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Background: Presence of micrometastases in the sentinel lymph node (SLN) is currently used to assess prognosis of melanoma patients. The immunoactivity within the SLN is known to be influenced by the primary tumor (PT), which may in turn impact the SLNs' metastatic state., Aim: We characterize the temporal dependence and underlying mechanisms of the immunological effects of the PT on the SLN., Methods: The prognostic value of SLN state as a function of PT removal time was evaluated. To put the results into a functional context, selected PTs and corresponding SLNs were analyzed for gene and protein expression patterns., Results: In a cohort of 202 patients with known distant metastasis and similar PT prognostic characteristics, SLNs removed before or within one week after the PT (IM-SLN) had a higher incidence of micrometastases than those removed at least one week after the PT (DEL-SLN). The immunoactivity in IM-SLN was found to be lower than in DEL-SLN. Specifically, in IM-SLNs, T helper 17 / regulatory T-cells were predominant, whereas in DEL-SLNs, cytotoxic γδT-cells were more frequent. The higher immune activity in DEL-SLNs was probably facilitated by CD209 + antigen-presenting cells. Indeed, in PT with high TGFβ expression CD209 + cells appear to be trapped and no increased immunoactivity was observed in DEL-SLN., Conclusions: Presence of micrometastases in DEL-SLNs have a higher negative prognostic value as in IM-SLNs since they indicate not only a melanoma's propensity to metastasize, but possibly also its capacity to escape immune responses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. VKD received a research grant, honoraria for talks and travel support from SUN Pharma. CR is employed by Merck Serono. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, outside the submitted work. SH has acted as a consultant and / or received travel assistance from BMS, Kyowa Kirin. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects (to institution) from Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Kyowa-Kirin, Admiral-Hermal. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Sanofi, and Sun Pharma, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, ICON, MerckSerono, Pfizer, and Sanofi. His group receives research grants from Merck Serono, IQVIA, and Alcedis. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort., Methods: Patients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR)., Results: Of 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14-3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93-2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients., Conclusion: Less than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival., Competing Interests: Declaration of Competing Interest GCL received travel support from Sun Pharma, Pierre Fabre, research funding from Novartis. RH is employee of Helios Kliniken GmbH. PT has received honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; and travel support from Bristol-Myers Squibb and Pierre Fabre. JU received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Bristol-Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Regeneron, Sunpharma outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO, outside the submitted work. JU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. AK served as a speaker and/or consultant and/or advisory board for MSD, AbbVie, Boehringer Ingelheim, Janssen, and Sanofi. PM declares research support from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Beiersdorf, Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Immunocore, Sanofi and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, and Pierre Fabre, outside the submitted work. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi/Regeneron, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi/Regeneron, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects (to institution) from Amgen, Merck-Serono, SUN Pharma, Sanofi/Regeneron, Kyowa-Kirin, Almirall-Hermal. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. MW received grants from Bristol-Myers Squibb and Merck Sharp & Dohme, consulting fees from Merck Sharp & Dohme, Immunocore and Novartis, lecture honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and Pierre-Fabre, and advisory board honoraria from Merck Sharp & Dohme. AP reports grants from Bristol Myers Squibb (BMS) and Merck Sharp & Dohme (MSD) outside the submitted work. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. DS reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) support; grants (or contracts) from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma. All other authors declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date., Methods: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV., Results: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2)., Conclusions: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations., Competing Interests: Declaration of Competing Interest All other authors declare no conflicts of interest for the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up., Methods: We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint., Results: The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group., Conclusions: The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma., Competing Interests: Declaration of Competing Interest Alexander MM Eggermont is an Editor-in-Chief for European Journal of Cancer and was not involved in the editorial review or the decision to publish this article. Susana Puig is an Editor for European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. Dirk Schadendorf is an Editor-in-Chief European Journal of Cancer Skin Cancer and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander C.J. van Akkooi: advisory board/consultancy honoraria from 4SC AG, Amgen, Bristol-Myers Squibb, Merck Serono-Pfizer, MSD-Merck, Neracare, Novartis, Pierre Fabre, Sanofi, Sirius Medical, SkylineDX; research grants from Amgen, Merck Serono-Pfizer, SkylineDX. Paolo A. Ascierto: a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon; research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi; travel support by Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. Victoria Atkinson: advisory board for and speeches fees from BMS, MSD, Novartis, Immunocore; travel support by Pierre Fabre. Christian U Blank: advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, Sandoz; research funding from BMS, Novartis, NanoString, 4SC; stock ownership of Flindr Therapeutics, Signature Oncology. Matteo Carlino: advisory boards or a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; honoraria from BMS, MSD, and Novartis. Stéphane Dalle: research grants to institution from MSD, BMS, Pierre Fabre; advisory board paid to institution by MSD and BMS; spouse employment Sanofi. Alexander MM Eggermont: honoraria for scientific advisory board or data monitoring committee activities from Agenus, Bioinvent, BioNTech, Boehringer Ingelheim, Brenus, CatalYm, Eurobio, GenOway, Imcheck, IO Biotech, Ipsen, IQVIA, ISA Pharmaceuticals, Merck KGA, Merck&Co/MSD, Pfizer, Pierre Fabre, QBiotics, Regeneron, Replimune, Sairopa BV, ScanCell, Scorpion Pharmaceuticals, Secarna, Sellas, SkylineDX BV, TigaTX, Thermosome, Trained Immunotherapeutics Discovery. Stock: IO Biotech, Sairopa BV, SkylineDX. Anna Maria Di Giacomo: advisor/board member for Merck, Roche, Bristol Myers Squibb, Incyte, Pierre Fabre, Sanofi, GlaxoSmithKline, SunPharma, Immunocore; honoraria from Merck, Bristol Myers Squibb, Sanofi, Pierre Fabre, GlaxoSmithKline, SunPharma. Immunocore. Dmitri Grebennik: employee of Merck & Co. Jean-Jacques Grob: advisory boards for Novartis, BMS, MSD, Philogen, Pierre Fabr, Sanofi, Roche, Amgen. Ralf Gutzmer: honoraria for lectures and advice from BristolMyers Squibb, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; support for participation in meetings from SUN Pharma, Boehringer Ingelheim and PierreFabre; research support (to institution) from Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal, Recordati. Andrew Haydon: advisory board member for BMS, MSD and Novartis. Rahima Jamal: honoraria for presentation and advisory board with Merck. PI in Merck-sponsored trials. Adnan Khattak: speaker honoraria, advisory board, and travel sponsorship from MSD. Michal Kicinski: research funding from MSD, BMS, Pierre Fabre, Immunocore, and JnJ. Clemens Kreplere: employee and shareholder of Merck & Co. James Larkin: relationships with the following companies: iOnctura, Apple Tree, Merck, BMS, MSD, Telix, Novartis, Philogen, Pfizer, Incyte, Eisai, Debipharm, GCO, TouchIME, Immatics, Insighter, Agence Unik, VJOncology, Royal College of General Practioners, Cambridge Healthcare Research, Royal College of Physicians, TouchExperts. Georgina V Long: consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Paul Lorigan: support for travel from MSD; research funding from Pierre Fabre and BMS; speakers bureau/consultancy for BMS and Pierre Fabre. Mario Mandala: advisory board and lectures for: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma; research grant from Novartis. Susana Puig: speaker for Almirall, BMS, Cantabria, ISDIN, La Roche Posay, Leo Pharma, MSD, Novartis, Pfizer, Roche, Regeneron, Sanofi, Sunpharma; advisory board of Almirall, BMS, ISDIN, La Roche Posay, Regeneron, Roche, Sanofi, Sun Pharma; involvement in research and trials of Abbvie, Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo Pharma, MSD, MEDA, Novartis, Polychem, Roche, Sun Pharma; husband has relationship with Almirall, Amgen, BMS, Biofrontera, Canfield, Cantabria, Fotofinder, GSK, ISDIN, La Roche Posay, Leo, Mavig, Nevisence, Novartis, Polychem, Roche, Sun Pharma. Educational activities for Abbie, Lilly, and ISD; ownership of Athena Tech & Dermavision Solutions. Caroline Robert: consultant/advisory board of Pierre Fabre, Sanofi, BMS, MSD, Novaris, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; consultant steering committee for Novartis, Regeneron, Pfizer, IO Biotech; consultant IDMC for Ultimovacs; speaker for Pierre Fabre, Sanofi, BMS, MSD, Novaris; travel by Pierre Fabre. Piotr Rutkowski: honoraria for lectures and advisory boards from MSD, BMS, Novartis, Pierre Fabre, Genesis Pharma, Medison Pharma. Shahneen Sandhu: research funding from Novartis/AAA, AstraZeneca, Merck Sharp and Dohme, Amgen, Genentech, Senwha, Bristol-Myers Squibb, Merck Healthcare and Pfizer; participation on advisory boards for Merck Sharp and Dohme, AstraZeneca, Novartis, SkylineDx and Abbvie (fees for attending go to research funds at the institution); honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen (all paid to the institution); chair of DSMB for 2 Novartis/AAA sponsored Phase III trials (no fee accepted for chair role). Dirk Schadendorf: a member of the advisory board, consultant or received speakers´ honoraria from: Astra Zeneca, BMS, CureVac, Daiichi Sankyo, Erasca, Haystack, Immatics, Immunocore, InFlarX, Lapcorp, Merck-Serono, MSD, Neracare, Novartis, Novogenix, PamGene, Philogen, Pierre Fabre, Pfizer, Regeneron, Replimune, Sanofi, Seagen, Sun Pharma, UltraVacs; research funding from BMS, Roche, MSD, Amgen & Novartis. Stefan Suciu: DSMB member of the NADINA study. Alfonsus JM van den Eertwegh: study grant from Bristol-Myers Squibb, Idera; travel expenses by Ipsen; advisory board of Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV. The remaining authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases., Methods: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival., Results: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy., Conclusions: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IPS had travel support by BMS and MSD, speaker fee by Pierre Fabre, Roche, BMS and MSD, and has served as consultant on advisory boards from MSD. SU had research support from BMS and Merck Serono; speakers and advisory board honoraria from BMS, MSD, Merck Serono, and Novartis; and meeting and travel support from Almirall, BMS, IGEA Clinical Biophysics, MSD, Novartis, Pierre Fabre, and Sun Pharma. FA had travel support by Novartis and MSD. AA has served on advisory boards and received travel funding from BMS, MSD, Novartis, Pierre-Fabre, Pfizer and Almirall. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. MSC is consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD, Sanofi and Novartis. PM is consultant advisor Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, Sun Pharma, Roche, Bayersdorf, Sanofi and Regeneron. Speaker fee by Pierre Fabre, Roche, BMS, MSD, Amgen, Sun Pharma, Sanofi and Novartis. Research funding from Novartis, MSD and BMS. RG received honoraria for advice and lectures from Bristol Myers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; travel and meeting support from SUN Pharma, Boehringer Ingelheim and PierreFabre; project support (to institution) from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal. AMM is a consultant advisor for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics.MW received honoraria from Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sanofi; is consult advisor for Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sun Pharma, Sanofi, Pierre Fabre; research Funding from Merck Sharp & Dohme (Inst), Millennium (Inst), Bristol Myers Squibb (Inst), Johnson & Johnson (Inst), Novartis (Inst). PL received honoraria from Novartis, Pierre Fabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, Oncology Education, Nektar; is consultant advisor for Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Novartis, Nektar; Speakers’ Bureau from Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre Fabre; Research Funding from BMS, Pierre Fabre; Travel, Accommodations, Expenses from Merck Sharp & Dohme, Bristol Myers Squibb. D.S.: Reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Neracare, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff)., Methods: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed., Results: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms., Conclusions: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron. Reinhard Dummer. Honoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVAX, touchIME, T3 Pharmaceuticals, Pfizer. Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVAX, Regeneron, Pfizer, T3 Pharmaceuticals. Research Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst). Keith T. Flaherty. Stock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics, FogPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, Nextech Invest. Consulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Debiopharm Group. Caroline Robert. Stock and Other Ownership Interests: Ribonexus. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer. Research Funding: Novartis (Inst). Ana Arance. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi. Speakers’ Bureau: Pierre Fabre, Novartis, MSD, Bristol Myers Squibb, Roche, Merck, Sanofi Research Funding: Pierre Fabre (Inst), Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Merck (Inst), Sanofi (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre. Jan Willem B. de Groot. Consulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier. Claus Garbe. Honoraria: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen. Consulting or Advisory Role: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen. Helen J. Gogas. Consulting or Advisory Role: Bristol Myers Squibb, MSD, Pierre Fabre, Sanofi. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi. Steering Committee Member: Amgen, Replimune. Research Funding: Amgen (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Iovance (Inst), Lilly (Inst), MSD (Inst), Pfizer (Inst), Pierre Fabre (Inst). Ralf Gutzmer. Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, Immunocore. Consulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, Delcath. Research Funding: Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi/Regeneron (Inst), Kyowa Kirin (Inst), Almirall Hermal GmbH (Inst). Travel, Accommodations, Expenses: Pierre Fabre, Sun Pharma, Boehringer Ingelheim. Ivana Krajsová. No disclosures or conflicts of interest to report. Gabriella Liszkay. Consulting or Advisory Role: Roche, MSD, Novartis, Bristol Myers Squibb/Pfizer, Sanofi, Pfizer. Speakers’ Bureau: Bristol Myers Squibb, MSD Oncology (Inst), Sanofi. Research Funding: Roche, Novartis (Inst), Incyte Corporation (Inst). Carmen Loquai. Consulting or Advisory Role: Bristol Myers Squibb (Inst), MSD (Inst), BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb (Inst), MSD (Inst), BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst). Mario Mandalà. Honoraria: MSD Oncology, Novartis, Pierre Fabre, Sanofi/Aventis, Bristol Myers Squibb/Sanofi. Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre. Research Funding: Novartis (Inst). Naoya Yamazaki. Consulting or Advisory Role: Ono Pharmaceutical, Chugai Pharma, MSD. Speakers’ Bureau: Ono Pharmaceutical, Bristol Myers Squibb Japan, Novartis, MSD. Research Funding: Ono Pharmaceutical (Inst), Bristol Myers Squibb Japan (Inst), Novartis (Inst), Astellas Amgen BioPharma (Inst), Merck Serono (Inst), Takara Bio (Inst). Paola Queirolo. Consulting or Advisory Role: Pierre Fabre, Roche, Novartis, MSD, Bristol Myers Squibb, Sun Pharma, Sanofi/Regeneron, Merck Serono. Carolin Guenzel. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Anna Polli. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Mahgull Thakur. Employment: Formerly Pfizer. Alessandra di Pietro. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Paolo A. Ascierto. Stock and Other Ownership Interests: PrimeVAX. Consulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seagen, ITeos Therapeutics, Medicenna, Bio-Al Health. Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst). Travel, Accommodations, Expenses: MSD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent evidence suggests additional immunomodulatory properties of RANKL inhibition possibly boosting the clinical efficacy of immune checkpoint inhibitors (ICI)., Methods: We conducted a prospective, multicentre clinical trial in unresectable stage IV melanoma patients with bone metastases who received denosumab in parallel with dual ICI (BONEMET) and performed comprehensive immune monitoring at baseline and 4, 12, and 24 weeks after initiation of therapy. Secondary endpoints included tolerability and efficacy. For comparison, biospecimens from melanoma patients treated with dual ICI without denosumab were analyzed accordingly and served as retrospective reference cohort., Results: In both the BONEMET (n = 16) and the reference cohort (n = 18) serum levels of 17 cytokines, including IFNγ were significantly increased after 4 weeks of treatment. Patients who received ICI and denosumab showed a significantly higher increase in serum CXCL-13 and a significant decrease in VEGFc compared with the reference cohort. While no changes in T cell composition were observed at 4 weeks, patients in the BONEMET cohort showed a significant decrease in the peripheral naïve T-cell population and an increase in CD8 + effector cells after 12 weeks. Treatment-related adverse events occurred with comparable frequency (93.8% in the BONEMET cohort versus 83.3% in the reference cohort). 7/16 patients in the BONEMET cohort and 8/18 patients in the reference cohort achieved disease control., Conclusion: Denosumab in combination with dual ICI modulates cytokine expression and T-cell composition in peripheral blood. The upregulation of CXCL-13, a key factor for initiating tertiary lymphoid structures, strengthens the hypothesis that denosumab indeed boost immunological effects., Competing Interests: Declaration of Competing Interest The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking., Methods: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies., Results: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only., Conclusion: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial., Patients and Methods: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs., Results: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53)., Conclusion: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oliver John Kennedy. None declared. Nina Glassee. Grants or contracts from any entity: MSD. Michal Kicinski. Grants or contracts from any entity: Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Pierre Fabre. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, MSD Australia, MSD, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stéphane Dalle. Grants or contracts from any entity: BMS, MSD - My Institution. Support for attending meetings and/or travel: BMS, Pierre Fabre, MSD. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, MSD, Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, MSD. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, MSD - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, MSD, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak. None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: BMS, MSD, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, MSD, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, BMS, MSD, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: BMS, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: BMS, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, Roche-Genentech, MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, BMS, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: BMS, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, BMS, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera. Consulting fees: BMS. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, BMS, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: BMS, MSD, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: MSD, BMS, Iovance Biotherapeutics. Consulting fees: BMS. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, BMS, Novartis, MSD, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Sara Gandini. None declared. Emanuel Buhrer. None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Mario Mandala. Participation to Advisory Board: BMS, MSD, Novartis, Pierre Fabre Pharmaceuticals. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Sara Valpione. Receipient of an Institutional Amgen Research Grant., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes., Methods: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered., Results: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy., Conclusions: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy., Competing Interests: Declaration of Competing Interest LH received speaker and consultancy fees from BiomeDx, BMS, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. AF received honoraria for presentations and travel support from: BMS, Novartis, Pierre-Fabre. AF reports on participation on Advisory Boards of MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional research grants from BMS Stiftung Immunonkologie for other financial or non-financial interests. AH reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, grants and personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, grants and personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, personal fees from Highlight Therapeutics, grants from Huya Biosciences, personal fees from Kyowa Kirin, personal fees from Iovance, outside the submitted work. CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. CR reports personal consulting fees from BMS, Roche, MSD, Sanofi, Pierre Fabre, Sunpharma, Pfizer, Regeneron. CR received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) from Pierre Fabre, Sanofi, BMS. CR reports personal fees (participation on a Data Safety Monitoring Board or Advisory Board) from Ultimovacs and Regeneron. CR reports stocks/stock options: Ribonexus. DS reports grants, personal fees, non-financial support and other from Novartis, BMS, Amgen, MSD & Array/Pfizer; personal fees and from 4SC, Agenus, Array BioPharma, Astra Zeneca, BioAlta, CureVac, Daiichi Sanyko, Erasma, Haystack, Immatics, Immunocore, InFlarX, Merck Serono, Pierre Fabre, PamGene, Philogen, Neracare NoviGenix, Ultimovacs, Sandoz/Hexal, Sanofi, Seagen, Sun Pharma, Regeneron, and Replimune. GMcA reports on grants or contracts from BMS, Genentech-Roche, Merck to his institution. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. GMcA reports on participation on Data Safety Monitoring or Advisory Board from Pierre Fabre and Pfizer (no payments) and on National Breast Cancer Foundation Board (Australia) (no payments). GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. HG reports on grants or contracts from BMS, Roche, MSD Oncology, Amgen, Novartis, Iovance Biotherapeutics to her institution. HG received consulting fees from BMS, MSD Oncology, Pierre Fabre, Sanofi/ Regeneron. HG received speakers honoraria from BMS, MSD Oncology, Pierre-Fabre, Sanofi/ Regeneron. HG received travel support from MSD, Amgen, Pfizer. JH received scientific grants from BMS, Sanofi, Sunpharma and consulting fees (for advisory boards) from GSK, MSD, Pierre Fabre, Onkowiessen, Sunpharma. JH received honoraria (talks) from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Pierre Fabre, Sanofi, Sunpharma. JH received meeting/travel support from BMS, Iovance, Sunpharma. JH reports on participation on a Data Safety Monitoring Board from Nekvax. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. MS reports on research support from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi, Novartis, Roche, Seattle Genetics, Takeda. MS reports on participation on Advisory Boards of Astra Zeneca, Avencell, Ichnos, Incyte, Janssen, Molecular Partners. MS received honoraria (speaker’s bureau) from: Amgen, BMS/Celgene, Janssen, Gilead/Kite, Novartis, Pfizer, Takeda. PA reports on grants and contracts from BMS, Roche-Genentech, Pfizer, Sanofi. PA received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck, Sharp & Dohme, Novartis, Merck Serono, PierreFabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, Bayer. PA received travel support from Pfizer, BIO-AI Health, Replimmune. PA reports on participation on a Data Safety Monitoring or Advisory Board from BMS, Roche-Genentech, Merck, Sharp & Dohme, Novartis, AstraZeneca, BoehringerIngelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, Erasca. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RK received meeting and travel support from SunPharma, Novartis, Pierre-Fabre. SG reports on clinical trials honoraria to institution from MSD, BMS, Sanofi, Pfizer, BioNTech, EORTC, I-O Biotech, Astra Zeneca, and Regeneron. SG received consulting fees from MSD and BMS and an Online Ticket for ASCO from BMS. TE received speaker and consultancy fees from BMS, Curevac, Merck, MSD, Novartis, Pierre-Fabre, Sanofi, Almiral Hermal, and SUN. TN reports on grants or contracts from NIH, BMS, Astra Zeneca to his institution. TN received consulting fees from Genentech, BMS, Roche, Sanofi, Roivant, Race Oncology. TN participated on Data Safety Monitoring Board/ Advisory Board from Genentech. TR declared speaker’s honoraria and travel grants from Therakos and SUN. AR, CE, MK, VM have declared no conflicts of interest. BR received support from BMS, Merck and Astrazeneca. BR received honoraria (for lectures, presentations, speakers bureaus, manuscript writing or educational events) from BMS, Merck and Astrazeneca. BR reports on participation on a Data Safety Monitoring Board or Advisory Board from BMS, Merck and Astrazeneca. All remaining authors have declared no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Purpose: The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB)., Methods: In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics., Results: Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22-2.52]) and OS (adjusted HR 1.64 [95% CI 1.04-2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89-1.60) or OS (adjusted HR 1.08; 95% CI 0.75-1.57)., Conclusions: Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS., Competing Interests: Declaration of Competing Interest E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, UCB and Almirall outside the submitted work. B.S. Honoraria from MSD, BMS, SUN Pharma, Allmiral, Novartis; Advisory Board for MSD, BMS, Pierre Fabre Pharma, Sanofi; travel support from BMS, Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. M.S. received speaker honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. R.G. declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Scuibb, Novartis, MSD. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Admiral, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, Delcath and Immunocore. C.L. receives personal fees and travel reimbursement from MSD, BMS, Merck, Sanofi, Almirall Hermal, Kyowa Kirin, Biontech, Pierre Fabre, Novartis and Sun Pharma outside the submitted work. K.K. has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. A.Z.M. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. J.M.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. E.G. received travel support from Pierre-Fabre, outside the submitted work. A.M. received travel support from Novartis, outside the submitted work. A.R. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma; outside the submitted work. D.S. received grants and other support from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen; personal fees from Boehringer Ingelheim; personal fees from InFlarX; personal fees and other support from Roche; grants, personal fees and other support from Novartis; personal fees from Incyte; personal fees and other support from Regeneron; personal fees from 4SC; personal fees from Sanofi; personal fees from Neracare; personal fees from Pierre-Fabre; personal fees and other support from Merck-EMD; personal fees from Pfizer; personal fees and other support from Philiogen; personal fees from Array, personal fees and other support from MSD Sharp & Dohme, outside the submitted work. E.L. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work.A.S. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of immunosuppressive therapy (IST) on immune-checkpoint inhibition (ICI) is unclear., Methods: Patients with unresectable advanced melanoma (MM) treated with ICI in the years 2011-2020 were identified from the prospective multicenter German skin cancer registry ADOREG. Patients with IST within 60 days before, or within 30 days after start of ICI were compared to patients without IST. End points were disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) determined by Kaplan-Meier method. Prognostic factors were evaluated in a Cox regression model., Results: Of 814 patients treated with ICI, 73 (9%) received concomitant IST, mainly steroids. Patients with brain metastases (BM) received IST more frequently (n = 34/130 patients; 26%), than patients without BM (39/684 patients; 6%). In patients without BM, IST initiated before, but not IST initiated after start of ICI was significantly associated with worse PFS (univariate hazard ratio (HR) 2.59, 95% confidence interval (95%-CI) 1.07-6.28, p = 0.035; multivariate HR 3.48, 95%-CI 1.26-9.6, p = 0.016). There was no association between IST and OS or DCR. In patients with BM, IST initiated before, but not after start of ICI was significantly associated with worse OS (univariate HR 2.06, 95%-CI 1.07-3.95, p = 0.031; multivariate HR 5.91, 95%-CI 1.74-20.14, p = 0.004). There was no association between IST and PFS or DCR., Conclusion: Patients receiving IST 60 days before start of ICI showed a tendency to an impaired therapy outcome. IST initiated within 30 days after start of ICI, mainly due to early side effects, did not affect the efficacy of ICI therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Corinna Kochanek: None. Catharina Gilde: None. Lisa Zimmer: served as consultant and/or has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre, Sunpharma, Sanofi and Novartis; outside the submitted work. Selma Ugurel: declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma; outside the submitted work. Friedegund Meier: has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche; outside the submitted work. Jochen Utikal: is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi; outside the submitted work. Claudia Pföhler: received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO; outside the submitted work. Rudolf Herbst: is an employee of Helios Kliniken Erfurt GmbH. Sebastian Haferkamp: declares research support from Bristol Myers Squibb speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre and Novartis; outside the submitted work. Julia Welzel: has received honoraria and travel support from Almirall, Bristol Myers Squibb, Novartis, Pierre Fabre and Merck Sharp & Dohme; outside the submitted work. Pia Dücker: declares research support from Bristol Myers Squibb, Merck and Novartis. Speakers and advisory board honoraria from Bristol Myers Squibb, Roche, Sanofi-Aventis, AbbVie, Merck Sharp and Dohme and Pierre Fabre; outside the submitted work. Ulrike Leiter: reports research support from Merck Sharp and Dohme, consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), Merck Sharp and Dohme (personal and institutional), Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, Merck Sharp and Dohme, Novartis, Roche, Almirall Hermal; outside the submitted work. Michael Weichenthal: None. Imke von Wasielewski: Honoraria: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Stemline, Kyowa Kirin. Consultant or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi; Travel, Accommodations. Expenses: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Stemline, Kyowa Kirin; outside the submitted work. Yenny Angela: None. Ralf Gutzmer: declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, and Immunocore; outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAF V600 -mutated melanoma., Methods: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed., Results: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; P Stratified =0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; P Stratified =0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively., Conclusion: In patients with BRAF V600 -mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EL received honoraria from Novartis, Medac, Bristol Myers Squibb, Sanofi, Sun Pharma, and Pierre Fabre, reports consulting/advisory roles with Bristol Myers Squibb, Pierre Fabre, MSD, Sanofi, and Novartis; and received travel/accommodations/expenses from Pierre Fabre, Bristol Myers Squibb, Medac, and Sun Pharma. HG received honoraria from Bristol Myers Squibb, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron; reports consulting/advisory roles with Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, and Sanofi/Regeneron; received research funding from Bristol Myers Squibb, Roche, MSD Oncology, Amgen, Novartis, and Iovance Biotherapeutics; and received travel/accommodations/expenses from Bristol Myers Squibb, MSD, Amgen, and Pfizer. LK-S reports consulting/advisory roles with MSD Oncology, Novartis, Roche, and Bristol Myers Squibb/Medarex; was on speaker’s bureaus for MSD Oncology, Novartis, Roche, Bristol Myers Squibb, Janssen, and AbbVie; and received travel/accommodations expenses from MSD Oncology and Roche. FM reports travel support and/or speaker’s fees and/or advisor’s honoraria from Novartis, Roche, Bristol Myers Squibb, MSD, Pierre Fabre, and Sanofi and research funding from Novartis and Roche. TKE reports consulting/advisory roles with Bristol Myers Squibb/Medarex, Sanofi/Regeneron, Novartis, and Pierre Fabre, and speakers' bureaus for Almirall Hermal GmbH. MZ reports a consultant/advisory role with Bristol Myers Squibb; speakers bureaus for Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre; research funding from Novartis; and travel/accommodations/expenses from Philogen. PAMT received honoraria from Almirall, Bristol Myers Squibb, Kyowa Kirin, Novartis, Pierre Fabre, Roche, Sanofi, and 4SC; reports consulting/advisory roles with Almirall, Bristol Myers Squibb, Novartis, Pierre-Fabre, Merck, Serono, Sanofi, Roche, and Kyowa Kirin; and travel/accommodations/expenses from Pierre Fabre and Bristol Myers Squibb. AHG received honoraria from Novartis, Almirall Hermal GmbH, MSD Sharp & Dohme GmbH, and Pierre Fabre Pharma GmbH; reports consulting/advisory roles with Novartis, Bristol Myers Squibb, and Pierre Fabre Pharma GmbH; and received travel/accommodations/expenses from Novartis and Pierre Fabre. RAH is an employee of Helios Kliniken. KCK reports honoraria from Bristol Myers Squibb, MSD, Novartis, and Sanofi-Aventis; reports consulting/advisory roles with Bristol Myers Squibb and MSD; received research funding from