Radiol Oncol 2020; 54(1): 119-127. doi: 10.2478/raon-2020-0003 119 research article Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab – real-world experience Nezka Hribernik1,2, Marko Boc1,2, Janja Ocvirk1,2, Jasna Knez-Arbeiter3, Tanja Mesti1,2, Marija Ignjatovic1,2, Martina Rebersek1,2 1 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University Of Ljubljana, Slovenia 3 University Medical Centre Maribor, Maribor, Slovenia Radiol Oncol 2020; 54(1): 119-127. Received 24 October 2019 Accepted 28 December 2019 Correspondence to: Assist. Prof. Martina Rebersek, M.D., Ph.D., Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 1 5879 975; E-mail: mrebersek@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Based on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question re- mains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials. Patients and methods. This observational retrospective cohort study included 138 consecutive metastatic treat- ment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019. Results. The estimated median overall survival (OS) was 25.1 months (95% CI, 14.6–35.6) and the median progression- free survival (PFS) was 10.7 months (95% CI, 5.9–15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3–4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment. Conclusions. Our real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients. Key words: immunotherapy; pembrolizumab; metastatic melanoma; treatment-naive Introduction The annual incidence of malignant melanoma is still rising steadily; in Europe it varies between 3 to 5 people per 100.000 in Mediterranean countries and 12 to 35 people per 100.000 in Nordic coun- tries.1 As for Slovenia, the average annual mela- noma incidence rate is estimated to increase to 34 men and 26 women per 100.000 (95% prediction in- terval) for the year 2019. That makes Slovenia one Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab120 of the European countries with the highest annual incidence of malignant melanoma. Approximately 78% of Slovenian patients with melanoma initially present with localized disease, 19% with regional disease and 3% with distant metastatic disease.2 All Slovenian melanoma patients in stage III and IV are treated with systemic treatment at the Institute of Oncology Ljubljana. Historically, patients with advanced melanoma had a median overall survival of around 8 months, with a 5 year overall survival of less than 10%.3 New treatment options, such as immunotherapy and targeted therapy are changing the landscape for these patients. Programmed cell death 1 (PD- 1) blockade is now a standard of care for all ad- vanced and metastatic melanoma patients in the first-line setting.1 A recent publication about the 5-year outcomes from a randomised, phase 3 trial Keynote-006 of pembrolizumab for ipilimumab- naive advanced or metastatic melanoma patients, showed a median overall survival (OS) of 38.7 months (95% CI, 27.3–50.7 months), median pro- gression-free survival (PFS) of 11.6 months (95% CI, 8.2–16.4), 5 year OS rate of 43.2% and 46% (95% CI, 41.0–51.4) objective response rate in an analysis of a subgroup of patients who received first-line treatment. They also showed a good toxicity pro- file, with grade 3–4 immune-related adverse events (irAE) reported by 17% of patients treated with pembrolizumab mono-immunotherapy.4 In melanoma patients treated with immuno- therapy or targeted treatment, it was shown that serum lactate dehydrogenase (LDH) and the num- ber of organs with metastatic involvement have the strongest predictive value for clinical outcome and for durable benefit.5,6 These factors were not presented in recently published papers on patients treated with pembrolizumab.4,7,8 However, it is still unclear whether these re- markable results are also obtained in daily clinical practice. In this paper, we aim to assess the efficacy and the toxicity of pembrolizumab in treatment- naive patients with metastatic melanoma in daily clinical practice and compare these parameters to those reported in clinical studies. Patients and methods We conducted an observational retrospective co- hort study analyzing 138 consecutive treatment- naive patients with metastatic melanoma, who re- ceived pembrolizumab at the Institute of Oncology Ljubljana between January 2016 and December 2018. Patients received pembrolizumab in two dif- ferent dosages: either 2 mg per kilogram of body weight every 3 weeks or a flat dose of 200 mg every 3 weeks (flat dose since May 2018). Patients with