAPY + CDK 4/6 INHIBITOR C CHT O FIRST-LINE TREATMENT • March - June 2017 - 12 x weekly vinorelbine 25 mg/m2 • Clinically improvement in PS (now 1), pain well controlled on analgetics, liver border palpable 8 cm above umbilical line • Lab Jun 2017: • AST 1.33 ukat/l, • ALT 1.52 ukat/l, • AF 8.46 ukat/l, • yGT 33.27 ukat/l, • bilirubin total 16 umol/l, Ca 15-3 >3000 kU/l, • LDH 3.07 ukat/l. n • CT (thorax, abdomen) Jun 2017: stable disease in liver voting QUESTION 3: AFTER VISCERAL CRISIS IS OVER ... WHAT WOULD YOU GIVE NEXT? A TAMOXIFEN B TAMOXIFEN + CDK 4/6 INHIBITOR C TAMOXIFEN + LHRH ANALOG D AI + LHRH ANALOG E AI + LHRH ANALOG + CDK 4/6 INHIBITOR F METRONOMIC CHT o SECOND-LINE THERAPY July 2017 - COMPLEEMENT-1: • Ribociclib 600 mg • Letrozol 2,5 mg • Goserelin 3,6 mg • Patient returned to work, asymptomatic, no analgetics needed, tumour left breast 2 cm, liver border not palpable • Lab Aug 2018: • AST 0.75 ukat/l, • ALT 0.96 ukat/l, • AF 4.32 ukat/l, • yGT 7.16 ukat/l, • bilirubin total 5 umol/l, • Ca 15-3 344 kU/l, • LDH 2.79 ukat/l O^ CT Jul 2018: stable liver metastasis (target lesion regression from Oct 2017 22 in 13 mm to 9 and 11 mm in Apr 2018) voting QUESTION 4: WHAT WOULD YOU GIVE AFTER PROGRESSION? A TAMOXIFEN B FULVESTRANT C FULVESTRANT + CDK 4/6 INHIBITOR D FULVESTRANT + ALPELISIB E EXEMESTANE + EVEROLIMUS F CHT o CONCLUSION • CHT is the optimal choice for the treatment of visceral crisis in luminal subtype of BC • Otherwise ET (+/- CDK 4/6 inhibitor) is the preferred option in endocrine-responsive BC o Onkološki Institut Institute of Oncology Ljubljana Case 6: Primary metastatic HER2+, HR+ BC Author: Luka Dobovisek, MD Mentor: Simona Borstnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA CLINICAL PRESENTATION 49-year old female, nurse (april, 2019) • 2 months history of cough • Skin changes in the right breast (peau d'orange) • Other medical conditions: none • Gynecological history: regular menses, lx partus • Family history: grandmother on her mother side had BC O CLINICAL PRESENTATION • Because of the cough hospitalized at the internal medicine department (pneumonia? pulmonary embolism?) Abnormal chest x-ray: effusion and pathological lesions Pleural puncture: atypical cells - malignant pleural effusion? O voting QUESTION 1: WHICH PROCEDURES WOULD YOU ORDER? A CT SCAN OF THE ABDOMEN AND THORAX B BONE SCAN C CORE NEEDLE BIOPSY (CNB) D PET-CT E A + B F A + B + C O IMAGING STUDIES CT (thorax, abdomen, neck): • Pronounced thickened skin of right breast • Signs of pulmonary lymphangitic carcinomatosis of the right lung with pleural effusion • Pericardial effusion • Diffuse osteoblastic infiltration of the skeleton O TUMOR BIOMARKERS AND STAGING • PATHOLOGY: • Core needle biopsy (17.4.2019): • IDC, Grade 2, ER 100%, PR 15%, Ki67 25%, HER2+ (IHK 3+) • LABORATORY: • Ca 15-3: 527 • AF: 2.40 • AST: 0.79 • GGT: 0.65 o voting QUESTION 1: FIRST-LINE THERAPY? A CHT + ANTI-HER2 THERAPY B ET + ANTI-HER2 THERAPY C CHT D ET o voting QUESTION 2: WHICH CHT WOULD YOU CHOOSE? A TAXANE B DOXORUBICIN + CYCLOPHOSPHAMIDE (AC) C GEMCITABINE + CISPLATIN D CMF o voting QUESTION 3: WHAT KIND OF ANTI-HER2 THERAPY? A TRASTUZUMAB B TRASTUZUMAB + PERTUZUMAB C NERATINIB D TRASTUZUMAB EMTANSINE (T-DM1) o FIRST-LINE TREATMENT • Docetaxel + Trastuzumab + Pertuzumab • No major AE • Taxane induced paronychia, nail changes, fatigue • Normalization of the tumor marker o voting QUESTION 4: HOW LONG DO YOU CONTINUE CHT? A 2 MONTHS B 4 MONTHS C 6 MONTHS D UNTIL BEST RESPONSE E UNTIL MAJOR ADVERSE EVENTS o voting QUESTION 5: WHAT KIND OF TREATMENT WOULD YOU GIVE AFTER COMPLETION OF CHT? A TRASTUZUMAB + PERTUZUMAB B TRASTUZUMAB + PERTUZUMAB + ET C TRASTUZUMAB + ET D ET 0 voting TION 6: WHAT KIND OF ENDOCRINE THERAPY WOULD YOU GIVE? A AROMATASE INHIBITOR B TAMOXIFEN C AROMATASE INHIBITOR + LHRH ANALOG D TAMOXIFEN + LHRH ANALOG o voting QUESTION 7: WHAT IS EXPECTED MEDIAN OVERALL SURVIVAL FOR THIS PATIENT? A 12 MONTHS B 24 MONTHS C 59 MONTHS o voting QUESTION 8: WHAT THERAPY WOULD YOU GIVE AFTER PROGRESSION? A CHT B TRASTUZUMAB EMTANSINE (T-DM1) C CHANGE THE ENDOCRINE THERAPY AND CONTINUE TRASTUZUMAB + PERTUZUMAB D NERATINIB o CONCLUSION • There are many therapeutical options in „triple positive" (ER+, PR+, HER2+) metastatic BC •Anti-HER2 therapy is the backbone of HER2+ BC treatment • Majority of patients with HER2+ disease have long OS Oonkoloski institut Institute of Oncology Ljubljana Case 7: Metastatic TNBC Author: Luka Dobovisek, MD Mentor: Simona Borstnar, MD, PhD 1st Summer School in Medical Oncology 3. - 6. September 2019 LJUBLJANA CLINICAL PRESENTATION 38-year old female (January, 2017) • Lump in left breast • Other medical conditions: none • Gynecological history: regular menses, 2x partus, uses contraceptive pills • Family history: aunt had a BC at similar age O IMAGING • Mammography: 21 mm tumor formation in upper outer quadrant of the left breast • US guided core needle biopsy with clip marking • US of left axilla: one pathological lymph node • FNA: adenocarcinoma • CT (thorax, abdomen): tumor formation in left breast, 3 pathological ipsilateral internal mammary nodes O TUMOR BIOMARKERS AND STAGING • Core needle biopsy: • IDC • Grade 3 • ER 0% • PR 0% • HER-2 neg. • Ki67 50% • Germline BRCA 1/2 negative O NACT AND OPERATION • 4x dd AC + 4x dd paclitaxel with growth factor support • CT (thorax): partial response in the left breast, complete response in internal mammary nodes (may, 2017) • Breast conserving surgery with SLNB and ALND (june, 2017) • Pathological examination after NACT: • Partial response in the breast: 9 mm residual tumor • 1/27 positive nodes: 5 mm, focal extracapsular extension, lymphovascular invasion o ADJUVANT CHT AND RT RT (august - september, 2017) • 50 Gy in 28 fractions Capecitabine 8 cycles (september, 2017 - february, 2018) Lower back and hip pain (april, 2018) CT (thorax, abdomen): • pathological lymph nodes in mediastinum, new lytic bone lesions (spine, ribs, right sacrum) O voting QUESTION 1: FIRST-LINE THERAPY FOR mTNBC BC? A GEMCITABINE - CISPLATIN B VINORELBINE C ERIBULIN D CAPECITABINE E TAXANE + IMMUNOTHERAPY (ATEZOLIZUMAB) F PALLIATIVE RADIATION THERAPY O METASTATIC DISEASE • Palliative radiation to the sacroiliacal joint (12 Gy) and 10th rib (9 Gy) Gemcitabine-cisplatin /3 week (june - September, 2018) • AE: fatigue, neutropenia (+ pegfilgrastim) • CT (thorax, abdomen): regression of nodal and skeletal metastases (september, 2018) • After 4 cycles refuses further therapy o voting QUESTION 2: WHAT WOULD YOU DO NOW? A ERIBULIN B VINORELBINE C CAPECITABINE D METRONOMIC CM E WAIT UNTIL PROGRESSION O METASTATIC DISEASE • NGS (Foundation One): • somatic mutation of BRCAl • FGFR2 amplification, TP53 mutation • MS-Stable • TMB-low (4 muts/Mb) • Olaparib (PARPi) 2x 300 mg (november, 2018) • AE: nausea, diarrhea, loss of appetite, fatigue, depression • She refuses further therapy after 2 weeks O DISEASE PROGRESSION • Pain in thoracic spine (january, 2019) • CT (thorax, abdomen): progression of skeletal metastasis and pathological fracture of TH9 and L2. • Confusion and headache (february, 2019) • CT (head): diffuse metastatic infiltration of the brain, intrametastatic hemorrhage, herniation in foramen ovale O voting QUESTION 3: TREATMENT FOR CNS METASTASIS? A RADIOTHERAPY B SYSTEMIC THERAPY C RADIOTHERAPY FOLLOWED BY SYSTEMIC THERAPY o PROGRESSION IN THE CNS • RADIOTHERAPY: • Palliative radiation to the head (30 Gy) • Palliative radiation to the spine Thç-L2 (20 Gy) • Hospitalized for symptomatic treatment and dies at the department (march, 2019) o CONCLUSION • mTNBC is the subtype with the worst prognosis with mOS approximately 1 year • TNBC remains a challenge in everyday clinical practice, new therapies are in active development • New therapies are needed for CNS metastasis in all BC types 1st Summer School in Medical Oncology -Standards and Open Questions Systemic treatment in advanced soft tissue sarcoma (STS): what is standard, what is new Mojca Unk, MD, MSc Institute of Oncology Ljubljana Department of Medical Oncology 3. - 6. September 2019 Audience.... 1st question • How confident are you in systemic treatment of advanced STS? • 1. very confident • 2. somehow confident • 3. not confident at all WHO Classification of Tumours of Soft Tissue and Bone Si Background • Heterogeneous group of rare neoplasms with mesenchymal origin • More than 70 different entities • Strong tendency toward local recurrence (10 -30 %) and metastatic^^^™ spreading (30 -40 %) • Lung: most common site of STS metastases • Pulmonary metastasectomy - the standard treatment for selected patients with limited lung disease • Chemotherapy - the most relevant role in the management of metastatic disease • Outcome for Ml disease - very poor (mOS 14-17 months) Fletcher et al.IARC 2013;Judson et al.Lancet Oncol. 2014; Ryanet al. JCO2016;Tapet al. Lancet. 2016. Prognostic factors • Age (> 60 y) • Lung; most common site • Size (> 5 cm) • liver; visceral STS • Grade (high) • Complex treatment (multidisciplinary • Mitotic count (high) decision); mostly systemic • Location (limb ortorzo) • Deep • Poor prognosis: mOS 0 14 m • Lymph nodes positive Pulmonary resection surgery of isolated lung metastases 5-y OS 32 % J Thorac Cardiovasc Sure. 1984 Feb;87C2):260-8. Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. • the tumour doubling time (20 days; mOS 22 vs 6 m) • the number of metastases on preoperative CT (4 mets; mOS 23 vs 6 m) • the disease-free interval (12 m; mOS 32 vs 10 m) STS - 1st line systemic treatment imtBtOnmi ZDT4; 15; Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial lanjudson^jaop Venveij, Hans Gelderblom, Jitrg T Hartrrann, Patrick Schoffski, Jean-Yves Way, J Martijn Kent, Josef 5u[ijar sky, Jeremy Whelan, Peter Hohenberger, Anders Kraaip-Hansen, Thierry Akindof. Sandrirte Marreaud. Saskk UtHre, Catherine Hermans, Cyril Fisher. Pur was C WHogendoorn A Paolo dei Tos, Wmette TA van deiGraaf, for the Furopean Organisation end Treatment of Cancer So ft Tissue and mOS 14.3 vs. 12.8 m Number at rkl Doxorubicin Clowinihidn and itoslaiiiicie ORR 26% vs. 14%,P< 0.0006 Number at risk Doxorubicin Doxorubicin and ifosfamide Mono/polychemotherapy author chemotherapy Pt (number) response rate survival Muss (1985) A/AC 104 NS NS Omura (1983) A/AD 146 NS NS Borden (1987) A/AD 186 AD 30% (p=.02) NS Lerner (1987) A/AD 66 AD 40% (LMS) NS Santoro (1995) A/AI/CYVADIC 449 NS NS Borden (1990) A/AV 195 NS NS Edmonson (1993) A/AI/APM 262 AI 34% (p=.03) NS Antman (1993) AD/MAID 340 MAID 32 % (p=.02) NS Judson (2014) A/AI 415 AI 26% (A 14%) NS Ryan (2013) A/APal 447 APal 28% (A 19%) NS NO SURVIVAL BENEFIT; doxorubicin 75mg/m2 is golden standard for more than 40 years! A- doxorubicin, C- cyclofosfamid, D-dacarabazin, I- ifosfamid. CYVADIC- cyclofosfamid, vincristin. doxorubicin, dacarabazin, MAID- mesna, doxorubicin. ifosfamid, dacarabazin. V-vincristin. APM-doxorubicin. cisplatin. mitomycin. Pal-palifosfamid .... no convincing evidence of superiority as upfront treatment • d™^ • Amrubicin (3rd gen) • nonrandomised single arm phase II: similar results as dox' » • cardiac sparing alternative Tims [months] • AI doxorubicin (prodrug of doxorubicin) with a pH-sensitive linker; activity in acidic tumour environment: enhancing activity and minimising toxicity phase 2b: aldoxo vs doxo ^ PFS (5.6 vs. 2.7 months;P= 0.02) ^ORR (25% vs. 0%) on-going phase Ib: safety and activity of aldoxo + ifo • Palifosfamide (active metabolite of ifosfamide) • Neg PICASSO III (palif+doxo vs doxo) Gupta et al. Invest New Drugs 2016; Chawla a al. JAMA 0ncol.2015; Verschraegen et al. JCO 2010 .... no convincing evidence of superiority as upfront treatment (the upfront administration of compounds known to be active in further lines ) GeDDiS: gem+doce vs doxo • no differential treatment effect by histological subtype (p=0-24) • superiority of single agent doxo: ORR (65.9% vs. 58.6%) • PFS(23 vs. 24 weeks) Trabectidin: 2 phase 2 trails • Trabectidin (3 or 24h inf.) vs doxo; neg • Trabectidin + doxo vs doxo; stopped for futility .... no convincing evidence of superiority as upfront treatment (monoclonal antibodies) ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). Tap et al. ASCO 2019. ANNOUNCE did not confirm that olaratumab + doxorubicin, followed by olaratumab monotherapy, improves OS over doxorubicin in pts with advanced STS. Further analyses are warranted to explore the inconsistent outcomes between the Ph 3 and Ph 2 studies. Lancet. 2016 July 30; 388(10043): 488-497. doi:10.1016/S0140-6736(16)30587-6. Olaratumab and doxorubicin versus doxorubicin alone in soft tissue sarcoma William D. Tap, MD1, Robin L. Jones, MD2-3, Brian A. Van Tine, MD3, Bartosz Chmielowski, MD4, Anthony D. Elias, MD5, Douglas Adkins, MD3, Mark Agulnik, MD6. Matthew M. Cooney, MD7, Michael B. Livingston, MD8, Gregory Pennock, MDS, Meera R. Hameed, MD10, Gaurav D. Shah, MD11. Amy Qin, PhD12, Ashwin Shahir, MD13. Damien M. Cronier, PhD13, Robert Maria Jr, MD14, Maria Conti, MD14, Jan Cosaert, MD12*, and Gary K. Schwartz, MD15 Obmunub 66 6} 60 57 52 51 50 47 43 41 pkndoxowbion Dowxubion 67 61 51 46 43 37 34 32 28 23 14 16 18 20 h 24 26 28 » 32 34 36 38 4< Tim« (months) 1 39 33 32 29 26 16 16 15 8 3 3 : Targeted therapy • Dermatofibrosarcoma protuberans (DFSP) and imatinib translocation COL1A1/PDGFB fusion gene ^ PDGFRB activation metastatic potencial- fibrosarcomatous (FS) component imatinib mesylate: ORR 60-70% FS-DFSP: translocation +, imatinib sensitivity + with RR ~ 80%, but shorter duration • Alveolar soft part sarcoma (ASPS) • Chemo resistant, MET overexpression • Antiangigenetic drugs: sunitinib, pazopanib, cediranib • MET inhibitors: crizotinib • Immunotherapy (phase 2: atezo and tremi/durva) • Solitary fibrous tumour (SFT) • NAB2-STAT6 fusion • Chemotherapy but also antiangiogenetic drugs: sunitinib, sorafenib, pazopanib, axitinib Doxorubicin remains the standard of care, with or without ifosfamide! STS - further line systemic treatment Further lines • Histology driven treatment: • Chemotherapy • TKI targeting angiogenesis • Other TKI • Immunotherapy • Best supportive care o Chemotherapy Gemcitabine (alone or in combintion) LMS : gem+doce; conflicting results Gem+vinorelbin clinical benefit rate 25% Dileo et al, cancer 2008 • Gem+dacarbazine mPFS4.2 vs. 2 m, p = 0.005 mOS 16.8 vs. 8.2 m, p = 0.014 clinical benefit rate (49% vs. 25%,p=o.oo9 Garcia del Muro et al, JC02011 m 2 s t'-J uwOIVM rw siiwji OTIC. Pautier et al. Oncologist 2012; Maki et al, JCO 2007 B Viirrabte Sulwi«Mip Ducarbams Irabcctcdm Diicarbazme fruited«!.!. Ail AH 15 4.2 HH 055 0.44 m 0.70 112/173 217/345 Lires ni prior chemotherapy 1 2-7 4.9 i-*— 049 0.23 m 104 11/23 W33 >t S 4i 056 0.43 to 031 101/1» 1BW7 ECOG PS 0 S 4J 0.51 0.36 to 0.71 52/86 104/171 fi 2.9 0.60 0.43 to 932 enw 113/174 Histafagic aibfype Leiarnyo sarcoma E 43 MH 055 0.42 ID 0.73 85/126 15V252 Nanutenna Ë 45 058 037to032 28M8 70/118 5 4.0 0.58 0.41 to 0B1 57/78 WI34 liposarwiroa S 3.0 0.55 0.34 to 0.87 27/47 63® Dcdflsreîiliatfid 3 2^ - 0.68 037 toli5 W£> 3^45 Myxoid ± round cell 5 S* 041 0.1? to 038 21/» Plsanurphic J S 0 D/lu 1.64 i/10 rears <65 a 4.1 060 0.46 In On «7/133 173/264 S 040 0.24 to 067 «/81 Se* Female fi 4? 