Novartis; and received travel/accommodations/expenses from Bristol Myers Squibb, MSD, Novartis, and Roche. DCZ declares no conflicts of interest. ZM received honoraria from Novartis, Janssen, La Roche-Posay, Bristol Myers Squibb/Medarex, Roche, MSD Oncology, AbbVie, Lilly, and Boehringer Ingelheim, and reports consulting/advisory roles with Lilly and Janssen. MG was on a speaker’s bureau for and received travel/accommodations/expenses from Bristol Myers Squibb. CG reports consulting/advisory roles with Bristol Myers Squibb, MSD Oncology, NeraCare GmBH, Novartis, Roche/Genentech, Sanofi, and CeCaVa; received honoraria from Bristol Myers Squibb, MSD Oncology, NeraCare GmBH, Novartis, Philogen, Roche/Genentech, Sanofi, and CeCaVa; and received research funding from Bristol Myers Squibb, NeraCare GmBH, Novartis, and Roche/Genentech. AR reports consulting/advisory roles with and received honoraria from Novartis and Bristol Myers Squibb; received research funding from Novartis, Bristol Myers Squibb, and Adtec; and received travel/accommodations/expenses from Novartis, Bristol Myers Squibb, Roche, and MSD. SU reports research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre, outside the submitted work. RG reports honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, and Immunocore; consulting/advisory roles with Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, and Immunocore; research funding from Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma, and Sanofi; and travel/accommodations/expenses from Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, and Sun Pharma. JJG reports consulting/advisory roles with Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre Fabre, Philogen, Pfizer, Merck, and Sanofi; participates in a speaker’s bureau for Novartis and Bristol Myers Squibb; received research funding from Pierre Fabre and Bristol Myers Squibb; and received travel/accommodations/expenses from Novartis, Bristol Myers Squibb, and Pierre Fabre. FK reports consulting/advisory roles with Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. JU is an advisory board member for and has received honoraria and travel support from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, LEO Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work. CW-K declares no conflicts of interest. SE declares no conflicts of interest. LZ; received honoraria from Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Roche, and Pierre Fabre; reports consulting/advisory roles with Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Novartis, Sanofi, Pierre Fabre, and Sun Pharma; received research funding from Novartis, and received travel/accommodations/expenses from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. DS received honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, Neracare, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, and Replimune; reports consulting/advisory roles with Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, and Nektar; participates in speaker’s bureaus for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, and Merck KGaA; received research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, Array/Pfizer, and Amgen; and received travel/accommodations/expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, and Sanofi/Regeneron., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions., Patients and Methods: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110)., Results: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients., Conclusions: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial., Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation., Results: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52-1.45) and DMFS (HR 0.82, 95% CI 0.47-1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37-1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56-1.69)., Conclusions: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma., Competing Interests: Declaration of Competing Interest Oliver John Kennedy. None declared. Michal Kicinski. Grants or contracts from any entity: BMS, MSD, Pierre Fabre. Sara Valpione None declared. Sara Gandini None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme (Australia), Merck Sharpe & Dohme, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle. Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp &. Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, Merck Sharp & Dohme Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, Merck Sharp & Dohme. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or. educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi- Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis. - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: Bristol Myer Squibb, Merck Sharp & Dohme, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche- Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, Bristol Myers Squibb, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, Bristol Myers Squibb, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb, Iovance Biotherapeutics. Consulting fees: Bristol Myers Squibb. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Mario Mandala. Participation to Advisory Board: BMS, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown., Patients and Methods: Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan-Meier approach., Results: Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS-mutated (NRASmut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33-47] in NRASmut patients and 41% [95% CI, 35-48] in NRAS-wild type (NRASwt) patients; 2-year OS was 54% [95% CI, 48-61] in NRASmut patients and 57% [95% CI, 50-64] in NRASwt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44-66] in NRASmut patients and 53% [95% CI, 41-67] in NRASwt patients; 2-year OS was 58% [95% CI, 49-70] in NRASmut patients and 62% [95% CI, 51-75] in NRASwt patients). The ORR to anti-PD1 was 35% for NRASwt patients and 26% for NRASmut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (>5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients., Conclusions: The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRASwt and NRASmut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Z. received travel support from Novartis, Sanofi Genzyme, and Bristol-Myers Squibb, outside the submitted work. Fri.M. has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre and Sanofi and research funding from Novartis and Roche. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. P.T. declares speakers and advisory board honoraria from Almirall, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera and 4SC; travel support from Bristol-Myers Squibb and Pierre-Fabre. A.F. served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT. She reports institutional research grants from BMS Stiftung Immunonkologie. U.L. served as consultant and/or has received honoraria from Allmirall Hermal, Roche, Merck Sharp & Dohme, Novartis, Sanofi, Sunpharma and travel support from Sunpharma and Sanofi outside the submitted work. Ja.U. served as consultant and/or received honoraria from BMS, MSD, medac, Novartis, Pierre-Fabre, Sanofi-Aventis and Sun Pharma. Jo.U. is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. J.W. received honoraria and travel support from MSD, Novartis and Pierre Fabre. C.G. is on the advisory board or has received honoraria from Almirall, Amgen, Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Janssen, MSD Sharp & Dohme, Novartis, Pierre-Fabre Pharma, Roche, Sanofi Genzyme, SUN Pharma and Sysmex/Inostix, research funding from Novartis and Sanofi Genzyme, and travel support from Bristol-Myers Squibb, Pierre Fabre Pharma and SUN Pharma, outside the submitted work. CG is co-founder of Dermagnostix and Dermagnostix R&D. RH is employee of Helios Klinikum Erfurt GmbH. Fra.M. (bitte beachten das Friedegund Meier auch mit F.M. abgekürzt wird) served as consultant and/or has received honoraria from Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. L.H. served as consultant and/or has received honoraria from Roche, BiomeDx, BMS, MSD, Novartis, Pierre Fabre, Sanofi, Therakos, Myoncare and Sunpharma outside the submitted work. S.H. served as consultant and/or has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma. C.W. served as consultant and/or has received honoraria from Amgen, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Kyowa Kirin, Novartis, Pierre Fabre, Sanofi, Takeda, and travel support from Bristol-Myers Squibb, Curevac, Pierre Fabre, and Novartis, outside the submitted work. H. L. no relevant conflicts of interest. S.K. received travel support from Sanofi Genzyme outside the submitted work. K.G. No relevant conflicts of interest. E.L. served as consultant and/or has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. D.S. reports grants and other from Bristol-Myers Squibb (BMS), personal fees from BMS, during the conduct of the study; personal fees from Amgen, personal fees from Boehringer Ingelheim, personal fees from InFlarX, personal fees and other from Roche, grants, personal fees and other from Novartis, personal fees from Incyte, personal fees and other from Regeneron, personal fees from 4SC, personal fees from Sanofi, personal fees from Neracare, personal fees from Pierre Fabre, personal fees and other from Merck-EMD, personal fees from Pfizer, personal fees and other from Philiogen, personal fees from Array, personal fees and other from Merck Sharp & Dohme (MSD), outside the submitted work. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; outside the submitted work. L.Z. served as consultant and/or has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. All other authors have nothing to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear., Methods: We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes., Results: From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼ 2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months., Conclusions: RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes., Methods: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG., Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response., Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Valerie Glutsch has received honoraria from Bristol-Myers Squibb (BMS) and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, BMS, Merck Sharp & Dohme (MSD), Sanofi Genzyme and SUN Pharmaceuticals Industries outside the submitted work. Anne Zaremba reports receiving travel support from Novartis, Sanofi Genzyme and BMS, outside the submitted work. Patrick Schummer has received honoraria from BMS, an institutional research grant from Novartis and reports travel support from Novartis, Lilly, Abbvie, Sanofi-Aventis and BMS, outside the submitted work. Peter Mohr declares research support from BMS, Novartis and MSD; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, BMS, MSD, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre Pharma, Sanofi Genzyme, Sun Pharma and Roche, and travel support from BMS, MSD, Novartis and Pierre Fabre. Imke Grimmelmann declares speakers and advisory board honoraria from Almirall Hermal, BMS, MSD, Novartis, Pierre Fabre Pharma, Sanofi Genzyme, Sun Pharma and Roche. Ralf Gutzmer has received honoraria for lectures (personally): Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, Sun Pharma, Sanofi, Pierre-Fabre. Honoraria for advice (personally): BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, Merck Serono, Pfizer, Immunocore. Research grants (to institution): Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, Sun Pharma, Sanofi, Almirall Hermal. Support for meeting participation: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre Pharma and research funding from Novartis and Roche. Claudia Pföhler has received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO, outside the submitted work. Michael Max Sachse reports speakers honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. Frank Meiss served as consultant and/or has received honoraria from Novartis, Roche, BMS, MSD, Pierre Fabre Pharma, Sanofi Genzyme and travel support from Novartis, Sun Pharma and Bristol-Myers Squibb, outside the submitted work. Andrea Forschner is on the advisory board or has received