prior systemic therapy and patients treated with a combination of PD-1/ cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibitors were ex- cluded from the analysis. The period of data col- lection took place from January 2016 to July 2019. All relevant data was collected from medical files and entered into a data base. Baseline data was analysed with regard to age, anatomic site of primary melanoma, actionable mutation, baseline serum LDH, number of organs with metastatic in- volvement and metastatic stage (M1a(0/1)-d(0/1), determined by using 8th version of the American Joint Committee on Cancer (AJCC) tumour, node, metastases (TNM) classification system).9,10 Efficacy was evaluated according to the response evaluation criteria in solid tumours (RECIST, version 1.1) by using computed tomography (CT) scan, positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET), magnetic resonance scans (MRI), clinical examination and laboratory tests.11 Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0.12 Statistical data was obtained using the SPSS soft- ware version 22 and survival rate was calculated by Kaplan-Meier method and compared using log- rank tests. The study was approved by the Institutional Review Board Committee (Approval number: ERIDEK-0084/2019) and was conducted in accord- ance with the ethical standards defined by the Declaration of Helsinki. The study was conducted with acknowledgement and consent of the sub- jects. Prior to treatment, patients have signed an in- formed consent for treatment and a consent allow- ing the usage of their data for scientific purposes. Results Patients and treatment Demographic and disease characteristics are de- tailed in Table 1. All patients were Caucasians. The median age was 65.4 years (range 25–87), the ma- jority of patients (60.9%) were males and in ECOG performance status 1 (51.4%). Among all patients, 116 (84.1%) had cutaneous subtype of melanoma. Twenty-five (18.1%) patients had BRAF V600 muta- tion, 21 (84%) of which had normal baseline lactate Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab 121 dehydrogenase (LDH). Serum LDH was elevated in 26.1% of all melanoma patients. The majority – 52 (37.7%) patients – had two organs with meta- static involvement. Median duration of exposure to pembrolizum- ab was 6.7 months. (range: 1 day – 36 months). At the time of data cut-off, 38 (27.5%) patients were still receiving pembrolizumab, others discontin- ued due to progressive disease (PD; n = 78; 56.5%), immune-related adverse events (n = 17; 12.3%) or physician decision (n = 5, 3.6%). Only two (1.4%) patients were retreated with pembrolizumab. There were five (3.6%) patients with underlying autoimmune or inflammatory disease (AID), two of which had psoriasis, one had psoriatic arthritis, TABLE 1. Demographic and disease characteristics of the patients Median age (range) – years 65.4 (25-87) Older than 70 years – n (%) 47 (48.9%) Male gender – n (%) 84 (60.9) Average body weight (range) – kilograms 79.5 (46 – 138) ECOG performance status – n (%) 0 53 (38.4) 1 71 (51.4) 2 12 (8.7) 3 2 (1.4) Anatomic site of primary Cutaneous 116 (84.1) Ocular 8 (5.8) Mucosal 7 (5.1) Unknown primary 7 (5.1) Actionable mutation – n (%) Wild type 94 (68.1) BRAF V600E 22 (15.9) BRAF V600K/M 3 (2.2) NRAS 3 (2.2) Not provided 16 (11.6) Elevated baseline LDH level (> 4.31 microkat/L) – n (%) 36 (26.1) Elevated baseline S100 level (> 0.105 microg/L) – n (%) 72 (52.2) Metastatic stage – n (%)* M1a (0) 28 (20.3) M1a (1) 6 (4.3) M1b (0) 29 (21.0) M1b (1) 2 (1.4) M1c (0) 32 (23.2) M1c (1) 22 (15.9) M1d (0) 13 (9.4) M1d (1) 6 (4.3) Organs with metastatic involvement – n (%) 1 47 (34.1) 2 52 (37.7) 3 19 (13.8) >3 20 (14.5) Further lines of systemic therapy – n (%) 41 (29.7) Radiotherapy during immunotherapy – n (%) 38 (27.5) LDH = lactate dehydrogenase *Following the 8th edition of the American Joint Committee on Cancer (AJCC) tumour, node, metastases (TNM) classification, to cases with normal level of the LDH are given the suffix (0) and to cases with elevated LDH level suffix (1). FIGURE 1. Kaplan-Meier estimates for overall survival (A) and progression free survival (B) according to different metastatic stages (p < 0.001). A B Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab122 one suffered from sarcoidosis and one from chron- ic inflammatory bowel disease. Only the patient with psoriatic arthritis had a flare of his AID. Most of the patients (n=118, 85.5%) received pembrolizumab per kilogram of body weight and only a minority (n=20, 