056 0,43 to 074 81/1* 141/739 Male fi 4,1 0.53 0.34 m 083 31/47 7IV1Û7 Race IMrfe fi 4 2 052 033 In 06« SWl?5 i rsim Niliwrflitf: £ as 0.65 0.40 to 1.03 30/43 44/76 BMF, kg/m* <30 fi 4.0 056 0.41 ID 0.75 72/112 12^203 >30 2 4.4 054 037 ID 030 4IV61 8Ï142 myxoid liposarcoma: t(12;16)(q13;p11) additional 'targeted' mechanism of action Inactivation FUS-CHOP oncogene Dacarbazinc — Trabsetedin Censored in dacarba?ine qmup + Censored ih irabectedin ijroup HR, 0.55;95% CI, 0.44 to 0.70 P=0.001 ^ii. rr Rutin rabmln ii v rfj Larbaansf jno 9EK CI (log M Nu. r.ik 173 Trab^tpHin 315 6 9 12 16 Time (monthsl ¿jjjjyiij} versus dacarbazine in previously treated patients with advanced linnsarroma nr Ipinmvnsarmma: a randomised, open-label, multicentre, phase 3 trial PatrickSc/tofjsii, SontChawlo, RobertGMofci, Antoine ftafiono, Hans Gdderblom. EdwinChoy, GiovanniGrignarti, VeiidianoCamanjo, Sebastian Bauer, Sun Young Rha, Jean-Yves Blay, Peter Hohenberger, Davjd D'Adamo, Mctthew Guo, BarfoszChniiefowsfcr, Axe) Le Cesne, George D Demetri, Shreyaskumar R Patei LPS: mOS 15^6 vs 8-4 m LMS: mOS 12-7 vs 13-0 m weekly paclitaxel seems to be an effective and well-tolerated treatment for patients with unresectable angiosarcoma Histology driven approach Histology Cytotoxic compounds with selective activity Leiomyosarcoma Gemcitabine ±docetaxef, trabectedin, dacarbazine Dedifferentiated iiposarcoma High-dose ifosfamide trabectedin, eribulin Myxoid Iiposarcoma Trabectedin, eribulin Synovia! sarcoma Ifosfamide, trabectedin Epithelioid sarcoma Gemcitabine Angiosarcoma/intimal sarcoma Gemcitabine, paclitaxel Alveolar soft part sarcoma Solitary fibrous tumour Dacarbazine Clear cell sarcoma Extraskeletal myxoid chondrosarcoma Perivascular epithelioid cell tumor Gemcitabine Epithelioid hemangioendothelioma Inflammatory myofibroblastic tumour Undifferentiated pleomorphic sarcoma High-dose ifosfamide, gemcitabine Dermatofibrosarcoma protuberans Frezza et al. BMC Medicine 2017 TKI targeting angiogenesis ¿gjgjjgfljJp for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial WinetteT A van derGraaf, Jean-Yves Bloy, SantPChow/a, Dang-Wan Kim, Bmfi Bui-Nguyen, PaaloGCasali, Patrick Schoffski, Massimo Aijlietta, Arthur P Staddon, Yasuo Beppu, Axel LeCesne, Hans Gelderblom, Ian RJudson, Nobvhrto Araki, Monro Ouali, Sandrine Marreaud, Rachel Hodge, Mohammwf R Dewji, CorreelCoens, George D Demetri, Christopher D Fletcher, Angela Paolo Dei Tos, Peter H a hen berger, on b 70- V V \ Numbef atrisk Paiopanib 2 B ■ 3 6 J 15 6 6 10? 63 9 12 IS IS 31 24 30 12 4 1 1 Median overall survival Metastatic disease Immunotherapy (Checkpoints inhibitors) Targeted therapies Drugs used in metastatic setting have been experimented in the adjuvant setting ADJUVANT TREATMENTS IN MELANOMA Agenda . Risk category . 90s-2016: Interferon . 2016: Ipilimumab ♦ 2017: New treatments . Immunotherapy: AntiPDI . Nivolumab . Pembrolizumab . Targeted therapies: ♦ Vemurafenib . Dabrafenib + trametinib MSS according to Stage III Groups 8th Edition international melanoma database • Stage group stratification based on both T- and N-category criteria • Tumor thickness • Ulceration • # LNs • Microsatellite/ITM/satellites • Recursive partitioning -> final = 4 stage groups • Significant heterogeneity Gershenwald. Scoiyer. Hess. Sondaketai. CA Cancer J Clin. 2017 Oct 13. doi: 10.3322/caac.21409. (Epub ahead of print] AJCC 2018: Stage III Survival Willekind 2017, TNM handbook 2017 Survival differentiation in stage IMA 7"' edition 8th edition Schedule Dose Frequency Duration Low dose 3miu 3 x weekly 18-24 months Intermediate dose Induction 10 miu 5 x weekly 4 weeks Maintenance 10 miu 3 x weekly 12-24 months 5 miu 3 x weekly 24 months High dose Induction 20 MIU/m2 5 x weekly 4 weeks Maintenance 10 MIU/m2 3 x weekly 11 months Short course Induction x 1 20 MIU/m2 5 x weekly 4 weeks Intermittent Induction x 3 20 MIU/m2 5 x weekly 4 weeks Q4 months Overall risk Dose High (N=1196) Peg-IFN (N=1256) Intermediate (N=2243) Low (N=2732) Very low (N=484) Event Free Survival 0.83 (0.72-0.96) 0.83 (0.76-1.00) 0.84 (0.74-0.95) 0.85 (0.77-0.94) 0.99 (0.80-1.23) Overall Survival 0.93 (0.80-1.08) 0.96 (0.82-1.11) 0.91 (0.79-1.04) 0.86 (0.77-0.96) 0.96 (0.76-1.21) INTERFERON A-METAANALYSIS 2017 Survival curve for event-free survival > * < t i ; i t » > t « I I 7 i t Reprinted from Eur Cancer, 82, Ives NJ. et al. Adjuvant interferon-a for the treatment of high-risk melanoma: An individual patient data meta-analysis: 171-183. Copyright 2Q17. wth ggrm'ss=Qn frQn s;sev1er_ INTERFERON A -METAANALYSIS 2017 Survival curve for Overall Survival A « » » 4 l i 1 • • 1« It* ♦ * i i: 14 % tO 1-7 65 years 54/120 63/114 0 70(0 49.1 01) Sei Male 106/258 141/269 0 69 (0 53. 0 88) Female 65/195 80/184 0 68(0 49,0 94) Stage (CRF) Stage 1Mb 48/165 60/148 0 68(0,47.1 00) Stage lllc 87/203 114/218 0 68(0 52, 0 91) Stage IVM1a-M1b 27/62 37/66 0 66(0 40,1 08) Stage IV M1c 8/20 10/21 0 78 (0 31.1 99) Not reported 1/1 0/0 Stage III: Ulceration Absent 64/201 100/216 0 61 (0 44. 0 83) Present 68/154 68/135 0 77 (0.55.1 08) Not reported ans 6/15 0 42(0 11.1 70) Stage III: Lymph Microscopic 46/126 59/134 0 75(0 51.1 10) node involvement Macroscopic 82/219 107/214 0 66 (0.49. 0 88) Not reported 7/25 8/18 0 53 (0 19.1 48) PD-L1 status <5%/indeterminat e 132/300 157/299 0 73 (0 58, 0 91) >5% 39/152 64/154 0 54 (0 36, 0 81) BRAF mutation status Mutant 73/187 95/194 0.73(0 54. 0 99) Wild-type 73/197 107/212 0 61 (0 45. 0 82) Not reported 25/69 19/47 0 85 (0 47.1 55) NIVO (n = 452) IPI (n = 453) AE, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Any AE 438 (97) 115(25) 446 (98) 250 (55) Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46) Any AE leading to discontinuation 44 (10) 21 (5) 193(43) 140 (31) Treatment-related AE leading to discontinuation 35(8) 16(4) 189(42) 136 (30) There were no treatment-related deaths in the NIVO group . There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and colitis), both >100 days after the last dose Acceptable toxicity profile Safety Summary NIVO (n = 452) IPI (n = 453) n (%) Any grade Grade 3-4 Any grade Grade 34 Any AE 438 (97) 115(25) 446 (98) 250(55) Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46) Any AE leading to discontinuation 44 (10) 21(5) 193 (43) 140 (31) Treatment-related AE leading 35 (8) 16 (4) 189 (42) 136 (30) to discontinuation There were no treatment-related deaths in the NIVO group There were 2 (0.4%) treatment-related deaths in the IPI group (marrow aplasia and colitis), both >100 days after the last dose KEYNOTE54 (B0RTC1325) Study Schema Randomized, phase 3 study of adjuvant PB/IBRO after complete resection of hicjvrisk stage III melanoma a 18 year old with melanoma Cbmplete surgical resection of stage III disease No ocular/mucosal melanoma No prior medical therapy for melanoma treatment No previous CTUV4 treatment Rart1:Rxt-suigcal Fàrt 2: Fbsf-recurrence Trial dates: 7/2015 -7/2023 (estimated) • Rimary endpoint: FFB(6 months), RFSpercentagewith PD-L1 positive tumor expression. • Secondary endpoints: DMFSand OS(overall vs PD-L1 tumor expression), AE NCTO2362594. Eggermont AMM, et al. NBigJMed 2018;378:1789-1801. KEYNOTE-54 (B0RTC1325): RFS ITT Population Overall Intentkxvto-Treat Ropulation No. at Rsk Ftembrdiajmab 514 Placebo 505 9 12 15 Mcnths 438 415 413 392 313 363 323 264 182 157 73 60 Total No. No. wtth Event Hazard Ratio (98,4% Cl) Pembro 514 135 0.57 (0.43-0.74) Placebo 505 216 1.00 P<0.001 by stratified log-rank test Ftembrolizunab Placebo 15 15 Eggermont AMM, et al. NBigJMed. 2018;378:1789-1801. -Ijjeimont KNOW 5MR ¿018 Recurrence-Free Survival: subgroup analysis by AJCC-8 (tont) AJCC-8 Stage IMC IM Ii " ü /0 II 3 « u «i « 50 Pcntniamt Puerto Treatment arm ToUl Even! HR im CD PlMM* 267 75 0 (0 33-0 70) tat» 239 121 Mmn mut Pviiut <0001 AJCC-8 Stage HID HR 0.69 Cl Ireitraitim Totll Event HIISKCI) Vi — Pmtrotorot 20 11 06SI02WOOI 4 — Puerto II 13 R(!«kk( 1 Logrjnk P-v«luc 0 3760 Ltr^1% 43.7% •n « y/o ' LI 0% Patients at risk 20 11 11 10 s 0 Ii 10 1 7 h-1-i-1- < -1- 0 -1-r C 3 6 9 il Patient Disposition and Treatment l. Eggermont AACR 2018 Pembroliiumab (N=514) Placebo (N=505) Started allocated treatment N=509 N=502 Reasons for discontinuation, % 96.3% 98.8% Normal completion 55.4 58.6 Disease recurrence 21.4 35.7 Adverse event 13.8 2.2 Patient/investigator decision 3.5 1.2 Other malignancy 0.8 1.0 Non-compliance/Other reason 1.3 0.2 Still on treatment, % 3.7 1.2 Median (IQR) doses received per patient 18 (9-18) 18 (8-18) ab (N-509) Placebo) Y-502) Any Grade Grade s3 Any Grade Grade 23 number cf patients (percent) Immune-related adverse events, regardless ofinvestigator attribution Any 190 (37.3) 36(7.1) 45(9.0) 3(0.6) Endocrine disorders 119 (23.4) 9(1.8) 2S(5.0) 0 Hypothyroidism 73 (14.3) 0 14 (2.8) 0 Hyperthyroidism 52 (10.2) 1 (0-2) 6 (1.2) 0 Thyroiditis 16 (3.1) 0 1(0.2) 0 Event Pembrolizumab (N- 509) Pliccbo (N- 502) Hypophysitis. including hypopituitarism 11 (2.2) 3 (0.6) 1 (0.2) 0 Any Grade Grade z3 Any Grade Grade z3 Type 1 diabetes mdlitus S (1.0) S (1.0) 0 0 number cf patients (percent) Adrenal insufficiency 5 (1.0) 1 (0.2) 4 (0.8) 0 Any adverse event 475 (93.3) 161 (31.6) 453 (90.2) 93 (18.5) Respiratory, thoracic and mediastinal disorders 24 (4.7) 4 (0.8) 3 (0.6) 0 Treatment-related adverse eventsf Pneumonitis or interstitial lung disease 17 (3.3) 4 (0.8) 3 (0.6) 0 Any 396 (77.8) 7S (14.7) 332 (66.1) 17 (3.4) Sarcoidosis 7 (1.4) 0 0 0 Fatigue or asthenia 189 (37.1) 4 (0.8) 167 (33.3) 2(0.4) Vitiligo Of severe skin reactions 27 (5.3) 3 (0.6) 8 (1.6) 0 Sbn reactions 144 (28.3) 1 (0.2) 92 (18.3) 0 Vitiligo 24 (4.7) 0 8 (1.6) 0 Rash 82 (16.1) 1 (0.2) 54 (108) 0 Severe skin reactions 3 (0.6) 3 (0.6) 0 0 Pruritus 90 (17.7) 0 SI (10.2) 0 Gastrointestinal conditions 20 (3.9) 10(2.0) 4(0.8) 2 (0.4) Diarrhea 97 (19.1) 4 (0.8) 84 (16.7) 3 (0.6) Colitis 19 (3.7) 10 (2.0) 3 (0.6) 1 (02) Arthralgia 61 (12.0) 3 (0.6) 55 (11.0) 0 Pancreatitis 2 (0.4) 1 (0.2) 1 (0.2) 1 (0.2) Nausea 58 (114) 0 43 (8.6) 0 Hepatobiliary disorders 9 (1.8) 7(1.4) 1(0.2) 1 (0.2) Dyspnea 30 (5.9) 1 (0.2) 15 (3.0) 0 Hepatitis 9 (1.8) 7(1.4) 1(0.2) 1 (0.2) Other immune-related averse events IS (2.9) 5 (10) S (1.0) 0 Nephritis 2 (0.4) Uveitis 2 (04) 2(0.4) 1(0.2) 0 0 0 0 Myositis 1 (0.2) Myocarditis 1 (0 2) 1 (0.2) 1 (0.2) 110-2) 0 0 0 Adjuvant Nivolumab and Pembrolizumab Effective in both BRAF mutated and wild-type melanoma pts in stage lll/(IV)! Well-tolerated in general (10-14% treatment discontinuations), but some rare, irreversible AEs BRAF AND MEK INHIBITORS Mechanism of action of BRAF and MEK inhibitors BRAF MONOTHERAPY IN THE ADJUVANT SETTING ESS1EM ongress BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients with completely resected BRAFV600+ melanoma at high risk for recurrence Karl Lewis,' Michele Maio,2 Lev Demidov.3 Mario Mandala,4 Paolo A. Ascierto,5 Christopher Herbert,6 Andrzej Mackiewicz,7 Piotr Rutkowski,8 Alexander Guminski,9 Grant Goodman,10 Brian Simmons.10 Chenglin Ye,10 Yibing Yan,10Dirk Schadendorf" 'University of Colorado Comprehensive Cancer Center. Aurora. CO. USA,2Division of Medical Oncology and Immunotherapy. Center for Immuno-Oncology. University Hospital of Siena. Siena. Italy; 3N N Blokhin Russian Cancer Research Center. Ministry of Health. Moscow. Russia: department of Oncology and Haematology. Papa Giovanni XXIII Cancer Center Hospital, Bergamo. Italy; 'Melanoma Unit. Cancer immunotherapy and Innovative Therapies. Istituto Nazionale Tumori Fondazione Pascale. Naples. Italy. «Bristol Haematology and Oncology Centre. Bnstol. UK; 'Department of Cancer Immunology. Poznan University for Medical Sciences. Med-POLONIA. Poznan. Poland; «Department of Soft Tissue/Bone Sarcoma and Melanoma. Mana Sklodowska-Cune Institute - Oncology Center. Warsaw. Poland; 'Melanoma Translational Research Group, Melanoma Institute Australia. Wollstonecraft, NSW. Australia; 10Ger»entech, Inc., South San Francisco, CA. USA; "Department of Dermatology. University Hospital Essen. Essen. Germany. German Cancer Consortium. Heidelberg. Germany COMBI-AD: STUDY DESIGN—AND EXTENDED FOLLOW-UP ANALYSIS IN 2018 Key eligibility criteria •Completely resected stage 111A (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma •BRAF V600E/K mutation •ECOG performance status 0 or 1 •No prior radiotherapy or systemic therapy •Tissue collection was mandatory at baseline and optional upon recurrence Dabrafenib 150 mg BID + ■ trametinib 2 mg QD ■ (n = 438) 2 matched placebos (n = 432) N = 870 • Primary endpoint: RFS • Secondary endpoints: OS, DMFS, FFR, safety BID, twice daily; DMFS, distant metastasis-free survival; D+T, dabrafenib + trametinib; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; FU, follow-up; QD, once daily. Long GV, et al. N EngiJ Med. 2017;377:1813-1823. PRESENTED BY GV LONG AT ESMO 2018 Relapse-Free survival 1-year, 88% (95% CI, 85%-91%) HR 0.49 (95% CI, 0.40-0.59) 2-year, 67% (95% CI. 62% 72%) 3-year, 59% (95% ci, 55*M%) 4-year, 54% (95% CI, 49%-59%) 1-year, 56% (95% CI, 51%-61%) 2-year, 44% (95% CI, 40%-49%) 3"ïear' 40 A UMr m (95% CI, 35%-45%) 4-year, JB/o (95% CI, 31%-11%) 12 16 20 21 28 32 36 40 44 48 52 56 60 64 Months Sines Randomization Dabrafemb * trametimb 1JU 11ft 381 3M 321 281 «I M W II» 1« » 11 13 Placebo 1» 3?? ?63 ?19 198 178 168 164 1.17 147 1?8 1(17 M ?7 4 Distant metastasis-free survival 1-year, 91% (95% CI, 88%-94%) HR 0.53 (95% CI, 0.42-0.67) 2-year, 77% (95% CI, 73%-82%) 3-year, 71% (95% CI, 67*76%) 4-year, 67% (95% CI, 62* 72%) 1-year, 70% (95%-C),«6%-?5%) 2-year, 60% (95% CI, 55*66%) 3-year, 57% (95% CI, 52*62%) 4-year, 56% (95% CI, 51*62%) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Months Since Randomization fe.*lklt )ibriftnlb » tnrwtlnlb 438 407 881 35? 3?7 ?85 XT> X,7 238 »9 185 150 9? 47 13 ? 0 >ld«bo 43? 330 765 »1 Jfll 179 169 165 159 149 130 108 64 ?8 4 I 0 IEM ongressl Overall survival (first interim analysis) Events, Median HR Group n (%) (95% CI), (95%CI)| mo Dabrafenib plus k trametinib 60(14) abrafanib plus trametinib 1 Prcspccificd sicnificoncc boundary (P 000010). 0.57 (0.42-0.79); J Placebo 93(22) (N™R) .0006' _________ IttIt- 1-7I- 1,11:1 I I -1 I I 'I' I^Iv I^IpItI :1 NR (NR-NR) NR From Randomizatio 0 E OH SJLJLJLI 1 @ I Months Since Randomization I 0 EH] Q 53 0 13 fcwtwl 2 ta* »17 I itcvtirtllJrfyjm I Acwytrt tl M> »11 001 IOIW/mwW* RESEARCH ARTICLE Wiley Statistics in Medicine Incorporation of frailties into a cure rate regression model and its diagnostics and application to melanoma data Jeremias Leao' ) I Victor Leiva; 5 I Helton Saulo1-' I Vera Tomazella5 . . i « + ¿(«-/<1 , Su(u: ,/.í) = i |. » > 0. - \2v/h(1 + ¿)/< hu(u:/i.¿) = «Pl v \2Mt¿>¡,/ u >0. evp yisi= ■ 2v/¿ + 4S+T | From (8) and evaluating (15) at s = Hod). we gel ihe unconditional SF under the BS frailty as «p(¿(I - yjü + 4/íoil) + l/\/¿77))(\Ji + <"ot11 + I + V^TT) Sj{l\6) = - 2 + 4//0íl»+ 1 Safety summary AE Category, n (%) Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) Any AE 422 (97) 380 (88) AEs related to study treatment 398 (91) 272 (63) Any grade 3/4 AE 180(41) 61 (14) Any SAE 155 (36) 44(10) SAEs related to study treatment 117 (27) 17(4) Fatal AEs related to study drug 0 0 AEs leading to dose interruption 289 (66) 65(15) AEs leading to dose reduction 167 (38) 11(3) AEs leading to treatment discontinuation3 114 (26) 12 (3) Any Occurence (exposure-adjusted) of AEs (>15% of patients) Over Time in Patients Who Received Dabrafenib Plus Trametinib Table 2. AEs Leading to Discontinuation (> 1% of patients) Dabrafenib + Trametinib Placebo N = 435 N = 432 Patients with any AE leading to discontinuation3 114(26) 12(3) Pyrexia 38 (9) 0 Chills 16(4) 0 Fatigue 8(2) 0 ALT increase 7(2) 0 Headache 6(1) 0 Arthralgia 5(1) 0 AST increase 5(1) 0 Nausea 5(1) 1(<1) Neutropenia 5(1) 0 Adjuvant Dabrafenib and Trametinib: highly effective and relatively well tolerated (good QoL despite 26% treatment discontinuations)! Adjuvant Melanoma Therapymew jobs to do! • Testing the new drugs for AJCC stage 2 melanomas („how much recurrence risk justifies how much risk for toxicities?") • Biomarker development for the selection of the best patients (and prediction of certain toxicities) • Addressing the issue of induction for resistance for potential stage IV setting • Neoadjuvant trials are mandatory! EXPLORATORY ANALYSIS OF THE PREDICTIVE VALUE OF TMB/lfn-y TM8 High/IFN y High 1MB HigMFN-y Lew 0 10 20 30 -10 50 co No at risk Months il.I _ v v i\ n M t> o 0 10 » 50 10 so No it risk Months o't— II IK 11 H H 3 pk'— 28 21 ic ic 13 3 o uk)— 23 15 12 12 10 1 i 1MB Low/IFN-y High 1MB LowflFN-y Low The analysis was not powered to assess treatment interactions, but results suggest that low TMB or high TMB/high IFN-y may be associated with greater RFS benefit than high TMB/low IFN-y 0 10 20 30 10 50 co 0 10 20 30 10 50 lo jt risk Months No It risk Months d.t-17 12 37 35 25 7 0 0.t — 5i 13 32 21 13 i pbo- 18 28 20 17 11 c 0 pbo — 55 22 10 13 9 \ Stage II: MK3475-716 Study Patients: 212 years of age Resected Stage I IB and Stage IIC Cutaneous Melanoma Stratify adult patients by T stage Patients <18 years old will be stratified to pediatric group Submit resected tissue Pembrolizumab Adult/Pediatrrc Dose IV q3 weeks 17 Cycles (approx. 