speaker's honoraria or travel support for congress participation from BMS, MSD, Novartis, Pierre Fabre Pharma, Roche. Institutional research support: BMS. Sebastian Haferkamp is on the advisory board or has received honoraria from Pierre Fabre Pharma, Amgen, Novartis, Roche, BMS and MSD, research funding from BMS and Novartis and travel support from Novartis, Roche, BMS, Pierre Fabre Pharma, MSD and Amgen, outside the submitted work. Julia Welzel has received speakers fees from MSD and Pierre Fabre Pharma. Patrick Terheyden declares honoraria from BMS, Novartis, MSD, Pierre Fabre Pharma, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera; travel support from BMS and Pierre Fabre Pharma, outside the submitted work. Rudolf Herbst reports speakers and advisory board honoraria from BMS, Immunocore, Novartis, Pierre Fabre, Roche and Sun Pharma outside the submitted work. Jochen Utikal is on the advisory board or has received honoraria and travel support from Amgen, BMS, GlaxoSmithKline, Immuncore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharma, Roche, outside the submitted work. Carsten Weishaupt is on the advisory board or has received honoraria and travel support from Amgen, BMS, Curevac, MSD, Novartis, Pierre Fabre Pharma, Roche and Sanofi. Alexander Kreuter reports speakers and advisory board honoraria from MSD, Böhringer Ingelheim, Infectopharm, Sanofi, MSD, and Abbvie. Pia Duecker is on the advisory board or has received honoraria from BMS, Novartis, Roche, Sanofi, MSD, and Pierre Fabre Pharma. Dirk Debus reports grants, personal fees, or non-financial support from Amgen, BMS, Kyowa Kirin, MSD, Mylan, Novartis, Pfizer, Pierre Fabre Pharma, Roche, and Sanofi. Dirk Schadendorf reports grants, personal fees and non-financial support from BMS, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Novartis, non-financial support from Regeneron, personal fees from Sanofi, personal fees and non-financial support from MSD, personal fees and non-financial support from Amgen, personal fees and non-financial support from 4SC, personal fees and non-financial support from Merck Serono, personal fees from Array, personal fees and non-financial support from Pierre Fabre Pharma, personal fees and non-financial support from Philogen, personal fees and non-financial support from Incyte, personal fees from Pfizer, outside the submitted work. Selma Ugurel reports research support from BMS and Merck Serono, speakers and advisory board honoraria from BMS, MSD, Merck Serono, Novartis and Roche and travel support from BMS and MSD, and Pierre Fabre Pharma, outside the submitted work. Anja Gesierich reports personal fees from BMS, MSD, is on advisory boards of BMS, Novartis, MSD, Pierre Fabre Pharma, Pfizer, Roche and Sanofi, travel support from BMS, MSD, Novartis and Roche, outside the submitted work. Bastian Schilling is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Incyte, Novartis, Roche, BMS and MSD, research funding from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb and MSD and travel support from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre Pharma, MSD and Amgen, outside the submitted work. All other authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts., Methods: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined., Results: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively., Conclusions: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GL has received travel support for congress participation: Sun Pharma. PJ declares no conflicts of interest. IM declares no conflicts of interest. AS declares no conflicts of interest. JCH receives a scientific grant from BMS, payments ad consultant from Pierre Fabre, MSD, Sunpharma and speaker honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi, GSK, Amgen, Almirall. AF Advisory board: Pierre-Fabre, Roche, Novartis, BMS, MSD, travel support for congress participation: Pierre-Fabre, Roche, Novartis, BMS, honoraria for talks: Roche, Novartis, BMS, MSD, CeGaT, research funding: Stiftung Immunonkologie BMS. All outside the submitted work. JE declars no conflicts of interest. FM has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. LR declares no conflicts of interest. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. MZ has served as consultant or/and has received honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, Novartis, Sanofi Genzyme and SUN Pharma. MS Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma, Immunocore. FR declares no conflicts of interest. AS declares no conflicts of interest. KS declares no conflicts of interest. FM served as consultant and/or has received honoraria from Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sunpharma and Bristol-Myers Squibb, outside the submitted work. RG Honoraria for lectures (personally): Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Honoraria for advice (personally): BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants (to institution): Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Almirall Hermal. Support for meeting participation: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. PT declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, Almirall, and 4SC; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work.BS is on the advisory board or has received honoraria from Almirall, Pfizer, Sanofi, Incyte, Novartis, Roche, Bristol-Myers Squibb (BMS) and MSD Sharp & Dohme, research funding from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb and MSD Sharp & Dohme and travel support from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme and Amgen, outside the submitted work. MS declares no conflict of interest. MH has been a member of advisory boards of Almirall Hermal, Sanofi-Aventis, MSD, 622 BMS, Novartis, and received speaker's honoraria from Galderma and Biofrontera. UL speaker fees: Roche, Novartis, Sanofi, MSD; consultancy: Roche, Sanofi, MSD, Novartis. AZ received travel support from Novartis, Sanofi Grenzyme, Sun Pharma, and Bristol-Myers Squibb, outside the submitted work. CM declares no conflicts of interest. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. EH declares no conflicts of interest. NB declares no conflicts of interest. DS D.S. Served as consultant, advisory board and/or speaker and has received honoraria from Amgen, Array, Bristol-Myers Squibb, Helsinn, Immunocore, InflarX, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, OncoSec, Pfizer, Philogen, Regeneron, Replimune, Sandoz, Sanofi, Sunpharma, 4SC and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Serono, Nektar, Novartis, Pierre Fabre, Sandoz, Sanofi, and 4SC, outside the submitted work. HW declares no conflicts of interest. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. KG declares no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial., Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS., Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers., Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Competing Interests: Conflict of interest statement Alexander Eggermont Consulting fees: Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck/MSD, Nektar, Novartis, Pfizer, SAiRoPA, Sellas, SkylineDx, TigaTx, TTxDiscovery. Payment or honoraria: Biocad, BMS, Merck/MSD. Participation on a Data Safety Monitoring Board or Advisory Board: GSK, Novartis and Pfizer. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences German Cancer Aid. Stock or stock options: SkylineDx and SAiRoPA. Rutger Koornstra Grants or contracts from any entity: Roche. Leonel Hernandez-Aya Grants or contracts from any entity: Bristol Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck, Polynoma, Corvus Pharmaceuticals, Roche, Genentech, Merck Serono, Amgen, MedImmune, Takeda Pharmaceuticals, Moderna Therapeutics. Consulting fees: Massive Bio, Bristol Myers Squibb - Advisory Board. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi, Regeneron Pharmaceuticals - Speakers bureau. Support for attending meetings and/or travel: Sanofi, Regeneron Pharmaceuticals, Bristol Myers Squibb. Anna Maria di Giacomo Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb. Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob Consulting fees: Bristol Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis - Speakers bureau. Support for attending meetings and/or travel: BMS, MSD Oncology, Novartis, Pierre Fabre. Ralf Gutzmer Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb. Caroline Robert Consulting fees: ROCHE, NOVARTIS, PIERRE FABRE, MSD, BMS, SANOFI, PFIZER, AstraZeneca. Oliver John Kennedy None declared. Paul Lorigan Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: BMS, Merck, GSK. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pierre Fabre, Novartis, MSD, BMS. Support for attending meetings and/or travel: BMS, Support to attend ASCO, MSD - Support to attend ASCO. Mario Mandalà Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, NOVARTIS, PIERRE FABRE, SANOFI. Participation on a Data. Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre - Advisory Boards. Michal Kicinski All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: Pierre Fabre - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution), BMS - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution). Stefan Suciu All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: BMS, Pierre-Fabre - Sponsor and provider of academic grants to other EORTC melanoma studies; payments were made to my institution. Sara Valpione None declared. Sara Gandini None declared. Christian Blank Grants or contracts from any entity: BMS, Novartis, NanoString, and 4SC. Consulting fees: BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre - Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Unity Cars – Stocks, Immagene BV – Co-founder. Alexander C.J. van Akkooi Grants or contracts from any entity: Amgen, Merck-Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC. Georgina V Long Consulting fees: GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, Specialised Therapeutics Australia Pty Ltd. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Participation on a Data: Safety Monitoring Board or Advisory Board: See consulting fees, All for advisory boards. Victoria Atkinson Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp & Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Merck - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Pierre Fabre, Merck Sharp & Dohme - Advisory Boards. Andrey Meshcheryakov Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino Payment or honoraria for lectures, presentations, speakers bureauads, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron Pharmaceuticals, QBiotics, Nektar, Eisai - Advisory Board. Shahneen Sandhu Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Merck Serono, Genentech, AstraZeneca - Funding to the institution. Consulting fees: Amgen, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Bristol Myer Squibb - Funding to the institution. James Larkin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare research, Royal College of General Practitioners, VJOncology, Agence Unik, Bristol Myers Squibb - Honoraria for lectures, presentations. Participation on a Data Safety Monitoring Board or Advisory Board: Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, MCA, Inselgruppe, Pfizer, Goldman Sachs, MSD - Advisory Board. Susana Puig Grants or contracts from any entity: Almirall - To My Institution, ISDIN - To My Institution, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Rohe Posay - To Me, Sanofy, Sunpharma - To Me, Pfizer, Roche, Regeneron - To Me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay - To Me, Pfizer, Roche, Regeneron - To Me, BMS, Sunpharma - TO ME. Support for attending meetings and/or travel: Almirall - TO ME. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofy - To Me, Sunpharma, Almirall - To Me, ISDIN, Pfzer, Novartis - TO ME. Paolo A. Ascierto Grants or contracts from any entity: Bristol Myers Squibb, Roche, Genentech, Array BioPharma - To my institution. Consulting fees: Bristol Myers Squibb, Roche, Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche, Genentech, Merck - Advisory Board. Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Piotr Rutkowski Grants or contracts from any entity: Novartis, Roche, Bristol Myers Squibb - My institution. Consulting fees: Bristol Myers Squibb, MSD, Novartis, Roche, Eli Lilly, Pfizer, Pierre. Fabre - Advisory Role - Personal fees. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen - Advisory boards, To me, Pfizer, Novartis, Eli Lilly - speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: See above - Advisory Board. Dirk Schadendorf Grants or contracts from any entit: Bristol Myers Squibb, Novartis, Roche, MSD Oncology, Array BioPharma/Pfizer. Consulting fees: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharna, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Sandoz. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA - speakers bureaus. Support for attending meetings and/or travel: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron. Participation on a Data Safety Monitoring Board or Advisory Board: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar - Advisory Board., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown., Methods: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined., Results: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed., Conclusion: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SMG has past advisory board relationships and travel grant support from MSD, BMS, Novartis and Roche. She received research time support from the University of Zurich and medAlumni. KBB received travel grant support from Novartis and honoraria from MSD. SL has no conflicts of interest to declare. AF has occasional advisory board relationships with Novartis, Roche, MSD and receives travel grant support from Novartis, Roche, BMS. MM has no conflicts of interest to declare. LZ served as a consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. CK declares travel support from Roche. RD has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Takeda, Pierre Fabre and Sun Pharma. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. ZE on prior advisory boards for Pfizer, Novartis, Genentech, Regeneron, Array, Eisai, OncoSec, Signatura, Sun Pharma; Research funding from Novartis and Pfizer. EB: Consulting as an advisory board member for Nektar and BMS. Clinical trial support from Lilly, Novartis, Partners therapeutics, Genentech and BVD. PA has advisory board relationships with BMS, Roche-Genentech, MSD, Array, Novartis, Amgen, Merck Serono, Pierre-Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, Sindax, Astra Zeneca and receives research funding from BMS, Roche, Genentech, Array. RG: Research support (to institution): Pfizer, Johnson & Johnson, Novartis, SUN, Amgen, Sanofi, Merck-Serono. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Merck-Serono and Sanofi. EAR has no conflicts of interest to declare. CH has no conflicts of interest to declare. DBJ has advisory board relationships with Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis and Oncosec and receives research funding from BMS and Incyte. AG: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. PK has occasional advisory board relationships with BMS, Roche, Amgen, Novartis, MSD and receives travel grant support from BMS and MSD. NB has no conflicts of interest to declare. JVC has no conflicts of interest to declare. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. MAW has an advisory role for Array Biopharma. JC has served as a consultant and has received honoraria from Sanofi-Genzyme and Bristol-Myers Squibb. VA has advisory board role for BMS, MSD, Novartis, Roche, Pierre Fabre, Nektar, Q Biotics; speakers fees from BMS, MSD, Novartis, Pierre Fabre, Limbic and travel support from BMS. JLS: honoraria from Bristol-Myers Squibb, MSD and Pierre Fabre. OM has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Pierre Fabre. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. JCH has research support from BMS, advisory board relationship with Pierre Fabre, Sanofi, Sun Pharma and MSD; receives speakers honoraria from BMS, MSD, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. BW receives research funding from BMS und MSD. LEH has no COI nor funding to disclose. DS: Dr. Schadendorf reports grants, personal fees and other from BMS, during the conduct of the study; personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from Novartis, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees from Sanofi/Regeneron, non-financial support from Merck, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, outside the submitted work. GM receives reimbursement of clinical trial costs to his institution from Roche-Genentech and Array Biopharma/Pfizer. PAO reports research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus and Roche/Genentech. CB has advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; has research funding (incl IIS funding) from BMS, MSD, 4SC, Novartis, NanoString; and has stock ownership from Uniti Cars, co-founder Immagene BV. CR has occasional advisory board relationships and receives honoraria from BMS, MSD, GSK, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi. RJS reports grant support from Merck and Amgen, as well as personal fees for consulting/advisory board membership for AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune. AH reports grant support and personal fees from Amgen, BMS, Eisai, Immunocore, MerckPfizer, MSD/Merck, Novartis Pharma, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and from SeaGen outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, OncoSec, Pierre-Fabre, QBiotics, Regeneron, Roche, Merck and Sanofi and received honoraria from BMS, MSD and Novartis. CG: Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. MAD: is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. He has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. AMM: Advisory board fees from BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF-targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting., Methods: The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan-Meier and univariate/multivariate Cox regression analyses were performed as appropriate., Results: median age at first diagnosis was 54 years (range 16-84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [N = 87] vs 5.0 months [N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33-0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32-0.70]) as well as the validation cohort (mPFS of 7.3 months [N = 80] vs 5.8 months [N = 32]; HR = 0.67 [95%CI 0.41-1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18-0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45-0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35-0.75, P = 0.0001)., Conclusions: In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.T. reported no relevant conflicts of interest. J.M. declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. A.Z. declares travel support from Novartis, Sanofi Genzyme and Bristol-Myers Squibb, outside the submitted work. R.M. reported no relevant conflicts of interest. E.C. reported no relevant conflicts of interest. G.L. declares travel support from Sun Pharma, outside the submitted work. P.J. reported no relevant conflicts of interest. R.H. declares speakers and advisory board honoraria from BMS, MSD, Novartis, Pierre Fabre, Roche and SUN-Pharma, outside the submitted work. P.T. declares honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; travel support from Bristol-Myers Squibb and Pierre-Fabre, outside the submitted work. J.U. declares advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi, outside the submitted work. C.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. J.Ul declares travel support: Medac, Sun Pharma; consulting: Bristol-Myers Squibb, Sun Pharma; lectures: Bristol-Myers Squibb, MSD, Merck, Novartis, Roche, Sanofi, Sun Pharma; grants: Novartis, outside the submitted work. A.K. reported no relevant conflicts of interest. P.M. declares research support (to institution): Bristol-Myers Squibb, Novartis, MSD. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Bayersdorf, Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN, Merck-Serono, Sanofi, outside the submitted work. R.G. invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, Merck Serono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre, outside the submitted work. F.M. declares travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche, outside the submitted work. E.D. reported no relevant conflicts of interest. M.W. reported no relevant conflicts of interest. J.K. reported no relevant conflicts of interest. I.M. reported no relevant conflicts of interest. A.S. reported no relevant conflicts of interest. A.P. reported no relevant conflicts of interest. E.L. served as a consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work. L.Z. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sun Pharma and Novartis, outside the submitted work.E.H. reported no relevant conflicts of interest. S.U. declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. D.S. reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. K.G.: No relevant conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: NF1-mutated tumours represent a small subset (10-15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date., Methods: This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432)., Results: Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively)., Conclusions: Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented., Methods: COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed., Results: Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups., Conclusion: The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients., Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately., Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%., Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Z.: received travel support from Novartis, Sanofi Genzyme, and Bristol Myers Squibb, outside the submitted work. M.P.: No relevant conflicts of interest. J.C.H.: received honoraria from talks: BMS, MSD, Roche, Novartis, Sun Pharma, Almirall, Sanofi, honoraria from adboards: Sun Pharma, Sanofi, Pierre Fabre, scientific grant: BMS. V.G.: received honoraria from Bristol Myers Squibb (BMS) and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, BMS, Merck Sharp & Dohme (MSD), Sanofi Genzyme and SUN Pharmaceutical Industries outside the submitted work. Z.F.: No relevant conflicts of interest. C.L.: served as consult and and/or has received honoraria and or received travel support from Roche, Novartis, Pierre Fabre, MDS, Merck, BMS, Sanofi, Sun Pharma, Biontech, Kyowa Kirin, Almirall Hermal outside the submitted work. D. R.-S. has received honoraria for talks from Roche and Pierre Fabre and has received travel grants from Novartis, Pierre Fabre and Sanofi Genzyme. R. G.: received honoraria: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabr; consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer; Funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi; travel, accommodations, expenses: Roche, BMS, SUN, Merck Serono, Pierre Fabre. J. U. is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. Se.H.: served as consultant and/or has received honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sun Pharma outside the submitted work. L.R.: No relevant conflicts of interest. K.C.K.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun pharma and Novartis, outside the submitted work. C.W.