14.5%) received a flat dose of 200 mg. Efficacy At data cut-off, 65 (47.1%) patients died. Estimated median OS was 25.1 months (95% CI, 14.7–35.6) and median PFS was 10.7 months (95% CI, 5.9–15.5) for all patients. In Figure 1, median OS and PFS ac- cording to different metastatic stages are shown. Among all of the 138 treated patients, 29 (21.0%) achieved complete response (CR), 31 (22.5%) achieved partial response (PR) and 23 (16.7%) achieved stable disease (SD). In total, 54 (39.1%) patients experienced a progression disease (PD). In survival rate analysis, median OS in patients with CR in PR was not yet reached, while median OS in patients with SD was 25.1 months (95% CI, 15.1– 35.2) and in patients with PD was 3.8 months (95% CI, 3.1–4.4) (Table 2, Figure 2). A survival rate analysis according to age (older or younger than 70 years), anatomic site of primary melanoma, actionable mutations, baseline LDH level and the number of organs with metastatic involvement was carried out. Older age, different anatomic sites of the primary melanoma and BRAF mutation were not associated with lower survival rates. The differences in survival rates according to anatomical site were not statistically significant (p=0.071). Namely, patients with cutaneous mela- noma had an estimated medium OS of 32.7 months (95% CI non-estimable). Patients with ocular mel- anoma had medium OS of 11.6 months (95% CI, 2.8–21.4) and patients with mucosal melanoma 4.4 months (95% CI, 2.8–5.9). However, the survival rate differences were sta- tistically significant (p=0.04) according to the num- ber of organs with metastatic involvement. The median OS for patients with one organ site con- taining metastases was not reached, while patients with two organs involved had the median OS of 23.1 months (95% CI, 14.4–31.6), patients with three organs involved had 17.7 months (95% CI non-esti- mable), and patients with more than 3 organs with metastatic involvement had 8.8 months (95% CI, 1.3–16.2) (Figure 3). Similarly, the differences in sur- vival rate according to the baseline levels of LDH were statistically significant (Figure 4, p < 0.001). The estimated median OS for patients with normal baseline LDH level was 32.7 months (95% CI non- estimable), whereas for patients with elevated base- line LDH the median OS was 4.8 (95% CI, 0.0. –11.2). Responses for patients with BRAF mutations were analysed in more details, out of all 25 (18.1%) patients, 7 (28%) achieved CR, 4 (16%) achieved PR and 5 (20%) patients SD, while 9 (36%) patients progressed. As for the subsequent lines of therapy, 41 (29.7%) patients received it. Most of them, name- ly 35 (85.4%) patients received chemotherapy, 5 (12.2%) received targeted therapy with BRAF and MEK inhibitors and only 1 (2.4%) patient received CTLA-4 inhibitor ipilimumab monotherapy. TABLE 2. Best overall responses and median overall survival for each group Response n (%) ORR 60 (43.5) DCR 83 (60.2) Best response CR 29 (21.0) PR 31 (22.5) SD 23 (16.7) PD 54 (39.1) No assessment 1 (0.7) CR = complete response; DCR = disease control rate; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease FIGURE 2. Kaplan-Meier estimates of overall survival according to best overall response (p < 0.001). Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab 123 Toxicity Table 3 presents the reported immune-related adverse events (irAE). They occurred in 88 (63%) patients, 12 (8.7) patients experienced grade 3 to 4 irAE and 16 (11.6%) patients permanently discon- tinued treatment due to irAE. There were no treat- ment-related deaths known from the data base. The most common treatment-related adverse events of any grade were elevation in liver transam- inase levels (25.4%), hypothyroidism (23.9%) and pruritus (20.3%). Grade 3 to 4 events that were re- ported in more than 1% of the patients were eleva- tion in liver transaminase levels (2.2%), arthralgia (1.4%) and pneumonitis (1.4%). There were a few cases of rare irAE. One patient developed limbic encephalitis, another adrenal insufficiency and two had documented nephritis. Discussion Results from this one-country, single centre retro- spective analysis showed inferior median OS, simi- lar median PFS and comparable ORR for the whole group of melanoma patients receiving pembroli- zumab in first line setting, compared to reported data from clinical studies. There are more possible reasons for these re- sults. Firstly, medium follow-up in our retrospec- tive analysis was shorter in comparison to pub- lished clinical trials. Secondly, the