1 year) Placebo IV q 3 weeks 17 Cycles (approx. 1 year) Primary Endpoint: RFS Secondary Endpoints: OS DMFS _Safely_ Rechallenge/ Crossover Pembrolizumab Adult/Pediatric Dose 17 Cycles for local or distant recurrence following surgical 35 Cycles for unresectable/ Ipi/Nivo combo: CA209-915 trial BRIM-8 Checkmate-238 Nivo+lpi Combi-AD Keynote-054 EORTC 18071 - Ipi Patients lie - lllc ( SN >lmm) 1MB, lllc or IV (no brain mets) lllc or IV (No Brain mets) IIIA ( >lmm), 1MB, NIC IIIA ( >lmm), IIIB, lllc (no Intransits) IIIA ( >lmm), IIIB, IIIC (no intransits) Mucosal melanoma excluded 3% excluded excluded excluded excluded Duration of therapy lyr lyr lyr lyr lyr lyr RFS 2yr DFS: 46.3% Vs 47.5% (lllc) lyr 70% vs 60% HR 0.65 75 -80% at 2 yrs 3yr 58% vs 39% HR 0.57 lyr 75% vs 61% HR 0.57 5yr 40% vs 30% HR 0.75 DMFS NA HR 0.73 NA HR 0.51 NA 5yr 48% vs 38% OS NA NA NA 3yr 86% vs 77% HR 0.57 NA Syr 65% vs 54% Patient selection for adjuvant treatment: potential criteria apart from efficacy Patient characteristics: age/gender Performance status Comorbidities Tumor characteristics: stage of metastasis (AJCC) Micro- versus macrometastases Mutational status Biomarkers (PD-L1 status) Treatment factors: oral vs. IV (intervals?) Potential toxicities (reversible vs irreversible) Approvals by FDA (USA) and EMA (EU) (November 2018)1-4 Interferon alfa-2b Dec 1995 Peginterferon alfa-2b Mar 2011 Ipilimumab Nivolumab Oct 2015 Dec 2017 Dabra/Tram March 2018 2000 î Î 2005 2010 Interferon alfa-2b Interferon alfa-2a Jun1997 Jun1999 Nivolumab Aug 2018 Pembrolizumab Dec 2018 For more information mil confoen« website: www.M*c20i 9 com st I SOUTHEASTERN EUROPE IMMUNOTHERAPY CONFERENCE Dear friends On beha'f of the i" Southetilen European Immunotherapy Conference Ofgarjinj Committee. «t « my great pica we to invtte you to the conférence to be he enjoy the conference and t Km yotM mterxt-on w th your colleagues from many dflerer« countnes wM jt mutate a creative exchange of idea» and wil be personaSy rew arding We thank you in advance for be>ng pat of this conference and hope to make the *" Southeastern European Imrrwnotherapy Conference in Zagreb a memorable eipenence for you. Ojvonn Hcrccf MO, PhD Melanoma 2020: standards of care and unmet needs Prof dr Lidija Kandolf Sekulovic Medical Faculty, Medical Military Academy Belgrade, Serbia Metastatic melanoma: standards of care SURGERY: For solitary metastases: PET-CT and brain MRI necessary before decision for surgery (+adjuvant therapy with anti-PDl) SYSTEMIC THERAPY: ° Checkpoint inhibitor immunotherapy: anti-PDl antibodies, anti-CTLA4 antibody Targeted therapy: BRAF and MEK inhibitors RADIOTHERAPY: STEREOTACTIC RADIOTHERAPY AND GAMMA KNIFE SURGERY for CNS and other distant sites Palliative for bone metastases, lymph nodes and soft tissues, CNS metastases SUPPORTIVE CARE Targeted therapy Checkpoint inhibitors Vemurafenib Cobimetinib Dabrafenib Trametinib Encorafenib Binimetinib Ipilimumab Nivolumab Pembrolizumab Atezolizumab Avelumab Durvalumab Systemic treatment of metastatic melanoma 2019 High mutational load = Immunotherapy effective BRAF INHIBITOR VEMURAFENIB Baseline 15 days BRAF inhibitor: treatment resistance Before Fix Vemurafenib, 15 weeks Venwafemb. 23 weeks Dabrafenib trametinib versus vemurafenib Encorafenib binimetinib versus vemurafenib Tim* (months) Number at rUk BRAFTOV1 * MEKTOVI 192 188 182 166 144 132 124 115 108 102 95 82 57 30 9 1 0 vennurafenib 191 134 166 140 115 lOO 39 83 77 71 62 56 30 19 8 1 0 Checkpoint inhibitor immunotherapy: anti-PD1 and anti-CTLA4 Combination immunotherapy: anti-PD1 plus anti CTLA4 Death or Disease Progression no. of pat rents/total no. Median Progression-free Survival mo (95% CI) Nivolumab plus Ipilimumab Ipilimumab 100- 90- — 80- £ _ 70- M ~ || 60- 50- 8 g. 40- So 1 30- 20- 10- 0 No. at Risk Nivolumab plus ipilimumab 72 Ipilimumab 17 30/72 NR 25/37 4.4 (2.8-5.7) Hazard ratio, 0,40 (95% CI, 0.23-0.68) P< 0.001 Nivolumab plus ipilimumab (N=72) i Ipilimumab (N=37) 5 Months EMA, April 2016 anti-PD1+anti-CTLA4: • Higher response rates • Faster response • Long-term responses • More frequent and more severe side effects Postow M et: al. ft tn^jl J Med 2015; 37 2:2006-R Anti PD1: efficacy Robert C et al. N Engl J Med 2015;372:320-30. Robert C et al. N Engl J Med 2015;372:2521-32. Brain metastases STAGE III: 10-13% of patients already have CNS mets (CT/MRI necessary in follow-up!) STAGE IV: 18-46% ON AUTOPSY 55-75% Frequent relapses in patients with regression of internal organ metastases Overall survival: 4 months after diagnosis (Fife et al, J Clin Oncol 2004) Fife KM. J Clin Oncol 2004; Sawaya RE, Brain Tumors. Philadelphia; 2001. Barnholtz-Sloan JS, 2004; Harrison BE, Am J Clin Oncol 2003; Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy K. A. Ahmed1, D. G. Stallworth2, Y. Kim3, P. A. S. Johnstone1, L. B. Harrison1, J. J. Caudell1, H. H. M. Yu1, A. B. Etame», J. S. VUeber5 & G. T. Gibney«"* Annals of Oncology27:434^)41.2016 Brain metastases HIRURGIJA 8.7 meseci Hirurgija + radioterapija celog mozga (WBRT) 8.9 meseci Samo radioterapija celog mozga (WBRT) 3.4 meseci Suportivna terapija 2.1 meseci STEREOTAKSNA RADIOHIRURGIJA: Lokalna kontrola bolesti 90% slučajeva Efikasnost slična hirurgiji Ukupno preživljavanje 5-11 meseci Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies European Journal of Cancer 75 f2G17) 169—178 He Siang Choong a, Serigne Lo b, Martin Drummond b, Gerald B. Fogarty b'd,e, Alexander M. Menzies b'e'r, Alexander Guminski b'e,f, Brindha Shivalingam b'c'e, Kathryn Clarke d, Georgina V. Long b-e-f, Angela M. Hong b'd'e'* Method: A total of 108 patients treated with SRS from 2010 to 2015 were included. Systemic treatment use within 6 weeks of SRS was noted. OS was defined as time from SRS to death or last follow-up, and BC was defined as absence of any active intracranial disease during follow-up. Univariate and multivariate Cox proportional hazard analyses were performed on clinico- Sunmnl Ian* (man»-» Fig. 1. Kaplan Meier plot for OS according to types of systemic treatment received — anti-CTLA4, anti-PDl and BRAFi ± MEKi (n = 104). «The one patient who had MEKi alone was excluded in the survival analysis. Table 5 Trials and retrospective series of systemic drug therapies in patients with active brain metastases. Systemic therapy Study Year No. of patients Patients received SRS Systemic therapy Median OS OS at 6 months OS at 1 year OS at 2 years Anti-CTLA4 Choong if aL 28 Y Ipilimumab 7.5 59«/. 41% 16% Kiess [26] 2014 46 Y Ipiliniumab 12.4 N/A 40-65% N/A Knisely [1-1} 2012 21 Y Ipilimumab 21.3 N/A N/A 47.2% Mathew [54) 2013 25 Y Ipilimumab 5.9 56% N/A N/A Margolin [ 15} 2012 72 N Ipilimumab 51 Asymptomatic (cohort A) 7.0 55% 31% 26% 21 Symptomatic (cohort B) 3.7 38% 19% 10% Anti-PDl Choong et aL 11 Y Anti-PDl 20.4 91% 78% 29% Ahmed [27] 2016 19 Y Nivolumab 11 8 78% 55% N/A BRAFi ± MEKi Choong et aL 39 Y BRAFi ± MEKj 82% 66% 44% Ly D [30) 2015 52 Y BRAFi r11.2 S N/A N/A N/A Wolf [31] 2015 31 Y BRAFi - (23% MEKi) TTZ 54% 41% N/A Ahmed [29] 2015 24 Y BRAFi CgaQ -1 6.7 (6.7-6.7) O 11.3(3.3-23.7) !-9- MiVO+IPi NIVO 50.9 (50.9-50.9) O 10 20 30 40 50 60 Circles represent medians; bars signify ranges Com b i nation i pi ii mu mab + nivo I u rrtab : Single agent nivolumabi - Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review Annals of Oncology 2& 2377-2365, 201 7 L. Khoja',2t, D. DayMl5t, T. Wei-Wu dien6'7'8, L. L. Siu3"4 & A. R. Hansen3-4* CTLA-4 mAb Wore likely to occur with PD-1 mAb Pneumonitis Myalgia Hypothyroidism Arthralgia Vitiligo Colitis Hypophysitis Rash Pruritus OR 95% Ci 6.4 3.2-12.7 5.0 2.9-8.7 4.3 2.9-6.3 3.5 2.6-4.8 3.5 2.3-5.3 8.7 5.8-12.9 6.5 3.0-14.3 2 1.8-2.3 1.8 1.6-2.1 14 13 12 11 10 9 8 7 6 5 4 3 2 p<0.0001 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Figure 2. The odds ratio (OR) of different immune-related adverse events (all grades) comparing PD-1 /PD-L1 versus CTLA-4 immune checkpoint inhibitors. E 0 OOCO WEWE EST PHUCTKF Annals of Oncology 28 (Supplement 4): 19-ivl42,2017 ctoi:10.1092/a inrwnt/ mdx22S CLINICAL PRACTICE GUIDELINES Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up+ J. B. A. G. Haanen1, F. CarbonneP, C. Robert3, K. M. Kerr4, S. Peters5, J. Larkin6 & K. Jordan7, on behalf of the ESMO Guidelines Committee" POSITION ARTICLE AND GUIDELINES Open Access Managing toxicities associated with ^ 1 ar immune checkpoint inhibitors: consensus recommendations from the Society for immunotherapy of Cancer (S1TC) Toxicity Management Working Group I. Puzanov,f, A. Diab21, K. Abdallah3, C. O. Bingham 111", C. Brogdon5, R. Dadu2, L. Hamad1, S. Kim2, M. E. Lacouture6, N. R. LeBoeuf7, D. Lenihan3, C. Onofrei9, V. Shannon2, R. Sharma1, A. W. Silk'2, D. Skondra10, M. E. Suarez-Almazor2, Y. Wang2, K Wiley", H. L Kaufman121, M. S. Emstoffrt and on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working Group Pu2artov etal. Journal for ImmunoTherapy of Cancer (2017) 5:95 Oncologist' Melanoma and Cutaneous Malignancies Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma AD IL DAUQ, Katv Ts At The Oncologist 2017;22:1-11 Optimizing combination dabrafenib and trametinib therapy Management Of BRAF and MEK IllhibitC in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists toxicities in patients with metastatic Victoria ATKINSON,' Georgina V. LONG,2 Alexander M. MENZIES,1 Grant MCARTHUR,5 Matteo S. CARLINO,4 Michael MILLWARD,' Rachel ROBERTS-THOMSON,' Benjamin BRADY,' Richard KEFFORD,' Andrew HAYDON' and Jonathan CEBON' Asia-Pacific Journal of Clinical Oncology 2016; 12{5uppl. 7): 5- melanoma Sarah J. Welsh and Pippa G. Corrie Ther Adv Med Oncoi 2015, VOL. 7[2) 122-136 Cutaneous adverse effects of targeted therapies Part II: Inhibitors of intracellular molecular signaling pathways James B. Macdonald, MD,ah Brooke Macdonald, BA,*1 Loren E. GoLitz, MD, J Am Acad Dermatol February 2015 Dose reductions for BRAFi MEKi A Oabrafenib 0 Trsmefinib ¡/VI C Vemuraferib D Cobimetinib= Figure 1. Recommended close adjustments and modifications fot dabrafenib (A), trametinib IB), vemuralenib (C), and cobimetinib ID). General management principles Targeted therapy Grade 1: continue TT, symptomatic therapy, diagnostic work-up Grade 2: ◦ Interruption of treatment, until grade 1, then reintroduce in decreased dose ◦ If reappear, second interruption until grade 1 than reintroduce with further dose reduction ◦ Diagnostic work-up ◦ Symptomatic therapy Grade 3 and 4 ◦ Interruption of treatment until grade 1, then reintroduce in decreased dose ◦ Diagnostic work-up ◦ Symptomatic therapy ◦ Consider switching to other BRAFi+MEKi General management principles Immunotherapy Grade 1: continue ICI therapy, symptomatic therapy, close follow-up Grade 2: ◦ hold ICI therapy ◦ diagnostic work-up ◦ start corticosteroid therapy and resume ICI when corticosteroid is tapered to <10 mg/day and patient remains symptom-free (grade 1) ◦ If irAE returns on resuming ICI: ◦ Grade < 2: temporarily hold ICI ◦ Grade > 3: permanently discontinue ICI ◦ If using combination anti-CTLA-4/anti-PD-1 immunotherapy, continue anti-PD-1 agent only Grade 3: ◦ withhold ICI; consider resuming ICI when ◦ corticosteroid is tapered to <10 mg/day and patient remains symptom-free (grade < 1) ◦ If irAE returns: permanently discontinue ICI ◦ consider hospitalization Corticosteroid use for irAE Grade of immune-related AE Corticosteroid management (CTCAE/equivalent) Additional notes - Corticosteroids not usually Indicated • If indicated, start oral prednisone 0.5-1 mg/kg/day if patient can take oral medication. • If IV required, start methylpredn ¡solone 0.5-1 mg/kg/day IV • If no improvement in 2-3 days, increase corticosteroid dose to 2 mg/kg/day • Once improved to 30 mg prednisone or equivalent/day) * Discontinue immunotherapy ♦ Continue intravenous corticosteroids - Start proton pump inhibitor for Gl prophylaxis • Add PCP prophylaxis if more than 3 weeks of immunosuppression expected (>30 mg prednisone or equivalent/day) Note: For steroid-refractory cases and/or when steroid sparing is desirable, management should be coordinated with disease specialists. AE, adverse event Puzanov et al. Journal for ImrrtunoTherapy of Cancer (2017) 5:95 Dermatologie toxicities Targeted therapy Immunotherapy Targeted therapy: BRAFi ◦ Follicular rash ◦ Maculopapular rash ◦ Hair thinning and curling ◦ cuSCC ◦ Palmar-plantar dysestesia syndrome MEKi ◦ Papulopustular rash ◦ Palmar-plantar dysestesia syndrome Checkpoint inhibitor therapy ■ Pruritus ■ Maculopapular rash ■ Vitiligo ■ Rare ■ Neutrophilic dermatoses ■ Lichenoid reactions ■ Bullous pemphigoid ■ AGEP ■ Alopecia areata/universalis TYPE > GRADE > MANAGEMENT Melanoma 2020: standards of care and unmet needs Dabrafenib trametinib 5-year OS update (phase II, BRF113220, part C) 0 6 12 18 24 30 36 42 43 54 60 66 72 Time Since Random Assignment (months) VOLUME 30 ■ NUMBER 7 - MARCH 1, 2018 Long G et al. J Clin Oncol 36:657-673. Nivolumab: heavily pretreated patients Overall Survival at 5 Years of Follow-up ■fr Atl ;n«nfi &B.HJÏ madiKfl and CI: 1 M 4l2.5-37.fi) Vf WYO J mç « g (pv«ie> 1t:1T|. ™fiin sno HKCI;]H iT.J-PiB;. 34% 5 yr OS Metastatic melanoma treatment 2019 • Five year OS rates: 30-35%, 65-70% do not survive Questions: 1. Duration of treatment? 2. Discontinuation of treatment? Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma Caroline Robert Antoni Ribas, OtnidHamid, Aiiil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffreys. Weber, Tara C Gangadhar, Richard W. Joseph Roxana Dronca, Amita Patnaik, HassaneZarour, Richard Keffortl Peter Hersey, Jin Zhang, James Anderson, Scott J. Diede, Scot Ebbinghaus, and F. Stephen Hodi Fig 2. Time to response and durability of response from the start of therapy in complete responders who discontinued pembrolizumab and proceeded to observation (n = 67>_ Bar length is equivalent to the time to the last imaging assessment by investigator review. CR, complete response; PD, progressive disease; PR, partial response. 0 6 12 18 24 30 36 42 48 64 Time Since the Start of Therapy (months) J Clin Oncol 36:1668-1674. I 1670 ® 2017 by American Society of Clinical Oncology Journal op Cunioil Oncology 100 90 - eo - 70 -60 -50-40-30-20-10- 6 12 13 24 30 36 42 48 Time Since Achieving CR (months) No. at risk: All patie nrts T05 97 90 18 B 54 5 muni m......^ 100 90 SO 70 60 50 40 30 20 10 .¿iüLJ, Ma. at risk: All patients 39 0 6 12 IS 24 30 36 42 Time Since Stopping Therapy (months) 48 42 Fig 3. Diseasfrfree survival (A) from time of experiencing complete response (CR) in all patients who achieved CR (n -105! and IR| from time of discontinuation of pembrolizumab in patents who discontinued after CR for reasons other than progression (n= B9). The hash marks designate patients who were censored at that time point. J Clin Oncol 36:1668-1674. Metastatic melanoma treatment 2019 • Five year OS rates: 30-35%, 65-70% do not survive Questions: 1. Can we improve further treatment outcomes? 2. Are there evidence available to guide our treatment decision on choosing the first line treatment? 