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Sanofi, Takeda and travel support from Amgen, Bristol Myers Squibb, Curevac, Pierre Fabre and Novartis, outside the submitted work. A.M.: has received speaker or consultant fees from AbbVie, Almirall, Novartis, Bristol Myers Squibb, Pfizer, and Roche, outside of the submitted work; A.M. is employed by Novartis; the work described in this publication was completed prior to his employment at Novartis. K. M.T.: served as consultant and/or has received honoraria from Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Sanofi, Sun Pharma, LEO, Galderma, and Candela and travel support from Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, and Candela, outside the submitted work. T.W.: received honoraria and travel support from Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, outside the submitted work. C.P.: received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Sanofi ‘Genzyme, Sun Pharma, Amgen and LEO. A. R.: reports non-financial support from Amgen, non-financial support from Roche, personal fees and non-financial support from Merck/MSD, grants and non-financial support from Novartis, grants and non-financial support from BMS, non-financial support from TEVA, grants from Adtec, outside the submitted work. S. U.: declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. L.Z.: served as consultant and/or has received honoraria from Roche, Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sun Pharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. N.S.: No relevant conflicts of interest. A.S.: No relevant conflicts of interest. F.K.: No relevant conflicts of interest. L.H.: served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Curevac, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sun Pharma and a research grant from Novartis, outside the submitted work. Fri.M.: has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Fra.M.: served as consultant and/or has received honoraria from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme and travel support from Novartis, Sun Pharma and Bristol Myers Squibb, outside the submitted work. M.S.: participated in advisory boards of Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Kyowa Kirin, Immunocore and Sanofi Genzyme. M.S. received travel accommodation and expenses by Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. B.S.: received personal honoraria from Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol Myers Squibb, Merck Sharpe & Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol Myers Squibb, Merck Sharpe & Dome, and Pierre Fabre, all paid to the institute. Su.H.: No relevant conflicts of interest. D.S: reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sun Pharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. E.L.: served as consultant and/or has received honoraria from Amgen, Actelion, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, Sun Pharma and travel support from Amgen, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Sun Pharma and Novartis, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear., Patients and Methods: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres., Results: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels., Conclusion: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency., Competing Interests: Conflict of interest statement Honoraria: R.G. (Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (Roche, BMS, MSD, Novartis, Sanofi, Pierre Fabre), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, Galderma, Candela, CSL Behring), K.C.K. (Merck sharp and Dohme, Novartis and Bristol Myers Squibb and travel support from Novartis), J.C.H. (BMS, MSD, Roche, Novartis, Sanofi), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Sanofi-Aventis), D.D. (MSD, Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, LEO Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, MSD, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, CureVac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Consultant or Advisory Role: R.G. (BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, Merck Serono, Bayer, Pfizer), C.P. (Roche, Novartis, Merck Serono), L.Z. (MSD, BMS, Novartis, Pierre Fabre, Sanofi), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre Fabre, LEO, CSL Behring) K.C.K. (BMS, MSD, Novartis, Pierre Fabre), J.C.H. (MSD, Sun Pharma, Pierre Fabre), S.U. (BMS, MSD, Merck Serono, Novartis and Roche), C.B. (Roche, BMS, MSD, Novartis, Merck Serono, Sanofi-Aventis, Pierre Fabre), D.D. (Novartis, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), R.H. (Roche, BMS, Novartis, Pierre Fabre), L.H. (BMS, Roche, Novartis, MSD, Amgen, Curevac, Sanofi, Pierre Fabre), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermal, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I.G. (Novartis, Roche, BMS, MSD, Sanofi), T.K.E. (Roche, Pierre Fabre, Novartis, BMS, MSD, Sanofi). Research Funding: R.G. (Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono, SUN Pharma, Sanofi), L.Z. (Novartis), K.C.K. (Novartis, Merck Sharp and Dohme), J.C.H. (BMS), S.U. (BMS, Merck Serono), J.U. (Apogenix, NOXXON Pharma, Elsalys Biotech, TILT Biotherapeutics, BioNTech RNA Pharmaceuticals, RHEACELL, Merck), L.H. (Novartis), F.M. (Novartis, Roche), I.G. (Roche, Pfizer, Novartis). Travel, Accommodations, Expenses: R.G. (Roche, BMS, SUN, Merck Serono, Pierre Fabre), C.P. (Roche, BMS, MSD, Novartis, Merck Serono, Celgene, AbbVie, LEO), L.Z. (BMS, Pierre Fabre, Amgen, Sanofi, Sun Pharma, Novartis), K.-M.T. (Roche, BMS, MSD, Novartis, Pierre-Fabre, LEO, Candela) K.C.K. (MSD, Novartis and Bristol Myers Squibb, Novartis), J.C.H. (Pierre Fabre, BMS), S.U. (BMS, MSD), D.D. (Amgen, BMS, MSD, Mylan, Novartis, Pierre Fabre, Roche, Sanofi), J.U. (Amgen, Bristol Myers Squibb, GSK, Leo Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi), C.L. (Roche, Pierre Fabre, Novartis, BMS, MSD, Merck, Almirall Hermall, Sun Pharma, Sanofi, BioNTech, Kyowa Kirin), F.M. (Novartis, Roche, BMS, MSD, Pierre Fabre), I. G. (Novartis, Roche, BMS, MSD). Stock ownership: none. Patent application/registration: none. Employment: none. No conflict of interest: C.R. and C.K. had no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking., Methods: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting., Results: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding., Conclusions: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Knispel: Travel support from Bristol-Myers Squibb and Amgen. Maximilian Gassenmaier: Consultant or Advisory Role: Novartis; Research funding: Novartis. Carmen Loquai: Advisory role/Speakers fee/Travel support: BMS, MSD, Merck, Novartis, Pierre Fabre, Sunpharma, Sanofi, Roche, Almirall Hermal, Biontech, Kyowa Kirin. Cindy Franklin: Advisory board or received honoraria of BMS and Novartis and received travel grants from BMS, Novartis and Pierre Fabre. Ralf Gutzmer: Personal Honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Consultant or advisory role: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, MerckSerono, Bayer, Pfizer. Research funding: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, all paid to the institution. Travel, accommodations, expenses: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. Bastian Schilling: Personal honoraria from Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pfizer/EMD Serono, Pierre Fabre and Roche; has an advisory role for Bristol-Myers Squibb, Merck Sharpe and Dome, Novartis, Pierre Fabre and Roche; and has received research funding from Bristol-Myers Squibb, Merck Sharpe and Dome, and Pierre Fabre, all paid to the institute. Andreas Stang: Speaker honoraria from Merck Serono. Selma Ugurel: Research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and Travel support from Bristol-Myers Squibb, and Merck Sharp & Dohme. Lisa Zimmer: Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; Consultant or advisory role: BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; Research funding to institution: Novartis; Travel support: BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. Carina N Owen: Travel support from Merck Sharp Dohme. Jessica C Hassel: Honoraria from BMS, MSD, Novartis, Roche, Pierre Fabre, Sanofi; Consultant or advisory role: MSD, Pierre Fabre, Sunpharma; Research funding: BMS; Travel support: Pierre Fabre. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Carola Berking: Honoraria from BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi-Aventis for consultancy and/or presentations on scientific symposia. Douglas B Johnson: Advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis and research funding from BMS and Incyte. Elisabeth Livingstone: Intermittent advisory board relationships with Roche, BMS, Novartis, Sanofi and Actelion and has received travel grants and honoraria from Roche, BMS, MSD, Amgen, Pierre Fabre, SunPharma, Novartis, Boehringer-Ingelheim, medac. Alexander M Menzies: Advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. Simone M Goldinger: past advisory boards for BMS, MSD, Roche and Novartis. Kai-Martin Thoms: Honoraria from BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO, Candela; Consultant or advisory role: BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO; Travel support: BMS, MSD, Roche, Novartis, Pierre Fabre, LEO. Dirk Schadendorf: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Array, Immunocore, InFlaRX, Nektar, Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Regeneron, SunPharma, Sandoz, Sanofi, Ultimovacs and 4SC. He also received research funds from Bristol-MyersSquibb, Roche, Amgen and Novartis. Travel support: BMS, Pierre Fabre, Sanofi, Nektar, Novartis, Roche, Merck Serono and Sunpharma. Dennis Niebel: Has received speakers’ honoraria or travel expense reimbursements from BMS, Novartis, GSK, Celgene and MSD. Judith Sirokay: Honoraria from Roche, BMS, MSD, Novartis, Consultant or advisory role: Novartis, MSD; Travel support: BMS, Pierre Fabre. Peter Mohr: Has/had a consultant/advisory role in the last 2 years for Amgen, Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Merck Serono, Pierre Fabre, Pfizer, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Travel support: Amgen, BMS, Merck Sharp & Dohme (MSD), Pierre Fabre, Sanofi, Novartis, Roche and Sunpharma. Laura Susok: Collaboration with BMS, Novartis, Sunpharma, MSD, Roche, Pierre Fabre. Paolo Ascierto: Has/had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array and travel support from MSD. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck Serono, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO, UCB, Sunpharma. Clinical studies: Novartis, BMS. Lucie Heinzerling: Consultant or advisory role: Amgen, BMS, Curevac, Novartis, Pierre Fabre, Roche, Sanofi, MSD; research funding (to institution): Novartis. Patrick Schummer: honoraria: Bristol-Myers Squibb (BMS); institutional research grant: Novartis; Travel support: Novartis, Lilly and BMS. Thomas Eigentler: Has/had a consultant/advisory role in the last 2 years for Bristol-Myers Squibb (BMS), Roche-Genentech, Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Philogen, Sanofi. He also received research funds from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD) and Novartis. Katharina C. Kähler: Serves as consultant to Roche, BMS, MSD, Pierre Fabre and received travel grants and speaker fees from Roche, BMS, MSD, Amgen, Pierre Fabre and Philogen. Julia Tietze: Honoraria from Roche, BMS, MSD, Amgen, Sanofi, Travel support: Pierre Fabre, Novartis, BMS. Georgina V. Long: Is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. All other authors (Felix Kiecker, Raphael Reinhard, Konstantin Drexler, Christopher Cann, Lydia Reinhardt, Carsten Weishaupt, Maria I Fleischer, Leonie Bluhm) declared to have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending., Methods: Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity., Results: Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan-Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity., Conclusions: PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated., Competing Interests: Conflict of interest statement M.S. received honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD) and Novartis and Pfizer. U.L. has received honoraria from Roche, Merck Sharp and Dohme, Novartis, SUN, Sanofi; has received speaker fees and advisory Board honoraria from Roche, Novartis, Sun, Sanofi; has received research funding from MSD. C.L. has been a member of the advisory board of BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, Novartis; has received speaker fees and travel reimbursement from BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, and Novartis. L.Z. has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; has been a consultant or a member of the advisory role from BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; has received research funding from Novartis; has received travel support from BMS, Pierre Fabre, Sanofi, Amgen, Novartis, and Sunpharma. S.U. has