characteristics of our patients differ from those in the clinical trials. Only patients with metastatic disease were includ- ed in our analysis. No patient in our research had an advanced or non-metastatic operable melano- ma, unlike the Keynote-006 trial, where 3.2% of pa- tients were without distant metastasis (M0). With regard to ECOG performance status, our patients were mainly in ECOG performance status 1, but some of them were also in performance status 2 or 3, probably due to comorbidities or higher tumour burden. There were 19 (13.8%) patients with brain metastases, some of them even had symptomatic brain metastases, which was an exclusion criteria in the Keynote-006 study. We know that patients with active brain metastases not only have a det- rimental survival due to their disease, but also require systemic glucocorticoids.13 That condition was shown to be associated with inferior outcomes for treatment with programmed cell death ligand 1 (PD-L1) blockade as corticosteroids play an im- portant role in feedback inhibition of inflammatory response and immune system homeostasis.14 TABLE 3. Immune related adverse events Adverse event* Any grade – no. (%) Grade 3-4 – no. (%) Any 88 (63.8) 12 (8.7) High AST, ALT 35 (25.4) 3 (2.2) Hypothyroidism 33 (23.9) 0 Pruritus 28 (20.3) 0 Rash 25 (18.1) 1 (0.7) Arthralgia 14 (10) 2 (1.4) Diarrhoea 13 (9.4) 1 (0.7) Fatigue 8 (5.8) 0 Pneumonitis 7 (5.1) 2 (1.4) Vitiligo 7 (5.1) 0 Other 12 (8.7) 4 (2.9) AST = aspartate transaminase; ALT = alanine aminotransferase *Events are listed in order of descending frequency. FIGURE 3. Kaplan-Meier estimates of overall survival according to number of organs with metastatic involvement (p = 0.04). A few patients with ocular and mucosal subtype of melanoma were included in our analysis, which also differs from the Keynote-006 trial, where ocu- lar melanoma patients were excluded.15 However, these patients were included in the Keynote-001 trial.7 These two subgroups of melanoma patients usually have worse results and they rarely confer durable remissions with immunotherapy. In pa- tients with metastatic ocular melanoma treated Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab124 with PD-(L)1 antibodies, including pembrolizum- ab, a disease control rate (DCR) of 12.5% and OS of 7.6 months was reported in a retrospective se- ries.16 As for the mucosal melanoma ipilimumab- naive patients, a post-hoc analysis of Keynote-001, 002 and 006 showed an ORR of 22% and a median OS of 14.0 months.17 Furthermore, in our analy- sis these patients performed worse compared to cutaneous melanoma. Ocular melanoma patients had a medium OS of 11.6 (95% CI, 2.8–21.4) and mucosal melanoma patients had a medium OS of 4.4 months (95% CI, 2.8–5.9). The difference was not statistically significant, probably due to a low number of patients with ocular or mucosal primary melanoma. However, for certain groups of patients, the results are outstanding. Patients with one organ with metastatic involvement and patients with stage M1a(0) had the best survival rate, with me- dian overall survival not reached at the data cut- off time. Patients with normal serum levels of LDH also had a significantly better survival rate than those with elevated levels. These results confirm that the number of organs with metastatic involve- ment and the level of serum LDH are important prognostic factors.5,6 Furthermore, ORR of 43.5% was comparable to ORR in Keynote-006 and Keynote-001, where it amounted to 46% (95% CI, 41.0–51.4) and 52% (95% CI, 43–60) respectively in the first line treatment. In these studies, some unique patterns of response were reported. One of them is pseudoprogression, which is described as a radiological progression that is followed by stabilization or response on the next imaging.18 In Keynote-001 trial, the incidence of tumour pseudoprogression was 7.3%.19 In our analysis, we did not collect data on this atypical re- sponse, therefore its influence on the response rate cannot be established. Actionable mutations BRAF and NRAS were present in only 28 (20.3%) patients. Additionally, quite a significant number of patients (n=16, 11.6%) did not receive molecular testing for actionable mu- tations. The percentage is higher than reported in the clinical trials. For example, in the Keynote-006 trial only 1% of patients had undetermined BRAF status. In our analysis, these were patients with contraindications for the targeted therapy, with oc- ular primary melanoma, where a BRAF mutation is very rare, and patients where testing