3. Does sequencing matters? Metastatic melanoma: ORR A 80 OS rates: 1st line treatment 3-year OS rate 4-year OS rate 5-year OS rate Dabrafenib trametinib 45 37 34 Pembrolizumab 51 45 40 Nivolumab 51 45 - Nivolumab+ipilimumab 58 52 - COMBI-D Schadendorf D et al. Eur J Cancer 2017 ID -O o ft 10 u. CL No. ,it risk Normal LDH, SLD<66 mm, organ stles<3 183 Normal LDH, SLD<66 mm, organ 31 Normal LDH, 5LD266 mm 102 LDHil ta'2»ULN 132 _CJ— Subgroup Median PFS (35% CI), mo Normal LDH, SLD*6S mm, organ sites3 Mormal LDH, SLD266 mm LDH E l to <2*ULN LDHMKULN 1-1.7 (9.5-10.3) 9.2 (7,2-15.4) 7.3 (5.6-8,2) 5 5(4.5-6 2) 12 24 Months from Randomised 124 35 44 3fi 79 20 26 22 55 12 16 11 3-vear OS and clinical factors Luke JJ The Oncologist 2019:24:1-15 LDH>ULN 3-year OS LDH18 years Treatment-naive patients Presence of BRAFV600E or V600K mutation in tumour tissue prior to enrolment ECOG PS 0-1 EIMCO 450 mg PO QD + BINI 45 mg PO BID Progression IPI 3 mg/kg IV Q3W * NIVO IV 1 mg'kg Q3W for 4 doses then NivO 3 mg.kg IV Q2W (until PD) IPI 3 mg kg IV Q3W + NIVO IV 1 mgkg Q3W for 4 closes then NIVO 3 mg.kg IV Q2W Progression ENCO 450 mg PO QD ♦ BINI 45 mg PO BID (until PD> FNCO 450 mg PO QD + BINI 45 mg PO BID After 8 weeks IPI 3 mg.kg IV Q3W ♦ NIVO IV 1 mg'kg Q3W for 4 doses then NIVO 3 mgkg IVQ2W 3rogression ENCO 450 mg PO QD + BINI 45 mg PO BID (until PDJ Primary endpoint OS Secondary endpoints PFS 2/3-Y S Best ORR DOR Safety QoL ImmunoCobiVem (Germany, France, Greece, Serbia-VMA) Run-in Phase Randomized Phase Follow-up phase NCT02224781 : Phase 3 Study of Dabrafenib + Trametinib Followed by Ipilimumat + Nivolumab vs Ipilimumab + Nivolumab Followed by Dabrafenib + Trametinib Randomised Phase 3 trial of dabrafenib + trametinib followed by ipilimumab + nivolumab at progression vs ipilimumab + nivolumab followed by dabrafenib + trametinib at progression in patients with advanced BRAF V600 mutant melanoma Primary endpolnt: • OS fate, defined as the proportion ot patiente alive arter 2 years or follow up time AdvancedJ metastatic unresectable melanoma n=300 ECOG PS 0 01 1 Patients may have had prior systemic therapy in the adjuvant setting however this must not have included a CTIA 4 or PD-1 pathway blocking antibody of a BRAFi/MEKt 1 M all ¡h1'1 m MBi ; : yîE ' : lijv Actual Study Start Date : July 13, 2015 Estimated Primary Completion October 2, 2022 Date : Secondary endpoints: • PFS (RECIST version 1 1) • Response rate (RECIST version 1 1J Objective: Does the initial tfeatmeot with the dabrafenib-trametinib combination (and subsequent ipilimumab iuvolumab) or ipilimumab nivolumab combinaiicn (and subsequent dabrafeniMrametifub combination; improve the 7 year OS significantly in patents writi nesec table staije in oi stage ÎV BRAFVS0Û (utaut melanoma? ROC curves confirm the poor performance of PD-L1 to guide patient selection: Fig. S4 Predictive biomarkers? No validated markers for 10 in melanoma ° PD-Ll: not standard of care ° MSI-high: not routine ° TMB mostly high in melanoma ° Main limitation: negative predictive value 0.75- ■a 0.50- 't/i o a. 10 mm • Growth of the tumor in the surrounding tissues and structures • Surgical treatment / irradiation is contraindicated due to the position of the tumor or would lead to significant morbidity / deformation / loss of function • Two or more repeated lesions in the same place1 T r > * 1. Basset-SeguinN. et al. MolCancer Ther2015; 1-9 5 BCC and Hedgehog signal pathway 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) Vismodegib zavira SMO, ki je osrednji posrednik signalne poti Hedgehog '.....*......... «** ^ PTCH Ni prenosa znotrajceličnega signala Vismodejib se veže na SMO «i prepreči prenos signala po sijnalni poti HeiJsehog l"*» Ni ciljnega izražanja <--■%. genov Zmanjšana rast tumorja in zvečana apoptoza 6 Table 1. Risk factors for recurrence Clinical Histological Location Low risk: trunk and limbs Aggressive subtype*: Intermediate risk: forehead, cheek, chin, scalp and neck -Morpheafornn High risk: nose and periorificial areas on the head and neck - Infiltrating -Basosquamous - Multifocal Size (largest tumor diameter) >1 cm for high-risk location >2 cm for low- or intermediate-risk location Clinical aspect Ill-defined lesions or morpheaform subtypes Disease status Recurrent level of evidence 3 (i.e., based on case-control studieS. •When several subtypes are associated, glooal prognosis depends or ttie component with the prrarest prognosis. Adapted with permission from [26]. Vismodegib in patients with advanced basal eel! ^ \ (§) carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial NkoleBassrt-Segiiia AjoriWausthl4JeonJittijoes&oit Remet Kunstjità, feîgittfOréra, Lau/mtMorl«, PaotoA Astiertct Lr» licit«, Carol in e Dut/mux, LucThomas, Thomas) auary, NicoJas Meyer, Bernard GurJIat, Rnnhairi Dummei, KatcFif^ D Scctt Ernst, Sarah Wi lia ms> Alfotofittipoldq IcannrsXyeos, .khcnHonsson Summary Background The Hedgehog pathway inhibitor vlsmodegtb has shown clinical benefit in patients with advanced basai ^ 16.-725-36 *ll patente (n=4Ä2-) Patients with >:f,I"ï advanced basal cell cardnoroi (n=453) PaSsnüwlth metastitEr baaltsfl canílnomi (n=29] Ccrrqilete 15s [PS] 1S3 (34%t Pirtlaj 9(31*) SJabléiâfaŒ 1:6 WD liepfrK) l&GW JSôgésJiifcriKease 15(3*} 11 (I* j A P4») M&in¡ynoí waiuatí 20 71 (&*) 4&IK) Chüar^r pb). ■[yiHiid«pai>ffïl--jwin-Li '■ i^n'imed disease in".];-¡ir dwiltiDul mE^L-nhlr cvn'-e 3/j TatfiA BKcrEspwise to treatment Vismodegib in patients with advanced basal cell ^ ^ ® carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial Nicole BasKt-Seguia Hauxhli JeanJ acques Greb. Soins» Kunstfetd, Brigit te Drcne, Laurent Merlin, Pooh A Axieiia Lea Licit.'o, Carolina Dutriouv, Luc Thomas, Thorwsjouary, Nicolas Meyer, B&nari Guilat, Rainhmri Dummw, Katefifç DSrett Emit, ScrraJi VJiliams, Aliwrtofittipo/dq ImnnvXynos, fohanHansson Summary Background The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basai ^ onmjcn 16.-725-36 AlPTEAEs Grade 3-5 TEA E5 <12 months' a "12 months' <12 months' ai2mcnth£ exposure (-n-314) sxposurefivlftB) ecpcrsunÉfn-314} eKposwe$n-l85) AJ^TEAI. Sf rata; LS40SK1 1313(41*) È4(45*) WLtîciespasTis 1S9G4*) L4û (Srrfei îl(7*) Atpecla 1E4 H'ITÎ 1(<1S} DyiçejEJa 139 (44*} 13D(70*.) 6(3*} 3(3*} welghlloss llopsst; Bi(44Hl 4(1») 14 (S») Asthenia 76 P4H) 4505«: s m 50*} D^treaïéd cppeirli! 74 P4*J 7 4(3*} AgaL-sIa 75 P4H) Î7PQS) 6(2%) 50*} ^HrjiH SO{lfl») 30(15*) 90*} 3(3*} ES (13*) 4J(3Ï*I 0 Dàïïtioee 33(11») 51(28*1 IWW 2(1*) Dan are n- forthe mra comma n trcni mar:- Kpcrgrnt jcp^hk events (TEftEa) cA airy grade, crem occurring in LCTfc cr more erf patients are- repareed. Iwrrtvwwe graded according tis National Cancer Institute Common TermirralDgr Criteria far Advene Events rerssan [Yersbn 4_0) TflHe 3: biddence of treaEiTiEnt-emei^rrtadv^e-EverïtEacccriilngito duration of vismodegib exposure /¿12 monïfis w <12 months- rt499) Vismodegib in patients with advanced basal cell ^ \ ® carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial Nkoleflessrt-Seguia Ajori Hauscb J4 Jmn Jacques dab, RameiKunstfeil 6igrttc0(éno, Uunmt Martin Pacta A Aaieîtq Léo licitia, Caroline Dut;mux, LucThomas, Thomas) ouary, Ni«Jas Meyer, Banari GuiJIat, Rejrhaid Dumnxr, ICateFjfe; D Sreft Ernst, SuraJi WÎ tarns, Altertcfittipolda IccnnnXyms, JohonHirnsson Summary Background The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basai imca on«jjeis 16.-729-36 100- _ --Lociilyadranccci|'n-i65) ' ---Met*statk(n-3i) ^"■h | Censored 80- ï 5 ^^-m m, 1 pi | 60- | '-«- . V | 40- I w 20- Dtyi 4 a 12 16 2C 24 28 Nuit,s «aï risk Timsffnoflth!-) loctyacwanced 4&5 1|4 150 65 23 S 0 Mecartalit 31 21 16 ia 4 t 0 0 FJjjure 2: KaplarvMelerptot of progressiarvfree survival In patlentswho had hKtologlcalfy confirmed basai cell careinofna Case from OIL 23. 9. 2013 19. 12. 2013 31. 7. 2014 Quick response to high-dose treatment Side effects: alopecia gr. 2 after one year of treatment, increased CPK gr.1, muscle cramps gr.1 ii Case from OIL Patient with Gorlin syndrome (multiple BCC) Side effects: alopecia gr.1 weight loss gr.2 increased CPK gr.1-3 Merkel's cells carcinoma (MCC) • MCC is a rare, aggressive and often deadly neuroendocrine skin cancer. • Growing incidence (in the United States it tripled between 1986 and 2001). • Possible connection with recently discovered polyomavirus (80% of MCC cells). • It often occurs in the sun exposed areas of the skin. There are two reasons for MCC • Through onco- proteins encoded with the Merckel's Cell Polycom virus (MCPyV) • The accumulation of mutations caused by UV radiation. • More often in immunosuppressed patients PRINCIPLES OF SYSTE MC THE RflPY1 Local Disease: ■ Adjuvant chemotherajy not recommended Regional Disease: ■ Clinical trial (preferred) ■ Adjuuant chemotherapy not routinely recommended as survival benefit has not been demonstrated in available retrospective studies, but could be used on a case-by-case basis if clinical judgement dictates »Cisplatin t etoposide i Carboplatin ± etoposide Disseminated Disease: ■ Clinical trial (preferred) ■ Avehrmab2 ■ Pentorolizumab2 ■ Hivolurrab2 ■ As clinical judgment dictates for patients vith contraindcations to checkpoint immunotherapy: »Cisplatin t etoposide »Carboplatin ± etoposide > Topotecan t (CAV): Cyclophosphamide, doxorubicin (or epirubicin), and vincristine 1When available and clinically appropriate, enrollment in a clinical trial is recommended. The literature is not directive regarding the specific chemotherapeuti offering superior outcomes, but the literature does provide evidence that Merhel cell carcinoma is chemos ensitnre, although the responses are not durable, agent listed above have been used lAiiih some success . ^Preliminary data from non- randomized trials in patient with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockade com| with cytotoxic therapy. The safety profiles for checkpoint immunotherapies are significantly diffe re nt f ro m cytotoxic therapies. Consult prescribing information recommendations on detection and management of immune-related adverse events associated with checkpoint immunotherapies . C linician and patient edu critical for safe administration of checkpoint immunotherapies. jgjr b i ared 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 ImmunolRes.2013;1(1):54-63; 2. AfanasievO, et al. ClinCancer Res. 2014;19(19):5351-60; 3. Goh G, et al. Oncotarget. 2016;7(3):3403-15. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial H own'd !. Kal' jrn cstJ pjjpiy Su 55*JJ, OmifHarnkf, Shaimdm Bhatjo, Patrick ierhtydm, Sandra P O'AngHo; XentCShr/i CâertrLeWpç Gerald PLmette, Mktiele Midla, Isaac B/owndJ, KaJ £>Leiws,,be hen H Lachr Kevin Chrn, Lisa Wchnki, Anja von Heydehned; Jean-Marie Gjillaot, PajINgfiiem • 88 patients were enrolled and received at least one dose of avelumab. • Patients were followed up for a median of 10-4 months (IQR 8 ■ 6-13 ■ 1). • The proportion of patients who achieved an objective response was 28 (31 ■ 8% [95 ■ 9% CI 21 ■ 9-43 ■ 1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. • Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in fi ve patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). lancet Oncol 2016; 17: 1374-85 Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial Howard!. KajJmarvJejJeiyltossell OrrMfHamtf, SbaJemiB Bhatia,Pctrid:Te.'heyderr, SandraPD'Angeto, (Cart CShiVi CfelrLebie GeraldPLrhettf, Mfriefc Midlo, Isaac Browne^ Karf Dinujs Jochen H iach, Kcm Chin, Liso Mohnki, An/a wn Heyathrad; jran-Mane Cu ills at. ftul Ngfwm et Oncol 2016; 17: 1374-85 Lancet Oncol 2016; 17: 1374-85 Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell ca rcinoma. et Oncol 2016; 17: 1374-85 Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy Paul Nghiem, MD, PhD1: Shai lender Bhatia, MD1; Evan J. Lipson. MDZ; William H. Sharfman. MD': Ragini R. Kudthadkar, MO5; Andrews. Brohl.HD'1; Phillip A. Friedlander, MD=; Adil Daud, MD°; Harriet M.KIuger, MD'; Sirnil A. Reddy, MD"; Brian C. Boulmay, MDS; Adam I. Riker, MD9; Melissa A. Burgess, MD10; Brent A. Hanks, MD, PhD"; Thomas Olencki, DO12; Kim Margolin, MD13; Lisa M. Lundgren, MS11: Ablta Soni, DO2; Nirasha Ramchurren, PhD"1; Candice Church, PhD15: Song 1. Park, MD15; Michi M. Shinohara, MD": Bob Salim, PhD"1: Janis M. Taube, MD2: Steven R. Bird. MS": Nageatte Ibrahim, MD": Steven P. Fling, PhD14; Blanca Hornet Moreno, MD, PhD"; Had Sharon, MD, MPH1"; Martin A. Cheever, MD1"; and Suzanne L. Topalian, MD2 In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote- 017), 50 adults naive 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 ClinOnco! 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 Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy Paul Nghiem, MD. PhD1; Shailender Bhatia. MD1; Evan J. Upson. MDZ; William H. Sharfman. MD': Ragini R. Kudthadkar, MD>; Andrew S. Brohl,MD";PhiIIip A. Friedlander, MD5; Adil Daud, MD°; Harriet M.Kluger, MD'; Sunil A. Reddy, MD"; BrianC. Boulmay, MD*; Adam I. Riker, MD9; Melissa A. Burgess, MD10; Brent A. Hanks, MD, PhD"; Thomas Ole neki, DO12; Kim Margolin, MD13; Lisa M. Lundgren, MS1*; Abha Soni, DO2; Nirasha Ramchurren, PhD"; Candice Church, PhD'5; Song 1. Park, MD15; Michi M. Shinohara, MD'5; Bob Salim, PhD16; Janis M. Taube, MD2; Steven R. Bird, MS"; Nageatte Ibrahim, MD1'; Steven P. Fling, PhD11; Bianca Hornet Moreno, MD, PhD1'; Bad Sharon, MD, MPH'"; Martin A. Cheever, MD1"; and Suzanne L. Topalian, MD2 No. at risk 2S 27 15 9 5 1 0 □ J ClinOncol 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 Table 2. Summary of data from trials of immunotherapy for the treatment of patients with advanced MCC Pembrolizumab Study' Chemotherapy refractory (second-line or later t Primary end point Patient and disease characteristics Median age (range), years Stage IIIB MCC, n (%) Stage IV MCC n (%) Prior lines of systemic therapy, n (%) 0 1 >2 Median baseline extent of disease (range), mm MCPyV-positive, n (%) Median duration of follow-up (range), months Minimum duration of follow-up, months Objective response race Overall, %(95% CD MCPyV-positive, % (n/Nl)* MCPyV-negative, %(tVN1) Response durability Number of patients with ongoing response at data cutoff, % (n/Nl) Median duration of response (range), monthse Kaplan-Meier estimate of proportion of responses with > 6 months' duration. % (95% 0) Durable response rate,«» (95% CI)' Progression-free survival Median, months (95%CI) 6-month rate, % (95%CI) Overall survival Median, months (95%CI) 6-month rate, % (95%CI) Treatment-related AE, n (%) Any grade Objective response rate by RECISTvl.l Confirmed best o1 69(13-182) 17(65) 7,6 (1.6-122) 56 (35-76) 62(10/16) 44 (4/9) 86(12/14) Not reached (2+ to 10+) Not reported 73 (33-88) 0 88(100) 0 52 (59) 36(41) 79 (16-404) 46 (52) b 10.4 (6-19) 32 (22-43)c 26 (12/46) 36(11/31) 82 (23/28) Not reached (3+ to 18+) 92 (70-98) a2S/26 patients had > 1 tumor assessment during tr b77/88 patients were evaluable for MCPyV status. CA repeated CI for the ORR in the modified intent-to-treat analysis set (95.9% O for the primary analysis) was calculated to account for the group sequential testing approach. dNl, number evaluable. e+ denotes a censored observation for durability of response. 