was not possi- ble due to lack of tumour tissue. At present, liquid biopsy is not performed at our institute. A comparison between patients with BRAF mu- tated melanoma and wild type melanoma showed no statistical differences in median OS, PFS and ORR. Due to a low number of patients with BRAF mutation (n=25, 18.1%), the conclusions are highly questionable. However, looking at the patients’ characteristics, most of them (84%) had normal LDH concentration, probably reflecting less aggres- sive disease and/or metastatic burden and making them the more suitable for immunotherapy. The type of the first line therapy in our BRAF mutated patients depended entirely on the physician’s deci- sion. Currently, there are several prospective trials evaluating the best first line approach for the pa- tients with BRAF mutated tumours: immunother- apy, targeted therapy or switching from the latter to the former after certain time. For the time be- ing, only exploratory analysis have shown that im- munotherapy might result in a better survival rate after one year of treatment.20 The patients with tu- mours threatening important organs or functions and those with high tumour burden and rapid pro- gression are advised to start with targeted therapy, which provides faster responses. As for older patients, the survival rate was not significantly different from that of younger ones. That gives us another confirmation that we can safely treat older patients with mono-immunother- py.20 Subsequent lines of systemic treatment of meta- static melanoma patients are not evidence-based at this time.1 A combination of BRAF and MEK in- FIGURE 4. Kaplan-Meier estimates of overall survival according to serum lactate dehydrogenase (LDH) (p < 0.001). Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab 125 hibitors is a good therapeutic option in the second line of systemic treatment only for patients with actionable mutation BRAF that have been treated with immunotherapy in the first line. In our group of patients, 5 (12.2%) of the patients who received second line therapy also received targeted therapy afterwards. The majority of other patients were treated with chemotherapy. The toxicity profile according to our retrospec- tive analysis is, as reported in clinical trials, very good. Only 8.7% of patients experienced grade 3 to 4 irAE and, more importantly, there were no treatment-related deaths. The incidence of irAE could be underestimated due to retrospective de- sign and unfamiliarity of clinicians with irAE at the beginning of using PD-1 treatment. We had limited experience with CTLA4 antibody ipilimumab us- age. Available literature was of great help, as first position papers were published online very soon.22 With more literature becoming available and with our increasing clinical experience, we learned to recognize irAE and to treat them more effective- ly.23-25 This also stands for patients with underlying AID, which we now know is not a contraindication for treatment with immunotherapy.26-28 Five (3.6%) patients from our group had AID and only one had a transient exacerbation of his autoimmune condi- tion. Another important question is the financial toxicity. The average body weight of our patients was 80 kg, meaning the average dose per kilogram was 160 mg. With a flat dose regimen we actually spent more money on the treatment than we did with a dose per kilogram. The financial difference between these two regimens is substantial, espe- cially for a country with limited resources, such as Slovenia. Due to a low number of patients that were treated with a flat dose in our study, the com- parison regarding the efficacy was not possible. We need prospective data to validate different doses of treatment, which could potentially lead to much wider access to these drugs.29 This highly effective treatment should stay affordable for countries such as ours, so we should continue searching for more optimal treatments with this medicine. The time spent on a treatment is also an important factor. An optimal duration of treatment has not been es- tablished yet, but data shows that patients in com- plete remission after being treated for more than 6 months have a low risk of relapse after discon- tinuation. This is not true for patients in partial re- sponse or those with stable disease, where the risk is higher. The optimal duration of treatment needs further prospective studies.30-32 This study contains some limitations. Firstly, the retrospective design of the study results in the lack of some important