'Durable response rate defined as the proportion of patients with a response of at least 6 months'duration and was estimated as the product of the objective response and the Kaplan-Meier estimate of 6 months' durability of response. Immune Checkpoint Inhibition Trials in MCC: Advanced Metastatic Disease Drug/Trial Target n Prior chemo Objective response Median follow-up Median PFS Median OS Pembrolizumab first-line1 (ICT02267603) CITN-09 PD1 26 No 56% 8 mo Not reached Not reached Avelumab first-line2 (NCTÛ2155647) JAVELIN Merkel 200 29 No 63% 3 mo Not reached Not reached Nivolumab first/second-line3 PD-1 15 IB 73% Ist-L 3+ mo Not Not (NCT02488759) CheckMate-358 10 Yes 50% 2nd! reached reached Avelumab second-line'''5 (NCTÛ2155647) JAVELIN Merket 200 PD-L1 88 Yes 3 mo 13 mo 1. Nghiem PTet of.: N Frrji J Med374;2W2 (2016); 2. D'Angelo SP et al,; A$C0 abstract 9530 (2017); 3. Topalian S et of.: Cancer fes 77(13 Suppl): abstract CT074 (2017); 4. Kaufman HL et al.: Lancet Oncol 17:1374 (2016); 5. Kaufman H et al.: J Immunother Cancer 6:7 (201i). Anti PD-1/PD-L1 in advanced MCC • ORR 1st line 56-73% • Previous ChT impairs 2nd line 33-50% outcome of anti-PD- 1/PD-L1 • PFS 1st line 17 mo (median) 2nd line 3 mo (median) • anti-PD-1/PD-L1 should be applied as first-line • OS 1st line median not reached treatment 2nd line 13 mo (median) • ChT should be postponed to 2nd line SCC • Second most common NMSC (20%) • Incidence is rising in last 30 years (50-200%) • Head and neck 80-90% • 90% have good prognosis SCC in transplanted patients 36 x higher incidence than usual (BCC: SCC 4: 1) Aggressive behavior - poor prognosis • Localized disease-surgery, electrochemotherapy • Radiotherapy • Advance disease - locally in systemic • Pplatinum based chemotherapy - no standard schemas, shorter durance of remissions - 3 months • Targeterd therapy: cetuximab (RR 21%), Panitumumab (31%) NCCN Guidelines. V2.2018. https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf. Tumor Mutational Burden in CSCC 1,000 /100 oT 10 LL £ o ra 1 | 0.1 o m 0.01 0 8.2 3.2 f 13.2 612 l / 1 1 ■ 1 SCCHN LUSC (178) (178) Melanoma (121) CSCC (39) Potential Formation of Sensitivity to Neoantigens Immunotherap 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. Cin Cancer Res. 2014;20:6582-6592. Rationale for Evaluating Checkpoint Inhibition in CSCC • High tumor mutation burden (TMB) and immunogenic cancer • High TMB may contribute to increased neoantigen production, which may increase tumor antigenicity1 • Immunosuppression is a well-described risk factor for CSCC (especially in solid-organ transplant patients)2 • PD-L1 expression has been observed in advanced CSCC3 1. Pickering CR, et al. Clin Cancer Res. 2014;20:6582-92; 2. EuvrardE, et al. N EnglJ Med. 2003;348:1681-1691. 3. Slater NA, et al. JCutanPathol. 2016;43:663-70. Candidates for Immunotherapy for Advanced CSCC • Patients with advanced CSCC • Locally advanced / metastatic disease • Patients who have failed prior surgeries • Patients who are not surgical candidates due to morbidity / potential disfigurement or low confidence of clear margins • Patients not candidates for radiotherapy Migden MR, et al. N Engl J Med. 2018;379:341-351. EMPOWER-CSCC-1 Study Design (NCT02760498) Group 1 - Adult patients with metastatic (nodal and/or distant) CSCC Group 2 - Adult patients with locally advanced CSCC Group 3 - Adult patients with metastatic (nodal and/or distant) CSCC* Cemiplimab 3 mg/kg Q2W IV, for up to 96 weeks (retreatment optional for patients with disease progression during follow-up) Tumour imaging Q8W for the assessment of efficacy Cemiplimab 350 mg Q3W IV, for up to 54 weeks Tumour imaging Q9W for the assessment of efficacy Tumour response assessment by ICR (RECIST 1.1 for scans; modified WHO criteria for photos) Key inclusion criteria • ECOG performance status of 0 or 1 • Adequate organ function • Groups 1 & 3: o At least one lesion measurable by RECIST 1.1 • Group 2: o At least one lesion measurable lesion by RECIST 1.1 criteria (for scans) or modified WHO criteria (for photos) o CSCC lesion that is not amenable to surgery or radiotherapy per investigator assessment Key exclusion criteria • 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 Data not yet available CSCC, cutaneous squamous cell carcinoma, ECOG, Eastern Cooperative Oncology Group, IV, intravenous, PD, programmed cell death, PD-L, PD-ligand, Q[n]W, every [n] weeks, RECIST 1.1, Response Evaluation Criteria In Solid Tumours version 1.1, WHO, World Health Organisation. 1. Guminskiet al. J Clin Oncol. 2019:37 (suppl, abstr9526) [poster presentation]. 2. Migden MR, et al. J CSnOncol. Gr0up 1: ^.C^-0? dft!LSePtimber 20 —ü! . . • , Group 2: Data cut-off date: October 10, 2018 2019:37 (suppl, abstr 6015) [poster presentation]. Baseline Characteristics in EMPOWER-CSCC-1 with Advanced CSCC (Group 1 and Group 2) Metastatic CSCC (N=59)1 Locally advanced CSCC (N=78)2 Median age, years (range) 71 (38-93) 74 (45-96) > 65 years, n (%) 43 (72.9) 59 (75.6) Male sex, n (%) 54 (91.5) 59 (75.6) ECOG performance status, n (%) 0 / 1 23 (39.0) / 36 (61.0) 38 (48.7) / 40 (51.3) Primary CSCC site, n (%) Head/neck 38 (64.4) 62 (79.5) Extremity 12 (20.3) 14 (17.9) Trunk 9 (15.3) 2 (2.6) Prior systemic therapy for CSCC, n (%) Any 33 (55.9) 12 (15.4) 1 22 (37.3) 10 (12.8) >2 11 (18.6) 2 (2.6) Prior radiotherapy for CSCC, n (%) 50 (84.7) 43 (55.1) Median duration of follow-up, months (range) 16.5 (1.1-26.6) 9.3 (0.8-27.9) Data cut-off date: Sept 20, 2018 (Group 1)1; Oct 10, 2018 (Group 2) CSCC, cutaneous squamous cell carcinoma; ECOG PS, Eastern Cooperative Oncology Group ''excludes ear and temple * includes arms/hands and legs/feet 1. Guminskiet al. J Clin Oncol. 2019:37 (suppl; abstr9526) [poster presentation]. 2. Migden MR, et al. J Clin Oncol. 2019:37 (suppl; abstr6015) [poster presentation]. Tumor Response Assessment by Independent Central Review in Patients with Advanced CSCC (Group 1 and 2) Metastatic CSCC (N=59)1 Locally Advanced CSCC (N=78)2 Median duration of follow-up, months (range) 16.5 (1.1-26.6) 9.3 (0.8 -27.9) Best overall response, n (%) Complete Response (CR) 10 (16.9) 10 (12.8) Partial Response 19 (32.2) 24 (30.8) Stable Disease 9 (15.3) 28 (35.9) Non-CR/non-PD+ 4 (6.8) 0 Progressive Disease (PD) 10 (16.9) 9 (11.5) Not evaluable* 7 (11.9) 7 (9.0) Objective response rate (ORR), % (95% CI) 49.2 (35.9-62.5) 43.6 (32.4-55.3) ORR by INV % (95% CI) 49.2 (35.9-62.6) 52.6 (40.9-64.0) Complete Response / Partial Response 4 (6.8) / 25 (42.3) 13 (16.7) / 28 (35.9) Disease control rate, % (95% CI) 71.2 (57.9-82.2) 79.5 (68.8-87.8) Durable disease control rate, % (95% CI)§ 62.7 (49.1-75.0) 62.8 (51.1-73.5) Median observed time to response, months (range)1 1.9 (1.7-9.1) 1.9 (1.8-8.8) Data cut-off date: Sept 20, 2018 (Group 1), Oct 10, 2018 (Group 2) fPatierts with non-measurable disease on central review of baseline imaging. include missing and unknown tumor response. §Defined as the proportion of patients without progressive disease for at least 105 days. ^Data shown are from patients with confirmed responses. INV investigator assessment 1 Guminski et al J Cin Oncol 2019 37 (suppl abstr 9526) fposter presentation! 2 Migden MR et al J Cln Oncol 2019 37 (suppl abstr 6015) fposter presentation!_ Best Percentage Change in Target Lesion in Patients with Advanced CSCC per ICR m co> 60 — c 40 SSI) 40 C « JS.g20 £g 0 -100 J Metastatic CSCC (Group 1)1Locally advanced CSCC (Group 2) I C°mp|ete response/partia| resp^COmplete response/partial response ü Stable disease Progressive disease Stable disease Data cut-off date: Sept 20, 2018 (Group 1), Oct 10, 2018 (Group 2) Bars show the best percentage change in the sum of target lesion diameters from baseline for 45 patients with metastatic CSCC who underwent radiologic evaluation per ICR and 56 patients with locally advanced CSCC who underwent photography evaluation per modified WHO criteria by ICR after treatment initiation. Lesion measurements after progression were excluded. Black horizontal dashed lines indicate RECIST 1.1 criteria for partial response (>30% decrease in the sum of target lesion diameters) and progressive disease (>20% increase in the target lesion diameters). Blue horizontal dashed lines indicate WHO criteria for partial response (>50% decrease in the sum of target lesion diameters) and progressive disease (>25% increase in the target lesion diameters). CSCC, cutaneous squamous cell carcinoma, ICR, independent central review, RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1, WHO, World Health Organization 1. Guminski AD, et al. J Clin Oncol 2019,37 (suppl, abstr 9526), 2. Migden MR, et al. J Clin Oncol 2019,37 (suppl, abstr 6015) Time to Response and Duration of Response in the Responding Patients with Advanced CSCC Metastatic CSCC1 A CR A PR • SD „. PD 9j NE § • Non-CR/non-PD Q. tfl ♦ Surgical removal ofo) target lesion ^ ♦ Ongoing treatment^ Ongoing study Locally advanced CSCC2 cr A PR • SD * PD ■ NE Ongoing treatment ■* Ongoing study 0 2 4 6 8 1012 1416182022242628 Months 0246 8 1012 141618 20 22 24 26 28 Months Data cut-off date: Sept 20, 2018 (Group 1); Oct 10, 2018 (Group 2) twenty-three of the 29 patients remain in response at time of data cut-off; of the 23 patients, 10 were still on study, 11 were in post-treatment follow-up and two were off study. Multiple progression everts for a single patient were possible due to discrepancies between investigator and ICR assessments of tumour response and because the protocol allowed option for treatment past progression in patients whom the investigator felt were experiencing clinical benefits. *Of the 34 responding patients, three had subsequent progressive disease. Among the remaining 31 patients who were in response at the time of data cut-off, 12 were still on study treatment, nine were in post-treatment follow-up, and 10 were off study. One patieit (sixth from bottom) had four progressive disease assessments due to discordance between investigator and ICR assessments of tumour response. CR, complete response; CSCC, cutaneous squamous cell carcinoma; ICR, independent central review; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. 1. Guminskiet 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]._ Kapian-veier tsumauon uveraii survival, progression-i-ree 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- Metastatic CSCC (Group 1) I Median PFS by ICR was 18.4 months (95% CI: 7.3-not evaluable) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 S 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 8 10121416182022242628 Months Number at risk 59 43 39 36 32 26 26 26 25 18 15 10 1 0 0 Median DOR not reached 0 2 4 6 8 101214161820222426 28 Months Number at risk 59 56 52 49 47 47 46 41 39 32 24 14 6 1 0 | Locally Advanced CSCC (Group 2)2 | Median PFS NR K-M Estimated PFS at 12 months 58.1% (95% CI: 43.7-70.0) Median OS NR K-M Estimated OS at 12 months 93.2% (95% CI: 84.4-97.1) Median DOR 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 inte^al; CSCC, cutaneous squamous cell carcinoma; ICR, independent central review; OS, overall suraval; PFS, progression-free surnval; 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]. Treatment-emergent Adverse Events (TEAEs), Regardless of Attribution, in Patients with Advanced CSCC Group 1 Metastatic CSCC (N=59)1 Group 2 Locally advanced CSCC (N=78)2 Overall (N=137)3 Any grade Grade >3 I Any grade Grade >3 Any grade Grade >3 Any 59 (100.0) 30 (50.8) 78 (100.0) 34 (43.6) 137 (100.0) 64 (46.7) Serious 24 (40.7) 20 (33.9) 23 (29.5) 19 (24.4) 47 (34.3) 39 (28.5) Led to discontinuation 6 (10.2) 4 (6.8) 6 (7.7) 5 (6.4) 12 (8.8) 9 (6.6) r ■ Metastatic CSCC (Group 1)1 Grade >3 TEAEs occurring in >1 patient > Cellulitis (n=4; 6.8%) > Pneumonitis (n=3; 5.1%) > Anemia, dyspnea, hypercalcemia, new primary CSCC, pleural effusion, and pneumonia (each n=2; 3.4%) Grade >3 TEAEs leading to treatment discontinuation > Pneumonitis (n=3; 5.1%) > Aseptic meningitis, confusional state, and neck pain (all in the same patient: n=1; 1.7%) Locally advanced CSCC (Group 2)2 Grade >3 TEAEs occurring in >1 patient > Hypertension (n=6; 7.7%) > Pneumonia (n=4; 5.1%) > Hyperglycemia and cellulitis (each n=3; 3.8%) > Breast cancer, fall, hyponatremia, lymphopenia, muscular weakness, pneumonitis, sepsis, and urinary tract infection (each n=2; 2.6%) Grade >3 TEAEs leading to treatment discontinuation > Pneumonitis (n=2; 2.6%) > Encephalitis, hepatitis, increased aspartate aminotransferase, pneumonia, and proctitis (each n=1; 1.3%) Data cut-off date: Sept 20, 2018 (Group 1); Oct 10, 2018 (Group 2) CSCC, cutaneous squamous cell carcinoma; TEAE, treatment-emergent adverse event. 1. Guminskiet al. J Clin Oncol. 2019:37 (suppl; abstr9526) [poster presentation]. 2. Migden MR, et al. J Clin Oncol. 2019:37 (suppl; abstr 6015) [poster presentation]. 3. Data on File, Regeneron Pharmaceuticals Inc. PD 1 antibodies in SCC Beafore treatment After treatment Boradori et al. Br J Dermatol, 2016. 175: 1382-6 Summary • 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 o Onkološki Inštitut Institute of Oncology Ljubljana SKIN TOXICITY OF IMMUNOTHERAPY CASE PRESENTATION 1 st Summer School in medical oncology Vermiglio Lucija, MD Dr. Mesti Tanja, MD PRESENTATION ► B. L., male, 58 years ► History of illness 0 ► PS WHO 1 ► July 2017 - painful mass in the right armpit (1 2x10x9cm) ► Biopsy - Malignant melanoma metastasis ► Primary tumour 0 ► T S-100, normal LDH ► BRAF + ► PET-CT FIRST LINE TREATMENT ► BRAF/MEK inhibitors: vemurafenib 960mg/1 2h/cont + cobimetinib 60mg/day/3weeks ◦ July to Oct 2017 ◦ Tumor size l 50% ► November 201 7 - Axillary lymph node resection. 50% 1 (3x3x3cm), R2 resection, N(9/22) ► December 2017 - BRAF/MEK inhibitors ► January - March 2018, RT TD 60Gy SECOND LINE TREATMENT ► May 201 8 - PD on PET-CT ► Immunotherapy - Pembrolizumab 200 mg ► Palliative RT TD 1 5Gy ► June 2018-the last application ofimmunotherapy Locoregional status June 2018: ► 4x3cm painfull mass in the right armpit, exulcerated, purulent discharge, right arm red, swollen + osteolitic areas in the right humerus, no fracture ► US arm - no DVT ► Amoxycillin + clavulanic acid ► Antibiogram: Aerobic (Enterococcus faecalis, Staphylococcus lugdunensis, Staphylococcus caprae, Corynebacterium simulans) + Anaerobic bacteria (Prevotella bivia, Peptoniphilus harei, Finegoldia magna, Veilonella atypica) ► Vancomycin + Metronidazol + Ciprofloxacin ► Severe generalized epidermolysis bullosa (50 - 60%) ► July 2018 - ICU ► Septicshockand multiorganicfailure SKIN BIOPSY ► Total necrosis of the epidermis - toxic epidermal necrolysis ► Immunofluorescence analysis: IgA mediated Epidermolysis bullosa ► Negative anti BP180 and anti BP230 (pemphigus bullosa) ► Possible anti-P450 pemphigus bullosa or pemphigus bullosa mediated by anti-Plectin Ab Severe or life threatening (grade 3-4) Any of the following ->50% of the skin surface - Generalised -Exfoliative - Ulcerative -Bulous dermatitis - Regular monitoring - Consider antihistamines -Consider topical steroids immunotherapy Moderate (grade2) Pruritic symptoms < 50% skin surface Affecting ADLS/sleep -Increase monitoring -Anti-histamines -Localised rash: Topical steroides based cream, 1% Hydrocortisone cream for face, Betamethasone valerate 0,1% to other sites -Extensive rash: prednisolone 0,5-1 mg/kg 3-7 days (max 60 mg/day) - Withhold treatment < grade 1 f -Omit next dose of immunotherapy - Begin oral corticosteroid therapy, if not commenced already - Monitor daily - Consider referal to dermatology team -Topical emollient Symptoms: PERSIST (>6 days) or WORSEN or RFI APSE -Initiate corticosteroid therapy over 3-6 weeks -Continue immunotherapy Symptoms: PERSIST (>6 days) or WORSEN or REI APSE -Admitt patient -Discontinued immunotherapy permanently -Contact dermatology For advice/biopsy -Commence IV hydration - High dose IV corticosteroid therapy (eg. Methylprednisolone 2mg/kg once/twice) -Regular ob's and fluid balance Amtihistamines -Topixal emollient cream Symptoms: Resolve or Improve to Mild -Discontinue immunotherapy permanently - Initiate corticosteroid taper over >2 months Mild (grade 1) Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana Systemic treatment of ovarian cancer i* Erik Škof 1st Summer School in medical oncology - Standards and open questions Institute of Oncology Ljubljana 6th september 2019 Onkološki Institute inštitut of Oncology Ljubljana Ljubljana Ovarian cancer burden in Europe Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Ovarian cancer - characteristics O Despite many improvements in medicine: — No effective prevention — No effective screening • no proven benefit from many studies — No early detection • no simptoms at early stage Result*: • >75% of patients have advanced stage at diagnosis (IIIC, IV) • 80% of patients have relapse of the disease • 5-year overall survival is only about 40% * Slovenian cancer registry 2016 O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana WHO classification of ovarian cancer (2014) > EPITHELIAL > STROMAL > SEX CORD > GERM CELL TUMORS > MONODERMAL TERATOMA > MESOTHELIAL > SOFT TISSUE > LIMFATIC AND IN MIELOIC > SECONDARY (METASTATIC) MANY COMBINATIONS POSSIBLE - MORE THAN 80 HISTOLOGY TYPES! | Epithelial Tumors 90% | Stromal Tumors 7% I Germ Cell Tumors 3% o Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Epithelial ovarian cancer- 5 types WHO 2014 Diagnostic Criteria per Cancer Type TYPE %of total MOLECULAR CHARACTERISTICS OTHER NOTES HGSOC 70% TP53mut, genomic instability STIC precursor, no BOT LGSOC 3.5% KRASmu>, BRAFmu' Mutations more common in SBOT CCC 10% ARIDla™1, PIK3CA"11", PIK3CAamp 15-30% with endometriosis ENDO igr ARIDla1™1, PIK3CA"1"', EBOT frequency of mutations 10% PTEN LOH, IÎ cateninmut similar to invasive, 15-30% associated with endometriosis ENDO îgr Tp53mui Recategorized as HGSOC Mucinous 3.6% 80%+ KRAS1™' Intestinal type only HGSOC: high-grade serous ovarian cancer, LGSOC: low-grade serous ovarian cancer, CCC: clear cell ovarian cancer, ENDO: endometrial ovarian cancer BRCA - 20+% O Prognosis depends on histology type Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Outcome FIGO Stage 111 Ovarian Cancer (GOG Trials #111, 114, 132, 152, 158, 172) — Serous 199 t,193 Endometrioid 33 133 — Clear cell 15 47 Aliv»D»sdToiaï — Serous 412 980 1,392 Endometrioid 60 106 166 — Clear cell 21 41 62 — Mucinous 6 2S 34 idometrioid Time on study {months) Winter WE 3rd, et al. J Clin Oncol. 