or interesting data. For ex- ample, the testing on PD-L1 expression was not performed, as it is not part of standard practice. Its clinical use in melanoma patients is limited at the time being, because the treatment with checkpoint inhibitors is effective regardless of the state of PD-L1.33 Second important limitation of our anal- ysis is a short follow-up time compared to recent publications, which reported 5-year outcomes. Our future perspective is to update the data, especially regarding the survival rate and the responses to treatment. We hope to see the same ongoing antitu- mor activity of pembrolizumab as it was seen in all randomized clinical trials with this drug.4,7 Another important limitation that could have impacted our results is the radiological evaluation using RECIST criteria, instead of immune RECIST (iRECIST).34 Nivolumab is another PD-1 inhibitor that is in- dicated for treatment of advanced or metastatic treatment-naive melanoma patients.35 In January 2016, when PD-1 inhibitor pembrolizumab started to be used for melanoma patients in Slovenia, this was the only PD-1 inhibitor that was reimbursed by medical insurance. Even when nivolumab was first reimbursed in June 2018, pembrolizumab continued to be used in this setting, due to less frequent applications of pembrolizumab at that time (every three weeks for pembrolizumab vs. every two weeks for nivolumab). Just recently, in October 2019, a combination of nivolumab with ip- ilimumab was first reimbursed, which presents an- other treatment option for this group of patients. 36 Lastly, in Slovenia there is still a lot of space for improvement in the area of melanoma systemic treatment. The priorities should be including our patients in clinical trials and a better organisation of supportive facilities. The lack of focus on these priorities is possibly reflected in data showing an increase in the mortality-to-incidence ratios in Eastern European countries compared to Western Europe.37 Conclusions The results from our retrospective analysis of treatment-naive patients with metastatic mela- noma treated with PD-1 inhibitor pembrolizumab showed inferior median OS and similar median PFS and ORR compared to reported data from clinical studies. However, the patients with normal serum levels of LDH and a small number of organs Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab126 with metastatic involvement had comparable sur- vival outcomes. The treatment resulted in a low toxicity rate and no treatment-related deaths. A lot still needs to be done in melanoma patient commu- nity so that the patients with bad prognostic factors can also achieve higher survival rates. This type of retrospective analysis gives us an insight into real-life patient care and represents an important contribution for oncological community and, most importantly, enables a better care for our patients. Acknowledgements The research was financially supported by The Slovenian Research Agency (ARRS), grant number P3-0321. References 1. Michielin O, Van Akkooi A, Ascierto P, Dummer R, Keilholz U, ESMO Guidelines Committee. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019. doi: 10.1093/annonc/mdz411 2. Cancer in Slovenia 2016. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2019. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): cutaneus melanoma. Version 2.2019. [cited 2019 Sep 18]. Available at: https://www.nccn.org/professionals/physician_ gls/pdf/cutaneous_melanoma.pdf 4. Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019; 20: 1239-51. doi: 10.1016/ S1470-2045(19)30388-2 5. Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol 2016; 36: 667- 73. doi: 10.1016/S1470-2045(16)30578-2. 6. Weide B, Martens A, Hassel JC, Berking C, Postow MA, Bisschop K, et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 2016: 22; 5487-96. doi: 10.1158/1078- 0432.CCR-16-0127 7. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ , Kefford R, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2019; 30: 582-8. doi: 10.1093/ annonc/mdz011 8. Schadendorf D, Livingstone E, Zimmer L. Treatment in metastatic melanoma - time to re-think. Ann Oncol 2019; 30: 501-3. doi: 10.1093/annonc/ mdz050. 9. Amid MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The eight edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017; 67: 93-9. doi: 10.3322/caac.21388. 10. Gershenwald JE, Scolyer RA, Hess KR, Sondak Vk, Long GV, Ross MI, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017; 67: 472-92. doi: 10.3322/caac.21409 11. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. doi: 10.1016/j.ejca.2008.10.026 12. National Cancer Institute (NCI). NCI Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. [cited 2019 Oct 17]. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ docs/CTCAE_v5_Quick_Reference_8.5x11.pdf 13. Glitza Oliva IC, Schvartsman G, Tawbi H. Advances in the systemic treatment of melanoma brain metastasis. Ann Oncol 2018; 29: 1509-20. doi: 10.1093/ annonc/mdy185 14. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of pembrolizumab or programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018; 36: 2872-8. doi: 10.1200/JCO.2018.79.0006 15. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Eng J Med 2015; 372: 2521-32. doi: 10.1056/NEJMoa1503093 16. Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 2016; 122: 3344-53. doi: 10.1002/cncr.30258 17. Hamid O, Robert C, Ribas A, Stephen Hodi F, Walpole E, Daus A, et al. Anitumor activity of pembrolizumb in advanced mucosal melanoma: a post- hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer 2018; 119: 670-4. doi: 10.1038/s41416-018-0207-6 18. Vrankar M, Unk M. Immune RECIST criteria and symptomatic pseudoprogression in non-small cell lung cancer patients treated with immunotherapy. Radiol Oncol 2018 52: 365-9. doi: 10.2478/raon-2018-0037 19. Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation of immune-related response criteria and RECIST v1.1. in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016; 34: 1510-7. doi: 10.1200/JCO.2015.64.0391 20. Urugel S, Rohmal J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer 2017; 83: 247-57. doi: 10.1016/j. ejca.2017.06.028 21. Archibald W, Victor AI, Strawderman MS, Maggiore RJ. Immune checkpoint inhibitors in older adults with melanoma or cutaneous malignancies: The Wilmot Cancer Institute experience. J Geriatr Oncol 2019; 11. doi: 10.1016/j.jgo.2019.07.005 22. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016; 27: 559-74. doi: 10.1093/ annonc/mdv623 23. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(Suppl 4): iv119-42. doi: 10.1093/annonc/mdx225 24. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immnune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36: 1714-1768. doi: 10.1200/JCO.2017.77.6385 25. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019; 16: 563-80. doi: 10.1038/s41571- 019-0218-0 26. Danlos FX, Voisin AL, Dyevre V, Michot JM, Routier E, Taillade V, et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer 2018; 91: 21-9. doi: 10.1016/j.ejca.2017.12.008 27. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blocade. N Eng J Med 2018; 378: 158- 68. doi: 10.1056/NEJMra1703481. 28. Leonardi GC, Gainor JF, Altan M, Kravets S, Dahlberg SE, Gedmintas L, et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and pre-existing autoimmune disorders. J Clin Oncol 2018; 36: 1905-12. doi: 10.1200/JCO.2017.77.0305 29. Renner A, Burotto M, Rojas C. Immune checkpoint inhibitor dosing: can we go lower without compromising clinical efficacy? J Global Oncol 2019; 5: 1-5. doi: 10.1200/JGO.19.00142 Radiol Oncol 2020; 54(1): 119-127. Hribernik N et al. / Metastatic melanoma patients treated with pembrolizumab 127 30. Jansen YJL, Rozeman EA, Mason R, Goldinger SM, Geukes Foppen MH, Hoejberg L, et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann Oncol 2019; 30: 1154-61. doi: 10.1093/annonc/mdz110 31. Robert C, Ribas A, Hamid O, Daud A, Wolchok Jd, Joshua AM, et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol 2018; 36: 1668-74. doi: 10.1200/ JCO.2017.75.6270 32. Lorigan P, Eggermont AMM. Anti-PD1 treatment of advanced melanoma: development of criteria for a safe stop. Ann Oncol 2019; 30: 1038-40. doi: 10.1093/annonc/mdz182 33. Daud AI, Wochok JD, Robert C, Hwu WJ, Weber JS, Ribas A, et al. Programmed death ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 2016; 34: 4102-9. doi: 10.1200/JCO.2016.67.2477 34. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trial testing immunotherapeutics. Lancet Oncol 2017. 18: e143-52. doi: 10.1016/S1470- 2045(17)30074-8 35. Robert C, Long GV, Brandy B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Eng J Med 2015; 372; 320-30. doi: 10.1056/NEJMoa1412082 36. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five year survival with combined nivolumab and ipilimumab in advanced melanoma. N Eng J Med 2019; 381: 1535-46. doi: 10.1056/NEJMoa1910836 37. Forsea AM, Del Marmol V, Stratigos A, Geller AC. Melanoma prognosis in Europe: far from equal. Br J Dermatol 2014; 171: 179-82. doi: 10.1111/ bjd.12923