2007;25(24):3S21^627. Time on study (months) O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Systemic treatment of epithelial ovarian cancer Treatment guidance by histologic type TYPE % Early stage Histology-specific treatment guidance presentation Bevacizumab Olaparib HT HT * No validated type-specific treatment **High grade reclassified and treated as HGSOC HGSOC: high-grade serous ovarian cancer, LGSOC: low-grade serous ovarian cancer, CCC: clear cell ovarian cancer, ENDO: endometrial ovarian cancer HGSOC 20% Chemotherapy, anti-angiogenic therapy, DNA repair inhibition therapy, radiation LGSOC 30+% *Consensus conference: chemotx or clinical trial CCC 25% ENDO 30% * ** Mucinous ? all *ls advanced stage/metastatic ovarian? r/o 61 source m 4 The Impact of Residual Tumor: What Is Optimal Debulking? (95%CI) 2.52 (2.26;2.81) 1.36 (1.24;1.50) 1-10 mm vs. 0 mm: >10 mm vs. 1-10 mm: log-rank: p < 0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) N = 3126 pts (95%CI) 1-10 mm vs. 0 mm: >10 mm vs. 1-10 mm: log-rank: p < 0.0001 2.70 (2.37; 3.07) 1.34 (1.21; 1.49) DuBois, Cancer (2009)115:1234 /^y Onkoloski i j Institut V^/ Ljubljana Institute of Oncology Ljubljana Ovarian cancer: primary systemic treatment • Postoperative (adjuvant) — goal is cure (stage I-III) — goal is life prolongation (stage IV) • Preoperative (neoadjuvant) — goal is radical debulking at interval surgery - cure? • Paliative ; — goal is decrease disease symptomes — goal is improvement of QoL o Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Ovarian cancer: primary systemic treatment Chemotherapy — platinum + taxane • majority of patients (except stage IA, grade I) First-Line Treatment of Advanced Ovarian Cancer Cisplatin+ Ciklofosfamid: OS 24 months. J^ + 14 mon Cisplatin+ Paklitaksel: Karboplatin + Paklitaksel: - standard - all histology types OS 38 months. OS similar less toxic better QoL O Onkološki Institute Inštitut of Oncology Ljubljana L|ubl|ana Ovarian cancer: primary sistemic treatment Bevacizumab Recombinant humanised monoclonal anti-VEGF antibody developed from the mice anti-VEGF antibody (MAb A4.6.1) — 93% of antibody has human origin — Recognises all human isomorphes of human VEGF molecule — Blood half-time is 21 days VEGF = vascular endothelial growth factor MAb = monoclonal antibody Presta LG, et al. Cancer Res 1997;57:4593-9 O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Ovarian cancer: primary systemictreatment Bevacizumab-mechanism ofaction Early effect Late effect Inhibition ofnewblood vessels growth and dissapperance ofalready formed blood vessels 1'2,3. Normalisation of remaining tumor vessels offers effective delivery of citotoxic drugs to the tumor cells1,4,5. Inhibition ofde-nuovo tumor blood vessels leads to tumor shrinkage 2,3,4 It X 1. Willetet al. Nat Med 2004; 2. Baluk, et al. CurrOpinGenet Dev 2005; 3. Ina m J Pathol 2004; 4. Gerber, et al. Cancer Res 2005;5. Jain, et al. Scier o Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Ovarian cancer: primary systemic treatment The role of bevacizumab n, he 10 iholahp to'jl i'al -/medici hi oaratkal jkfjtcle GOG-218 Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer Burger RA, et al. N Engl J Med. 2011 ; 365(26):2473J483. RitMltA eurg«. M D. MtrllF Brad?. f»ll 0 .MHIt-WiA BSttoTr^kM.i;-, glnl f ftirtilng, m □ . emdtaf j mmfc. m d . Hflten hutr^. m s . Hctwrr 5 ivi^nrrd, M n . Hotmrtl r* Hflmeslqf, m D .jefirey Foviio. m f). ftmjamln E Grasr M 0 , l/itthew Eonntj. M.o'. MiduJ.!- Bi-nn M.D. Ph D . i ShiX >1- M " "r tht^^il^oT^^On^^r^iMP* fh. Hiw EMJUJEI XGriSLHftL C hflEDlCIlfB ÖR10IWA.L JkaTtCLB A Phase 3 Trtal of Bevacizumab in Ovar ¡an Cancer Tlmsthy 1 Pirrtn, M Ann Marl» Swit, Wl.ö Jüotut PfUt«»r, M.D , Jiin»lh»n A ImWiinn, M D , Eile Lnirami, M n, fiunnw ttutarnm. M D, Mark S Caaf. MD. Philip Beaio. IV) Andjit Cervantes. M.C\. Christian IGiriidrfr, M D, Afidr^i du M.p , J 4 Ii ii 5rfifinj1|, M D , iilristFlmmlftM D , AnIMftthLt, M D.. Flena CelLlniWI. M.D, ShiTfldih £bi(w. m b, Chirll» Courier. M C?, Main Lsrttialarr, tvl D , FridÄit Salle, M.ü , MantcCT R. Miria.M.c . Arto Lemman, M.f , Murin Ojllt«, M D.. Csn Stark, M D, Wnndl Ql. M. D.,ror tha ICOM/ Invastiirtorr* ICON-7 L ■ Peiren TJ, et al. N Engl J Med. 2011 ; 365(26) :2484-2496. O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Ovarian cancer: primary sistemic treatment The role of bevacizumab: GOG-218: Schema Maintenance 15 months (16 cycles) ICON71AGO-OVAR 11: Study Design jI Caifcoplatiii AUC 5 or ( j J Paclitaxel 175 mg/n2 II Caitoplaän AUC 5 or S* j j PaclitMEl 175 mg/m2 Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana Ovarian cancer: primary systemic treatment The role of bevacizumab - prolongs PFS ICON 7 Updated PFS 2011 PFS - progression-free survival Onkološki Institute inštitut of Oncology Ljubljana Ljubljana Ovarian cancer: primary systemic treatment The role of bevacizumab o The role of neoadjuvant chemotherapy Onkološki Institute inštitut of Oncology Ljubljana Ljubljana - definition of operable/inoperable disease? Role of Radical Surgery and Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: Report on the Consensus Paper Gynecologic Oncology Ciinicdl Commentary Neoadjuvant chemotherapy in advanced ovarian cancer: On what do we agree and disagree? Ve roerte I, du Bois A, et al. Gynecol Oncol. 2013:128(1)6-11 O The role of neoadjuvant chemotherapy - two randomised studies: no difference in OS Onkološki Institute inštitut of Oncology Ljubljana Ljubljana CHORUS Overall Survival d i ú j ¡i 11 * i t! y à Ü h iS d « # MrOnl "■»«i-irç ht Ib i» la i)! q t h -tí i i itTuiilniidnjh ]:i :n i« iíi n; 3! ■i il hoe S, et al. Lancet 2015 J» NACT + IDS vs PDS: ITT Overall Survival Criticism: - poor surgery in both studies - only 20% of pts had radical primary debulking o Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana The role of intraperitoneal chemotherapy-1 Effective but toxic Intraperitoneal Therapy Improves OS, But Toxicity Is Increased Meta-analysis shows OS benefit of intrap (HR = 0.80; 95% CI: 0.70-0.91 eritoneal chemotherapy P =.0007)1 Study name HR HR an< 95% CI Taipei t.130 . • However, use is limited by delivery issues and toxicity • In GOG-0172, only 42% of patients r intraperitoneal chemotherapy2 eceived all 6 cycles of Criticism: - old i.v. chemotherapy used, - inapropriate doses of i.v. chemotherapy,... O Onkološki Institute inštitut of Oncology Ljubljana Ljubljana The role of intraperitoneal chemotherapy-2 GOG Protocol 252: Stage ll/lll Disease: Small Volume Residual Epithelial Ovarian Cancer Optimal Stage III __ No prior therapy • Phase III N ■ PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days Cisplatin 75 mg/m i2 (IP d2) III Paclitaxel 135 mg, 'm2 (d1, 3h) Paclitaxel 60 mg/i ti2 (d8, IP) Bevacizumab (C2+ C22) X 21 days GOG Protocol 252: Overall Survival (OS) ITT (All Eligible Patients) Current IV chemotherapy appears at least as effective e modified IP chemotherapy, with median OS exceeding historical data from GOGD172 Conclusions: Up-to date i.v. chemotherapy with bevacizumab is: - as effective as i.p. cht (the same OS) - less toxic - In EU intraperitonal cht is experimental only treatment Onkološki Inštitut _ Ljubljana Systemic treatment of relapsed ovarian cancer O Institute of Oncology Ljubljana When to treat relapsed disease? EORTC 55955 - CA 125 elevation vs. Clinical/radiologic relapse 1.00 > 0.75 - > Abs diff at 2 yrs: -0.1% (95% CI diff: -6.8, 6.3%) Early Delayed 0.50 - o t HR: 1.00 (95% CI: 0.82-1.22; P = .98) 12 18 24 30 36 42 Mos Since Randomization 48 54 Patients at Risk, n Early 265 247 211 165 131 94 Delayed 264 236 203 167 129 103 72 69 51 53 38 38 31 31 60 22 19 Rustin G, et al. ASCO 2009. 0 0 6 /"V Onkološki Institute i j Inštitut of Oncology V^/ Ljubljana Ljubljana Systemic treatment of relapsed ovarian cancer: Predictive and prognostic factors that influence the treatment selection: Disease related: Patient related:  • Platinum-free interval • Response to prior chemotherapy • Histology type • Molecular (BRCA) • Simptoms • Performens status • Age • Side effects • Comorbidities • Patient wishes (hair, etc.) Onkološki Inštitut . r . . — Ljubljana Systemic treatment of relapsed ovarian cancer: O Institute of Oncology Ljubljana Resistance to platinum (PFI<6 months) Non-platinum cht - monotherapy -ORR: 10-30% - OS: <12 months PLD - Docetaxel - Etoposide (oral) - Gemcitabine - Topotecan - Paclitaxel (weekly) - bevacizumab Partial sensitivity to platinum (PFI 6-12 months) Cht - platinum comb. •ORR: 30-60%% • PFS : 7 months • OS: 23 months Pakli + Karbo PLD + Karbo Gem + Karbo PLD + trabektidin olaparib bevacizumab w Full sensitivity to platinum (PFI>12 months) Surgery Cht - platinum comb. -ORR: 60+% -OS: 30+ months > Pakli + Karbo PLD + Karbo Gem + Karbo > Olaparib > bevacizumab ORR - objective response rate; PFS - progression-free survival, OS - overall survival O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana Systemic treatment of relapsed ovarian cancer Bevacizumab PFI<6 mes: pF|>6mes: AURELIA: prolongs PFS for 3 months OCEANS: pr°longs PFS for 4 months FS - progression-free survival OS - overall survival No benefit in OS o Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana Systemic treatment of relapsed ovarian cancer Olaparib - PARP* inhibitor INHIBITS SINGLE-STRAND DNA REPAIR Single-strand breaks Duble-strand breaks Olaparib Base excision l Repair (BER) Homologous recombination (HR) * polyADP ribose polymerase In base excision repair (BER), a damaged base is excised resulting in the formation of a single-strand break, which is enzymatically repaired. Two principal mechanisms are used in the repair of double-strand breaks: homologous recombination (HR) and non-homologous end joining (NHEJ) BRCA 1/2 mutation Jackson SP and Bartek J. Nature 2009;461:1071-1078 O PARP inhibition in preexisting HR deficit: Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana Olaparib - the princip of synthetic lethality -aw. PARP - polyADP ribose polymerase; HR -homologous recombination Synthetic lethality Synthetic lethality is the term used when defects in two pathways lead to cell death, while a defect in either of the individual pathways is not deleterious2 PARP inhibition impairs the repair of singlestrand breaks1 Single-strand breaks lead to replication fork collapse and the occurrence of doublestrand DNA breaks during DNA replication2 HR mechanism repairs double-strand DNA breaks 1. Jackson SP and Bartek J. Nature 2009;461:1071-1078; 2. De Lorenzo SB et al. Front Oncol 2013;3:228; o Systemic treatment of relapsed ovarian cancer Onkološki Inštitut L]ubl|ana Institute of Oncology Ljubljana Olaparib maintenance treatment improves PFS in patients with platinum sensitive SSSSSSti. Study 19 relapsed ovarian cancer13 reached) solo BRCAm Ovarian Cancer Kaplan-Meier estimate of investigator-assessed PFS rrm 5 5 a a a i a a î ? Î ! ž i ! • ^^^PFS = progression-free survival; CR = complete response; PR = partial response; po = per oral; bid = twice a day; HR = hazard ratio; CI = confidence interval ^^^^^^^^TfcEngl J Med. 2012;366(15):1382-1392; 2. Gourley C, et al. J Clin Oncol 2017;35(suppl); poster related to abstr 5533; 3. Pujade- ■017 Sep;18(9):1274-1284 Onkološki Institute Inštitut of Oncology L]ubl|ana Ljubljana Ovarian cancer: Slovenia O • Since 2014: - All patients with HGS* cancer of ovaries, fallopian tubes or PPSC are offered to perform germline BRCA genetic testing at diagnosis (or at relapse) - The aim of BRCA genetic testing is treatment with olaparib (not just prevention of breast and ovarian cancer) - Active searching for BRCA+ patients (confidential data) Since 2019: - All patients with HGS* cancer of ovaries have somatic BRCA testing at diagnosis HGS* - high-grade serous ZhangS, etal. Gynecol Oncol. 2011;121(2 Latest Highlight in ESMO 2G18 O Onkološki Institute Inštitut of Oncology Ljubljana Ljubljana SOLO-1 - Phase III trial to investigate maintenance therapy with olaparib in newly diagnosed BRCAm ovarian cancer SOLO-1 is a global randomised multicentre placebo controlled Phase HI study Newly diagnosed, FIGO stage III-IV, high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer Germline or somatic BRCAm ECOG performance status 0-1 Cytoreductive surgery* In clinical complete response or partial response after platinum-based chemotherapy Olaparib 300 mg bid (N=260) 2:1 randomisation Stratified by response to platinum-based chemotherapy Study treatment continued until disease progression Patients with no evidence of disease at 2 years stopped treatment Patients with a partial response at 2 years could continue treatment 2 years' treatment if no evidence of disease Primary endpoint Investigator-assessed PFS (modified RECIST 1.1) Secondary endpoints PFS using BICR PFS2 Overall survival Time from randomisation to first subsequent therapy or death Time from randomisation to second subsequent therapy or death HRQoL (FACT-O TOI score) r interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV disi nt central review; ECOG = Eastern Cooperative Oncology Group, FACT-O = Functional Assessment of Cancer Therapy - Ovarian Cancer, FIGO = ogy and Obstetrics, HRQoL = health-related quality of life, PFS = progression-free survival, PFS2 = time to second progression or death, RECIST = id Tumours, TOI = Trial Outcome Index PARP = poly(ADP-ribose) polymerase, BRCAm = BRCA gene mutation 'ct2/showiNCT01844986 (accessed October 2018) Placebo (N=131) Onkološki Inštitut Ljubljana Institute of Oncology Ljubljana Systemic treatment of ovarian cancer SOLO 1: Olaparib reduced the risk of progression or death by 70% vs. placebo1 After a median follow-up of 41 months, the median PFS had not been reached in the olaparib arm (vs. 13.8 months in the placebo arm)1 60.4% progression free at 3 years a 10 0 Olaparib Olaparib Placebo Events, N (%) 102 (39.2) 96 (73.3) Median PFS (months) NR 13.8 HR=0.30 95% CI: G.23, G.41 p 25%) neutropenia, QT prolongation, bradycardia, cardiac failure, GIT perforation, renal impairment CGritinib [+ ROSI) nausea, vomiting, diarrhea, constipation, fatigue, | appetite, | weight, abdominal pair, hepatotoxicity, f creatinine, rash, anemia, esophageal disorder (> 10%) QT prolongation, bradycardia, hyperglycemia, T amylase and lipase alectinib 1« RET) generation ALK TKI constipation, edema, myalgia [> 20%) hepatotoxicity, ^ CPK, bradycardia, photosensitivity brigatinib [+ ROSI) ^ glucose, insulin, CPK, lipase, amylase, AP, aPTT, 4- lymphocytes, phosphate, leucocytes, anemia, nausea, diarrhea, fatigue, cough, headache, rash, vomiting, dyspnea, hypertension, myalgia, peripheral neuropathy (> 25%) bradycardia visual disturbance lorlatinib [+ ROSI) 3rd generation ALK TKI hyperlipidemia, peripheral neuropathy, cognitive effects, edema, fatigue, weight increase, diarrhea, arthralgia (> 20%) | amylase, lipase, AV block, LVEF decrease anti VEGFR tyrosine kinase inhibitors Compound Specific toxicity sunitinb pazopanib axitinib tivozanib cabozanitib sorafenib regorafenib thyroid dysfunction, dysphoria, palmar-plantar erythrodysaesthesia syndrome thromboembolism, hypertension, cardiac failure, Q.T prolongation hemorrhages, GIT perforation/fistulas, impaired wound healing liver toxicity, proteinuria, fatigue, taste disorder Take home message • Toxicity varies between patients. • Beware of drug interactions! • During its management patients may be referred to doctors of other specialities. • Low grade toxicity importantly influence the quality of life of patients. IMMUNE-RELATED ADVERSE EVENTS OF IMMUNE CHECKPOINT INHIBITORS Nezka Hribernik, MD Martina Rebersek, MD, PhD Institute of Oncology Ljubljana 1st Summer School in Medical Oncology September 2019 Characteristics of irAE • They are reversible if treated promptly • If left untreated they progress to more severe state • If treated early, severity and duration decreases • Any organ can be affected • Average 6 -12 weeks after initiation of therapy • Can occur — Within days of the first dose — After several months of therapy — After discontinuation of therapy Pre-treatment evaluation and diagnostic tests to consider • WHO PS • History — Detailed questioning for autoimmune, infectious disease, endocrine and organ-specific disease history (NOT contraindication, but should be well controlled!) — History of base line bowel habit (frequency of bowel movements, usual stool consistency) • Blood tests: - CBC, CMP, TSH/T3/T4, HbAlc, total CK - Infectious disease screen: HBsAg/sAb/cAb,HCAb, CMV Ab, HIV Ab/Ag p24 • Dermatologic examination • Pulmonary test (SaO2), cardiac tests (ECG, Trop I/T ) • Additional screening tests recommended in patients with pre-existing organ disease/at risk of organ-specific toxicity (8 am ACTH, cortisol, NT pro-BNP, 6MWT ...) General approach to management of irAEs Grade Management ICI Notes 1 Supportive measures Close monitoring Continue (exept some: pneumonitis/ neurological/ cardias irAEs) Outpatient 2 Corticosteroids Immediate vs delayed Withhold ICI (continued once AEs < G1) Outpatient with close team contact or inpatient 3 Immediate corticosteroids and additional IMA if required Withhold or discontinue ICI Inpatient (except some: skin/ hepatitis) 4 Immediate corticosteroids With early use of additional IMA Discontinue ICI Inpatient Consider transfer to experienced centre! Puzanov I, et al. J Immunother Canc 2017; L Spain ESMO 2018 • Development of irAE is not required for ICIs benefit; some irAE (e.g., vitiligo) may be more clearly associated with ICIs efficacy. • The clinical outcome of patients on ICIs is not affected by the use of immunosuppressive agents or the management of irAE. • Reintroducing ICIs should be made on an individual basis, taking into account the clinical setting and specific clinical need of each patient (severity of initial irAE, age). • Age alone should not be used to exclude patients from treatment, benefit appears to be similar regardless of age. TAKE-HOME MESSAGES! • MULTIDISCIPLINARY APPROACH — Baseline assessment — Ongoing assessment — PATIENT & PHYSICIAN EDUCATION — Management protocols — Collaboration with emergency departments, GPs, specialists, visiting nurses!! • AWARENESS IS NEEDED AMONG CLINICIANS ACROSS DISCIPLINES GIVEN THE INCREASE IN USE OF THESE AGENTS. APENDIX: Dr. Dobrila: Systemic treatment of metastatic gastric cancer (Tuesday 03.09.) Dr. Plestina: Systemic treatment of metastatic colorectal cancer (Tuesday 03.09.) Dr. Skrbinc: Systemic treatment of germinal tumors (Wednesday 04.09.) Systemic treatment in advanced gastric cancer Prof. Renata Dobrila-Dintinjana, MD.PhD. Clinical Hospital Center, Rijeka School of Medicine, Rijeka Croatia Advanced Gastric Cancer Locally advanced OS: 11 months Resectability (Same survival of initially resectable patients) A 3-drug regimen (tumor response) Metastatic OS: 3 months Palliation QoL; Survival A 2-drug regimen (no toxic regimen) Cascinu S, et al. Br J Cancer 2004. Locally advanced disease: 1. The most active regimen ? 2. The role of surgery? Triplet vs doublet: Better Response 40/50% vs 20/30% Which regimen? FLOT pCR FLOT 16% ECX 11% CDDP/5FU 3% High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxonjbicin, 6S-leucOVOrin, glutathione, and filgastrim in patients will iocdiiy advanced, Unresectable gastric canccn a report Dm the Italian Group for the Study of Digestive vie I. Cancer (GISCAD) Cascinu S, et al. Br J Cancer 2004. Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets • NO biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab andpembrolizumab...... • Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Subtypes Targets Targeted Agents EBV PIK3CA Idelalisib, Taselisib PD-L1/L2 Pembrolizumab, Nivolumab, Durvalumab, Avelumab, Atezolizumab MSI MLH1 silencing Pembrolizumab, Nivolumab, Durvalumab, Avelumab, Atezolizumab PIK3CA, Idelalisib, Taselisib EGFR Erlotinib, Gefitinib ERBB2 Trastuzumab ERBB3 Pertuzumab PD-L1 Pembrolizumab, Nivolumab, Durvalumab, Avelumab, Atezolizumab CIN EGFR Erlotinib, Gefitinib VEGFA Bevacizumab, Ramucirumab CCNE1, CCND1, CDK6 Palbociclib, Ribociclib, Abemaciclib GS RHOA - CLDN18 - Lionel Kankeu Fonkoua 1 and Nelson S Yee 2, "Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets. Biomedicines 2018, 6, 32; doi 10.3390/biomedicines6010032w iww.mdpi.com/ioumal/biomedicines Proposed treatment algoritm (Salati et al. ESMO Open 2017;2:e000206. doi:10.1136/esmoopen-2017-000206) Locally advanced Metastatic 1° line 2° line Triplet (FLOT?) i_ ECOG 0-1 Doublet (folfox) _I ECOG > 2 Good tolerability to first line; no taxanes Poor tolerability to first line; previous taxanes, patient preferences (no alopecia) I 3° line Paclitaxel + Ramucirumab ECOG 0-1; good response and tolerability to 2° line Ramucirumab ECOG 0-1; poor response and tolerability to 2° line O? BSC ECOG > 2 Irinotecan; clinical trials ^^KBC Ik ZAGREB Systemic treatment of metastatic colorectal cancer prof.dr.Stjepko Plestina Department of Oncology UHC Zagreb, Croatia RAS wild type Left-sided ras cancers only wild type RAS wild type 4L therapy, BSC, or clinical trial Other anticancer therapy, BSC, or clinical trial Other anticancer therapy, BSC, or clinical trial Anti-VEGF ■ Anti-EGFR Bevacizumab Cetuximab Panitumumab Other anticancer therapy, BSC, or clinical trial van Cutsem. Ann Oncol. 2016;27:1386. RAS mutation RAS wild type Left-sided ras cancers only wild type RAS wild type 4L therapy, BSC, or clinical trial Other anticancer therapy, BSC, or clinical trial Other anticancer therapy, BSC, or clinical trial Anti-VEGF ■ Anti-EGFR Bevacizumab Cetuximab Ramucirumab Panitumumab Ziv-aflibercept Other anticancer therapy, BSC, or clinical trial van Cutsem. Ann Oncol. 2016;27:1386. 1L 2L 3L 4L Anti-VEGF ■ Anti-EGFR RAS mutation RAS wild type Regorafenib or TAS-102 therapy, BSC, or clinical trial Other anticancer therapy, BSC, or clinical trial Left-sided RAS cancers only wild type RAS wild type Bevacizumab Cetuximab Ramucirumab Panitumumab Ziv-aflibercept Other anticancer therapy, BSC, or clinical trial van Cutsem. Ann Oncol. 2016;27:1386. • A wealth of evidence indicates that primary tumour location is prognostic • Patients with left-sided tumours have longer survival outcomes than patients with right-sided tumours • The prognostic value appears independent of chemotherapy backbone • Genetic differences between right- and left-sided tumours may account for some of the prognostic effect • Right-sided primary tumours occur more frequently with increasing age and are more likely to have concomitant genetic features associated with poor outcomes: BRAF MT, MSI-H, and increased methylation • Both clinical trial and real-world data suggest that bevacizumab provides clinical benefit regardless of primary tumour location • The totality of data suggests that cetuximab and panitumumab have efficacy in left-sided CRC, but EGFR inhibitors are not equaly beneficial to patients with right-sided primary tumours • The NCCN guidelines draw the same conclusion that bevacizumab works regardless of tumour location whereas anti-EGFRs are only effective in left-sided tumours: "only patients whose primary tumours originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease" REKONI© Overview of CMS Predictive Data in mCRC CMS1 > OS with CALGBS0405 1st line RAS wild-type RCT(n=392) FOLFOX-cetuximab vs. FOLFOX bevacizumab FOLFOX-bevacizumab, CMS2 > OS with FOLFOX-cetuximab Almac Xcell FFPE FIRE-3 1st line RAS wild-type RCT (n=385) FOLFIRI-cetuximab vs. FOLFIRI bevacizumab CMS4 > OS with FOLFIRI-cetuximab Custom Nanostring FFPE CAPOX-bevacizumab vs. CMS2/CMS3 > OS with CAIR02 1st line all-comers RCT (n=311) CAPOX-bevacizumab-cetuximab cetuximab {.RAS/BRAF wt) IHC FFPE MAX 1st line all-comers RCT(n=237) Capecitabine +/-mitomycin +/-bevacizumab CMS2/CMS3 > PFS with bevacizumab Almac Xcell FFPE Japan 1st line all-comers Retrospective (n=193) Oxaliplatin vs. Irinotecan CMS4 > PFS and OS with Irinotecan Agilent FF CORRECT 3rd line all-comers RCT (n=) Regorafenlb vs placebo CMS4 > OS with Regorafenib Afflmetrix Array FFPE FFPE, Formalin-Fixed Paraff in-Embedded; IHCimmunohistochemistry; OS, overall survival; PFS, progression-free survival; RCT, randomized clinical trial. StintzingS, et al. J Clin Oncol. 2017;35(suppl; abstr3510); Lenz HJ, et al. J Clin Oncol. 2017;35(suppl; abstr3511); Okita A, et al. Oncotarget. 2018;9:18698-18711; Teufel M, et al. J Clin Oncol. 2015;33(suppl; abstr3558). Current Treatment Paradigms in Metastatic Colorectal Cancer • Better, but still pure prognosis • Some patients with "limited" stage IV disease can be cured by an interdisciplinary approach • Addition of biologics to chemotherapy has improved outcomes, but to a more limited extent than hoped • Identification of molecular predictive factors is improving potential for individualized therapy • Attempts are under way to expand the role of immunotherapy beyond treating patients with microsatellite instability-high CRC mCRC - Multidisciplinary Therapeutic Decision Tumor characteristics Patient characteristics Histopathology Previous treatment w Patient preference Goals of therapy Biomarkers Team Work ESMO 2017 GUIDELINES Fit patients Unfit | Category May be unfit Unfit 1 Treatm ent goal Cytoreduction (tumor shrinkage) Disease control (control of progression) Palliation Molecular profile RAS WT RAS MT BRAF MT RAS WT RAS MT BRAFMT Any Any First line Preferred choice(s) ChT doublet + EGFR antibody ChT doublet + bevacizumab FOLFOXIRI + bevacizumab ChT doublet + bevacizumab or doublet + EGFR antibody ChT ChT doublet + bevacizumab FOLFOXIRI +/-bevacizumab FP + bevacizumab BSC Second choice(s) FOLFOXIRI +/-bevacizumab FOLFOXIRI +/-bevacizumab ChT doublet + bevacizumab FP + bevacizumab ChT doublet + bevacizumab Reduced-dose ChT doublet - Third choice(s) ChT doublet + bevacizumab FOLFOXIRI FOLFOXIRI If RAS WT may consider EGFR antibody therapy - Maintenance Preferred choice FP + bevacizumab FP + bevacizumab FP + bevacizumab FP + bevacizumab FP + bevacizumab FP + bevacizumab FP + bevacizumab Second choice Pause Pause Pause Pause Pause Pause FP - Second line Preferred choice(s) ChT doublet + bevacizumab ChT doublet + bevacizumab ChT doublet + bevacizumab ChT doublet + bevacizumab or doublet + EGFR antibody ChT ChT doublet + bevacizumab ChT doublet + bevacizumab - Second choice(s) ChT doublet + EGFR antibody or FOLFIRI + aflibercept/ramucirui mab FOLFIRI + aflibercept/ ramucirumab FOLFIRI + aflibercept/ ramucirumab FOLFIRI + aflibercept/ramucir umab FOLFIRI + aflibercept/ ramucirumab FOLFIRI + aflibercept/ramucirumab - Third line Preferred choice(s) ChT doublet + EGFR antibody or irinotecan + cetuximab Regorafenib or trifluridine/tipiracil Regorafenib or trifluridine/tipiracil ChT doublet + EGFR antibody or irinotecan + cetuximab Regorafenib or trifluridine/tipiracil Regorafenib or trifluridine/tipiracil - Second choice(s) EGFR antibody monotherapy EGFR antibody monotherapy - Third choice(s) Regorafenib or trifluridine/tipiracil Regorafenib or trifluridine/tipiracil - 10 O* Onkološki Inštitut > Institute of Oncology Ljubljana Systemic treatment of germ-cell tumors Dr. Breda Škrbinc, dr.med. OI Ljubljana, 4.9.2019 o Fig. 1 | Schematic representation of the types of testicular germ cell tumours https://doi.org/10.1038/s41572-018-0029-0 NATURE REvIEWS | DISEASE PRIMERS (2018) GCT histopathology Testicular cancers are one of the most diverse areas of human pathology GCNIS Seminoma (50 %) Nonseminoma ( 40 % ) Embrional carcinoma Yolk sac tumor Choriocarcinoma Teratoma postpubertal type Mixed germ cell tumors ( 10 % ) Multidisciplinary treatment O Teratoma postpubertal type M. pi II . Belli ,'S - «i^ijSk V ■i O ** > » - ' 3 * C - 0 H- r. J ■ A -v.-^V *-;* Chemoresistant Exclusive treatment modality - radical surgery O Cisplatine based chemotherapy Success story in metastatic GCT treatment 70% of mGCT patients cured with first line ChT 30% mGCT relapsing • up to 70% long term susviviors - one salvage ChT line • up to 25% long term survivors - 2 or more ChT lines 10-15% of primarily advanced and 3-5% of all GCC patients fail established platinum-based standard treatments and potentially die of the disease O C! NH3 • Adjuvant chemotherapy • Chemotherapy for the metastatic disease • Salvage treatment O Radiotherapy versus single-dose carboplatin in adjuvant ^ treatment of stage I seminoma: a randomised trial RTDOIivet, MD Mason, GMMead,U von dellUaase, GJSffljstinJKJoffc fide Wit, N Aass, JDG/aham, i! Coleman, SJKirk, 5 PStennmg,forthe MRCT[19 collaboraton an (¡The EORTC 30982 collaborators* 1477 patients from 70 hospitals in 14 countries randomly assigned to receive: • Radiotherapy (para-aortic strip or dog-leg field) or • one injection of carboplatin dose based on the formula: 7 X [glomerular filtration rate X 25] mg The primary outcome measure - the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. o 1-0-1 0-9- 08- — Radiotherapy f 0-7- — Carboplatin g 0-6- O S- S' °'4- £ o-j- 0-2- 0-1- 12 24 36 48 60 72 ¿A Months from randomisation Numbersatnsfc Radiotherapy 904 873 823 &94 448 309 4S 12 LarboplaLin 57 3 552 523 425 288 124 31 6 figure 3: Relapse-flit rate by allocated treatment Patients' diary card data Comparison between radiotherapy and carboplatin treatment At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were : O^ -1-0% (90% CI -2-5 to 0^5) by direct comparison of proportions • 0-9% (-0-5 to 3-0) by a hazard-ratio-based approach. • Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. o Risk factors • Tu size (no deffinite cut off value) • Stromal invasion in rete testis • 12% RR - no RF • 16% RR -either of two RF • 32% RR - both RF Both RF should be considere O 8. Who should be offered adjuvant chemotherapy? Seminoma. In clinical stage I seminoma, several studies have found a low risk of relapse {^3%J in patients without RFs ¡87, 88, 93]. In these patients, adjuvant chemotherapy will therefore result in over-treatment in ^95% of cases. In patients with a higher risk of relapse, adjuvant chemotherapy remains an option. Adjuvant carboplatin reduces the risk of relapse by '--'60% [93], which provides a number-needed-to-treat (NNT) value in the range of 15-20 to prevent one relapse. Recommendation 8.1: Patients with seminoma and a low risk of relapse should not be offered adjuvant chemotherapy. Le^UM'MdkL'! Ill- Strength of recommendation: C Level of consensus: 91% (30) yes, 6% (2) no, 3% (1) abstain (33 voters) Recommendation 8.2: In patients with seminoma and a higher risk of relapse, surveillance or adjuvant carboplatin are options. Lu'lJ ufu idlilLL. Ill Strength of recommendation: C Level of consensus: 91% (30) yes, (33 voters) (2) no, 3% (1) abstain Recommendation 8.3: In patients with seminoma, patient autonomy should be taken into account following thorough provision of information regarding the pros and cons of the alternative TrrrrwirwTO^r Level of evidence: III Strength ofrecom men dation: C Level of consensus: 91% (30) yes, (33 voters) (2) no, 3% (1) abstain Lymphovascular invasion validated RF O ® Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell | Tumors: Results of a Prospective j* Multicentric Study r. Klaus-Peter Dieckmann, Prof12; Arlo Radtke, PhD3; Lajos Geczi, MD, PhD4; Cord Matthies, MD5; Petra Anheuser, MD2; r+ Ulrike Eckardt, MD6; Jörg Sommer, MD7; Friedemann Zengerling, MD8; Emanuela Trenti, MD9; Renate Pichler, PhD10; Hanjo Beiz, MD11; Stefan Zastrow, MD12; Alexander Winter, MD13; Sebastian Melchior, Prof14; Johannes Hammel, MD14; Jennifer Kranz, MD15; Marius Bolten, MD16; Susanne Krege, Prof17; Björn Haben, MD18; Wolfgang Loidl, MD19; Christian Guido Ruf, MD20; Julia Heinzelbecker, MD21; Axel Heidenreich, Prof22; Jann Frederik Cremers, MD23; Christoph Oing, MD24; Thomas Hermanns, MD25; Christian Daniel Fankhauser, MD25; Silke Gillessen, MD26; Hermann Reichegger, MD25; Richard Cathomas, MD27; Martin Pichler, Prof28; Marcus Hentrich, MD29; Klaus Eredics, MD30; Anja Lorch, Prof31; Christian Wülfing, Prof1; Sven Peine, MD24; Werner Wosniok, PhD3; Carsten Bokemeyer, Prof24; and Gazanfer Beige, PhD3 miR-371a-3p outperforms the classical biomarkers and represents a highly sensitive and specific new iomarkerfor TGCC J Clin Oncol 2019 CI/, ,,NH3 of ^nh3 Jfe • Adjuvant chemotherapy • Chemotherapy for the metastatic disease • Salvage treatment o EUROPEAN UROLOGY 6 8 ( 2 0 1 5 ) 1 0 5 4 -1 0 6 8 Printed D} grata strafte w 9>?3CI3 1:22:53 sv. For aeso-isl use only. Not äfprcued ftf «KiDuilOT. Copyrighto 2C1S Nattial Carrererenslve Cancsr Newort, inc.. All Rjghs RawvM. I National Comprehensive Cancer I Network* NCCN Guidelines Version 1.2019 Testicular Cancer NCCN Guidelines Index Table of Contents Discussion RISK CLASSIFICATION FOR ADVANCED DISEASE (postorchiectomy)3 Risk Status Nonseminoma Seminoma Good Risk Testicular or retroperitoneal primary tumor and No nonpulmonary visceral metastases and Post-orchiectomv markers- ail of: AFP < 1.000 nstfmL ftCG < 5,000 iu/L LDH < 1.5 k upper limit of normal Any primary site and No nonpulmonary visceral metastases and Normal AFP Any hCG Any LDH Intermediate Risk Testicular or retroperitoneal primary tumor and No nonpulmonary visceral metastases and Post-orchiectomv markers- anv of: AFP 1,000-10,000 ng/mL hCG 5.000-50.900 iu/L LDH 1.5-10 x upper limit of normal Any primary site and Nonpulmonary visceral metastases and Normal AFP Any hCG Any LDH Poor Risk Mediastinal primary tumor or Nonpulmonary visceral metastases or Post-orehiftctnmy markers- any of: AFP > 10.000 ng/mL TiCG > 50.000 iu/L LDH > 10 x upper limit of normal No patients classified as poor prognosis Source: Figure 4 from the International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: A Prognostic Factor-Based Staging System for Metastatic Germ Cell Cancers. J Clin Oncol 1997; 15(2):594-603- Reprinted with permission of the American Society of Clinical Oncology TabLe 11 Serum AFP and hCC Levels in GCTs" CCT histological subtype AFP hCC Yotk sac tumour ++ Seminoma - ± Embryonal carcinoma ± ± Choriocarcinoma - ++ Teratoma ± AFP, a-tetoprotein;GCT, germ ceil tumour; hCC, human chorionic gonadotroph^. ++,strongly positive levels;±, levels may be negative or moderately positive; —, negative levels. 0» NATURE REVIEWS | UROLOGY VOLUME 13 | DECEMBER 2016 Table 2. Chemotherapy regimens in metastatic seminoma and non-seminoma O BEP Cisplatin Etoposide Bleomvcin EPb CispJatin Etoposide ViP/PEr Ci splat in Etoposide Ifosfamide TIP" Paclitaxel CispJatin Ifosfamide VelP® Vinblastine Ifosfamide Pinlntin TI-CEf Paclitaxel Ifosfamide Car bop Latin Etoposide CE8 Carboplalin Etoposide (Repeat cycles 20 mg/m" 100 mg/m* 30 mg (Repeat cycles 20 mg/m2 100 mg/m" evety3 weeks) Day l-Day I Day I, every 3 weeks) Day l-Day I- ■5 5 8,15 (Repeat cycles 20 mg/m" 75 mg/m" every 3 weeks) Day l-Day 1- (Repeat cycles 250 mg/m" 25 mg/m2 l-5g (Repeat cycles 0.11 mg/kg 1.2 g/m2 ?n mpfnr every 3 weeks) Day 1 Day 2-5 Day 2-5 every 3 weeks) Day I +1 Day 1-5 fhTY hi (T1 cycles 1-2 every 2 weeks) 200 mg/m2 Day 1 2.0 g Day 2-4 (CE cycles 3-5 every 3 weeks) AUC = 7 Day 1-3 400 mg/m2 Day 1-3 (Two cycles, may be preceded by VelP) 700 mg/m2 Day 1 750 mg/m2 Day 1-3 Annals of Oncology 24 (Supplement 6): vï125-vï132, 2013 C! NH3 Jfe • Adjuvant chemotherapy • Chemotherapy for the metastatic disease • Salvage treatment O Multidisciplinary treatment Treatment For Testicular Cancer o Late relapse of mGCT recurrent GCT more than 2 years from completion of initial chemotherapy in the absence of a second gonadal primary tumor evidence of new lesions, or sequentially increasing serum tumour markers (AFP or HCG), more than 2 years after >3 cycles of cisplatin-based chemotherapy Table 2. Chemotherapy regimens in metastatic seminoma and non-seminoina BEP" Ci splat in Etoposide Bleomycin EPb Ci splat in Etoposide VIP/PEI" Ci splat in Etoposide TIP Paclitaxel Cisplatin Ifosfamide Vinblastine Ifosf amide Pinlnrm o TI-CEf Paclitaxel Ifosfamide Carboplatin Etoposide CE8 Carboplatin Etoposide (Repeat cycles every 3 weeks) 20 mg/m" Day 1-5 100 mg/rcr Day 1-5 30 mg Day 1,8,15 (Repeat cycles every 3 weeks) 20 mg/m2 Day 1-5 100 mg/m3_Day 1-5 (Repeat cycles every 3 weeks) 20 mg/m2 Day 1-5 75 mg/m2 Day 1-5 (Repeat cycles every 3 weeks) 250 mg/m" Day 1 25 mg/m2 Day 2-5 1.5 g Day 2-5 [BepEIt LVLI 0.11 nag/k| 1.2 g/m2 ?fimpfnr Day 1 + 2 Day 1-5 RflY 1-1 ■ (T1 cycles 1-2 every 2 weeks) 200 mg/m2 Day 1 2.0 g Day 2-4 (CE cycles 3-5 every 3 weeks) AUC = 7 Day 1-3 400 mg/m2 Day 1-3 (Two cycles, may be preceded by VelP) 700 mg/m2 Day 1 750 mg/m2 Day 1-3 Annals of Oncology 24 (Supplement 6): vï125-vï132, 2013 A phase !! trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial GM Meatt", MH Cirllrn' It Huddart', P Harper', GJi Rustln*. PA Cook®, &P StennlnSe and H Mason1 on behalf olthe HRC Testicular Tumour Working Part/ 'Medkd flvnfcjy h.' C ':r,ri West W'mg Southampton ■".-,-fiTj I tosplM Soutframptrwi SO J A A5T>r gham tffi IUTTS.t>-n Trust, aim^ghom BI5 ZlH JFUyyal Atosden Hosptal, Suttat SM2 5PTh '■> 'Guy': Htapirof [ondon SE1 9RT, 'it 5Mt Vernon Hospital, Hampf HAS 2RN, :,t aMRC W.' fmdfao WWI 2D* Uti 'Vdnfe H«f«o( Gjn^fCM 7M, UK 43 eligible pts ( relaps after BEP 1st line for mGCT) TIP x 4 (G-CSFgiven at the discretion of the investigator) Primary outcomme measure - response to TIP o CR = complete response; PR = partial response; IR = incomplete response; ITS = failure-free survival; 95% CI — 95% confidence interval. Table 2 Response rates, FFS and overall survival Response (N, %) Favourable Favourable Complete resection Treatment (CR+PR) (CR+PR+CR(S)) I-year I-year overall of viable malignancy failure/early response rate response rate FFS rate survival rate Group CR PR MK-ve CR(S) IR death (FFRp) (95% CI) (FFRC) (95% CI) (95% CI) (95% CI) All patients 8 £19%) IB (4295) 5(12%) 8(19%) 4(9%) 60% (44-75) 72% (56-85) 38% (23-53) 70% (56-84) MSKCC good risk 7(27%) 12(46%) 2(8%) 3(12%) 2(8%) 73% (52-88) 81% (61-93) 43% (23-63) 81% (64-98) MSKCC poor risk 1(6%) 6(35%) 3 (18%) 5(29%) 2(12%) 41% (18-67) 59% (33-82) 29% (8-51) 53% (29-77) CR = complete response: PR = partial response; IR - incomplete response; FFS = Failure-free survival; 95% CI — 95% confidence interval, Table 3. Patient Characteristics Found to be Prédictive of Survival in the Univariate Analysis Characteristic Mo. of Patients All patients Primary lumor site Gonadal Extragonadal Retroperitoneal metastases No Yes Prior best response Incomplete Complete Refractory status10 Absolute refractory Refractory Relapsed Pretreatment HCG continuous variable 37 16 1 3 14 3 3 11 NA Abbreviation: NA, not applicable. Hgupë j iuivui, «m yipjk1 i^'iitm. Median Survival ¡months) 12 3 9 12 24 7 7 2 i NA NA 04 .03 © 2005 Cancer Research UK Survival by risk group Months from the start of TIP Numbers at risk - Good 26 20 10 5 2 — ■ Poor t? 9 4 1 0 Figure 4 Survival by hsk group. British Journal of Cancer (2005) 93(2), 178 - 184 Salvage therapy of testicular cancer High dose chemotherapy o ORIGINAL ARTICLE High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors Lawrence H. Einhorn, M.D., Stephen D. Williams, M.D., Amy Chamness, B.A., Mary J. Brames, R.N., Susan M. Perkins, Ph.D., and Rafat A honour, M.D. Retrospective study 184 pts 2nd line (135) 3rd or subsequent lines (49) Table 3. Results of Multivariate Cox Proportional-Hazards Analysis and Prognostic Score." ( Prognostic Variable Third-line or subsequent chemotherapy Platinum-refractory disease IGCCCG high-risk stage Hazard Ratio [95% CI) 2.19 (1.35-3.56) 1 74 (1.01-3.00) 1.67 (1.00-2.78) P Value 0.002 0.05 0.05 ß Regression Coefficient 0.78 0.55 0.51 Prognostic Scorev 3 2 2 *The hazard ratio is for disease progression. IGCCCG denotes International Germ Cell Cancer Collaborative Group. -¡"The score was calculated by dividing the regression coefficient by 0.51, multiplying by 2.0, and rounding to the nearest whole number. TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis Darren R. Feldman, Jae! Sheinfeld, Dean F. Bajcriti, Patricia Fischer. Stefan Turkula, Nicole Ishill, Sujata Patii, Manjit Bains, Lilian M. Reich, George J. Basi, and Robert J. Mother Retrospective analysis: 107 pts Unfavorable prognostic features (incomplete response to 1st line, relapse/incomplete response to cisplatin/ifosfamide based CDCT salvage, ekstragonadal primary) • m follow-up: 61 months • 50% CR and 8% PR neg TM; • No relapses occurred after 2 years. • 24 of primary mediastinal nonseminomatous GCTs are continuously disease free 5-year DFS 47% } 12 !4 3G 40 GC 7? &4 96 TOB 130 T32 144 Iffi 165 130 ftLdafc Time (months) 107 65 45 30 34 27 19 16 14 B S N - 107150 died) Median survival: not reached Median follow-up for survivors: 61 months 5-year OS 52% a 12 24 36 48 60 72 64 96 10B 120 132 144 156 165 1 „ . t Time (months) fta.slnEfc 107 75 S3 44 37 30 22 16 15 9 5 Original article A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours J.-L. Pico1, G. Rosti2, A. KramarJ*, H. Wandt4, V. Koza5, R. Salvioni6, C. Theodore', G. Lelli7, W. Siegert8, A. Horwich9. M. Marangolo", W. Linkesch10, G. Pizzocaro6, H.-J. Schmoll", J. Bouzy1, J.-P. Droz12 & P. Bi roil % for the Geni to-Urinary Group of the French Federation of Cancer Centers (GETUG-FNCLCC), France and the European Group for Blood and Marrow Transplantation (EBMT) Armtis vfOnctiogy 16:1152-1IS9.2005 doi:IO. K»3/anrorc;/nidi228 Published online 31 May 2005 IT-94 trial February 1994 and September 2001, 280 patients from 43 institutions in 11 countries • arm A: four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) • arm B: three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support \ \ .............................. negative study ^ ................. S, Treatment -4PETVeIP -----3PEWeIP+CarboPEC ,,,, 161 Treatment - 4-PEFVeIP -----3PEL'VeIF+CarfcoFEC ^ M E*'i$!ure 1. Event-lira: survival. Iijli I.1 1, Disease-fro: survival Iront n™ oloverall treatment evaluation among patients in crjmplcte remission. TIGER: international, prospective Phase III trial Stratification by IPFSG risk class and Continent N=420 Inclusion Criteria TIP (n=210) TI CE (n=210) •Histologically-confirmed GCT •PD following ls,-line chemo •>3 but <6 cycles of prior cisplatin-based chemo •Adequate organ function for HDCT •Any primary site K Primar»- Endpoint Overall Survival Secondary Endpoints • PF S • Favorable RR (CR / PR-m) • Toxicity & treatment-related mortality • Validation of IPFSG model • Biological correlates (SNP analyses) Sponsor: Alliance (USA, D. Feldman), E0RTC (Europe, T. Powles), Movember O 2018 ASCO ANNUAL MEETING BT: FfcOF. A. LOKH Presented By Anja Lorch at 2018 ASCO Annual Meeting Table 4. Relapsed GCC: International Prognostic Factors Study Group classification [1] Parameter Score points 0 1 2 3 Primary site Gonadal Extragonadal Mediastinal non-seminoma Prior response CR'PRm- PRm-/SD PD PEL months >3 <3 - AFP salvage Normal <1000 >1000 hCG salvage <1000 >1000 - Score sum (values from 0 to 10) Regroup score sum into categories: (0) = 0; (1 or 2) = 1 : (3 or 4) = 2; (5 or more) = 3 Add histology score points: pure seminoma = -1: non-seminoma or mixed tumours = 0 Final prognosis score {-1 = very low risk; 0 = low risk: 1 = intermediate risk; 2 = high risk. 3 = very high risk) O AFP, a-fetoproiein: CR. complete remission: GCC . germ cell cancer: hCG, human chorionic gonadotroph^: PD. progressive disease: PFL progression-free interval; PRm-. partial remission, negative markers: PRm-. partial remission, positive markers; SD. stable disease. Annals of Oncology 29: 1658-1686, 2018 (supplements) insufficient evidence to determine whether CDCT or HDCT produces superior outcomes as first-salvage chemotherapy r~ either CDCT or HDCT acceptable options for first- salvage chemotherapy O O TabitS.'Diir« treatment ne' regimens used for second or subsequent salvage Single agent Regimen Dose Sehe du le Reference Gemcitabine lOOOnTg/m* 1200 mg/m' dl, St 15q3w dl. S, 15q3w [241] |242] Oxaliplatin 60 mg/m' or 85 mg/mJ dl, 15 q4w [243] Paclitaxel 170 mg/m*' 225 mg/m 250 mg/m' 250 mg/m3 d1.q3w dl.qîw dl,q3w d1,q3w |244] |245] [246] [247] Oral etc po side 50 mg/m''/day Continuously |24i] Two drug combinations Regimen Dose Sehe dule ftelcrcrtc Gemcitabine Oxafiptarin 1000mg/mJ or 1250 mg/W 130 mg/m' dl,8q3w dl.q3w [249-253] Gemcitabine Paclitaxel 1000 mg/m3 100 mg/rcr dl,8.35q4w [2K253] Three drug combinations Regimen Dose Schedule Refcrercc Gemcitabine Oxafiptarin Paclitaxel 000 mg/m' 130 mg/m' SO mg/m*1 dl.Scßw dl.qïw d1,8q3w [254] Gemcitabine Gsplatîn Paclitaxel 800 mg/m' 50 mg/m' 80mg/mJ d1,8q3w dl,8q3w d1,8q3w [255] d, day, q3w, eveiy 3 weeks q4vy. every 4 weeks. Annals of Oncology 29: 1658-1686, 2018 Palliative treatment in GCT o Phase 1 / II studies KollmansbergerC trastuzumab HER2/neu expressing GCT inn Oncol 1999 Rick 0 talidomid platinum refrar' Eur J Cancer 2006 Feldman DR sunitinib relapsr .actory GC Invest New Drugs 2010 Feldman DR tivantinib jd or refractory A CTX refractory GCT expressing KIT relapsed or refractory GCT Invest New Drugs 2013 Einhorn LH imatinibmesik J Clin Oncol 2006 Necchi A pazor Ann Oncol 2017 Fenner M jiimus multiply relapsed GCT Journal of Cancer Research and Clinical Oncology, 2018 Adra N multiply relapsed GCT, pembrolizumab no other treatment option Annals of Oncology, 2018 ^ k^_/ RESEARCH CANCER BIOMARKERS Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Le et al., Science 357, 409-413 (2017) the genomes of cancers deficient in MMR contain exceptionally high numbers of somatic mutations i j> sensitivity to immune checkpoint blockade O ESiVDEr ORIGINAL ARTICLE Phase II trial of pembrolizumab in patients with platinum refractory gerrrKell tumors: a Hoosier Cancer Research Network Study GUI4-206 N. Adra'*, L H. Einhorn1, S. K. Althouse2, N. R Ammakkanavar1, D. Musapatika3, C. Albany1, D. Vaughn4 & N. H. Hanna' • Single arm phase II trial investigating pembrolizumab 200mg i.v. Q3 weeks until disease progression • Primary end point ORR using immune-related response criteria • Patients with relapsed GCT and no curable options • 12 patients enrolled, median age 38 years, • all patients had nonseminoma, • six patients had late relapse (>2 years) • 2 patients had positive PD-L1 staining • No CR or PR observed • 2 pts radiographic SD ( 28 and 19 weeks), • both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining #1. SUMMER SCHOOL IN MEDICAL ONCOLOGY IS SPONSORED BY: PLATINUM SPONSORS: ^MSD GOLDEN SPONSOR: (!) NOVARTIS OTHER SPONSORS: sanofi GENZYME ~^SERVIER Swixx rvlGRCK Janssen J nil Pharm a Swiss