received research support from Bristol Myers Squibb and Merck Serono; has received speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche; has received travel support from Bristol Myers Squibb, Merck Sharp and Dohme. R.G. has received honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre; has been as a consultant or a member of the advisory role from BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre Fabre, 4SC; has received research Funding from Novartis, Pfizer, Johnson & Johnson, Amgen, Merck Serono; has received travel fees, accommodation fees and expenses from Roche, BMS, SUN, Merck Serono and Pierre Fabre. K.M.T. has received honoraria from BMS, Roche, MSD, Novartis, Pierre Fabre, LEO, AbbVie, Galderma, Candela; has been as a consultant or a member of the advisory role from BMS, Roche, MSD, Novartis, Pierre Fabre, LEO, Sun Pharma, AbbVie; has received travel grants from BMS, Roche, Novartis and Pierre Fabre. A.H.E has received advisory honoraria from Biotest AG, MSD Oncology, Galderma, Janssen Cilag, AbbVie, as well as speaker's honoraria from Roche Pharma. J.C.H. has received honoraria for talks from BMS, MSD, Roche, Novartis; has been an advisory board member for MSD and Pierre Fabre; has received scientific grant support from BMS; has received travel grants from BMS and Pierre Fabre., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up., Methods: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups., Results: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM., Conclusions: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma., Competing Interests: Conflict of interest statement P.A.A. served a consulting or advisory role for BMS, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes. P.A.A. received research funds from BMS, Roche-Genentech, Array and received travel fees from MSD. R.D. had intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi and Catalym outside the submitted work. H.J.G. reports receiving consulting fees from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen and Pierre Fabre and research funding from Bristol-Myers Squibb, Merck Sharp & Dohme and Roche outside the submitted work. K.T.F. served as a member of the Board of Directors for Clovis Oncology*, Strata Oncology*, Vivid Biosciences*, Checkmate Pharmaceuticals ; served as a member of the Corporate Advisory Board for X4 Pharmaceuticals*, PIC Therapeutics*; served as a member of the Scientific Advisory Board for Sanofi, Amgen, Asana, Adaptimmune, Fount *, Aeglea, Array BioPharma, Shattuck Labs *, Tolero, Apricity *, Oncoceutics*, Fog Pharma *, Neon, Tvardi *, served as a consultant Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Cell Medica, Debiopharm*; and as a stock shareholder. A.A. has received honoraria from, had a consulting or advisory role with or been a member of the speakers bureau for Novartis, Roche, Merck, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi and Amgen outside the submitted work and has received travel expenses from the same companies. M.M. has received personal fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis and Pierre Fabre outside the submitted work. G.L. has received consulting and advisory board fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Amicus, Boehringer-Ingelheim and Novartis outside the submitted work. C.G. has received personal fees and research funding from Novartis and Pierre Fabre during the conduct of the study. C.G. has received personal fees for presentations and consulting or advisory roles from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, NeraCare, Philogen, Roche and Sanofi and research funding from Bristol-Myers Squibb, Neracare, Roche and Sanofi outside the submitted work. D.S. has received personal fees and patients’ fees from Pierre Fabre and Array BioPharma during the conduct of the study. D.S. has received honoraria and travel expenses from, has a consulting or advisory role with, been a member of the speakers bureau for and received personal fees from, Amgen, Boehringer Ingelheim, LEO Pharma, Roche, Novartis, Hexal, InflaRx, Helsinn, GI Innovation, Immunocore, Sanofi, Neracare, Merck Sharp & Dohme, Incyte, Regeneron, 4SC, AstraZeneca, Bristol-Myers Squibb, Pierre Fabre, Merck-EMD, Pfizer, Philogen, Ultimovacs and Sun Pharma, all outside of the submitted work. I.K. is an advisory board member for and has received travel expenses from Bristol-Myers Squibb, Novartis and Merck Sharp & Dohme during the conduct of the study. R.G. received research support from Pfizer, Johnson&Johnson, Novartis, Amgen, Merck Serono; received honoraria for lectures from RochePharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck Serono, Pierre Fabre, AstraZeneca, SUN; received honoraria for advice from RochePharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Takeda, Pierre Fabre, Merck Serono, 4SC, Incyte, SUN; Support for participation in meetings from Bristol-Myers Squibb, Pierre Fabre, Merck Serono, SUN, RochePharma. J.W.B.dG. received personal fees from Roche, Bristol-Myers Squibb, Pierre Fabre, Servier, Novartis and Merck Sharp & Dohme outside the submitted work. C.L. reports receiving personal fees from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, LEO Pharma, Amgen, Biontech and Sun Pharma outside the submitted work. A.G. is an employee at Pfizer Inc. M.D.P. is an employee at Pfizer Inc. C.R. is a consultant for Pierre Fabre, Roche, Novartis, Bristol-Myers Squibb, Merck, Array BioPharma, Merck Serono and Amgen outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients., Methods: BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed., Results: All BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed., Conclusions and Relevance: These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients., Trial Registration: ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The tumor burden within the sentinel lymph node (SLN) is not included in the 8th edition of the American Joint Committee of Cancer (AJCC) melanoma classification. Therefore, we analysed the prognostic relevance of the SLN tumor burden in the stage III subgroups., Patients and Methods: A total of 736 patients with melanoma with positive SLN and long-term follow-up (mean, 64.4 months; median, 59.0 months) were assessed. SLN tumor burden was evaluated by the maximum diameter of the largest deposit in all patients., Results: By univariate Kaplan-Meier analyses, melanoma-specific survival (MSS) of patients in stage IIIA, IIIB and IIIC and lower sentinel tumor burden (cut-offs ≤0.5 mm and ≤1 mm) was significantly better than that in patients with higher sentinel tumor load (>0.5 mm and >1 mm). By multivariate analysis using the Cox model, the maximum diameter of the largest deposit (cut-off ≤0.5 mm versus >0.5 mm and cut-off ≤1 mm as continuous variables) represented an independent prognostic parameter for MSS in stage III patients. Cut-off of 0.5 mm showed a slightly higher area under the receiver operating characteristic curve (AUC = 0.617) when than the cut-off of 1 mm (AUC = 0.599)., Conclusion: The prognosis of patients with stage III melanoma can be determined more precisely if the SLN tumor burden is considered, also within the existing AJCC subgroups. Thus, this parameter should be included in future classifications, and our study provides benchmarks in estimating prognosis and counselling patients with melanoma with positive sentinel nodes beyond the 8th AJCC Cancer Staging Manual. The optimal cut-off remains for SLN tumor burden remains to be determined, but our results suggest that a cut-off lower than 1 mm is preferable., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Limited data are available on nivolumab in challenging subgroups with advanced melanoma. We report outcomes of nivolumab after prior ipilimumab in patients who are typically excluded from clinical trials., Patients and Methods: In this phase II, single-arm, open-label, multicentre study (CheckMate 172), patients with advanced melanoma who progressed on or after ipilimumab received nivolumab 3 mg/kg, every 2 weeks for up to 2 years. The primary objective was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: At a minimum follow-up of 18 months, grade ≥3 treatment-related select AEs with the most variation across subgroups were diarrhoea and colitis (1.1% [n = 11] and 0.3% [n = 3] for the total population [n = 1008]; 0.6% [n = 1] and 0.6% [n = 1] for patients with an asymptomatic central nervous system [CNS] metastasis [n = 165; 16.4%]; 4.5% [n = 3] and 3.0% [n = 2] for patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 2 [n = 66; 6.5%]; 2.4% [n = 2] and 0% for those who experienced a grade 3/4 immune-related AE [irAE] with prior ipilimumab [n = 84; 8.3%]; and 0% and 0% for autoimmune disease [n = 25; 2.5%], respectively). Median overall survival was 21.4 months in the total population and was 11.6, 2.4, 21.5, and 18.6 months in patients with a CNS metastasis, ECOG PS 2, a grade 3/4 irAE with prior ipilimumab, and autoimmune disease, respectively., Conclusions: In this large, phase II clinical trial of patients with advanced melanoma who progressed on or after ipilimumab, nivolumab demonstrated a safety profile consistent with that of prior clinical trials. ClinicalTrials.gov ID: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The American Joint Committee on Cancer (AJCC) 8th staging system introduced several revisions. To assess the impact of the 8th edition American Joint Committee on Cancer (AJCC8) staging system on subgrouping and survival, patients with melanoma from two tertiary skin cancer centres were classified according to both the 7th edition American Joint Committee on Cancer (AJCC7) and AJCC8., Methods: A total of 1948 patients aged ≥18 years with cutaneous melanoma stage II-IV were included. The impact of sex and age on reclassification was assessed by log binomial models. The inverse probability of censoring weighting method was used to compute ROC curves from time-to-event data to assess the discriminatory ability of AJCC7 and AJCC8. Melanoma-specific survival (MSS) and overall survival (OS) were calculated, and age- and sex-adjusted MSS hazard ratios were estimated using Cox proportional hazards models., Results: Of all, 23.5% of patients were assigned a different subgroup when classified according to AJCC8. Owing to upshifting to stage IIIC (AJCC7 24.8% vs. AJCC8 50.8%), patient numbers of stages IIIA and IIIB decreased from 28.7% to 16.2% and 46.5% to 28.3%. The prediction accuracy for AJCC7 and AJCC8 was comparable (integrated time-dependent area under the curve [AUC] of 0.75 and 0.74, respectively). Five-year MSS of IIB and IIC AJCC8 was poor and lower than that of IIIA AJCC8 (80%, 67% and 89%, respectively). Compared to results of the International Melanoma Database and Discovery Platform, 5-year MSS was 10-15% points lower for stages IIC, IIIB and IIIC., Conclusions: Upshifting affects primarily stage III subgroups, while effects in stage II are minor. Stage IIB/C (AJCC8) patients have 67-80% MSS and should be considered for adjuvant treatment, while in stage IIIA, the indication of adjuvant treatment is questionable., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab., Patients and Methods: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ≥3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively., Conclusions: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS., Gov Id: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib., Patients and Methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated., Results: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event., Conclusion: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies., Trial Registration: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38)., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy., Patients, Methods and Results: Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00])., Conclusions: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence., Patients and Methods: Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS., Results: The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 [95% confidence interval {CI} 9.3-15.1]; 9.8 [95% CI 6.9-12.6] versus 5.1 [95% CI 2.7-7.5]; P = .03)., Conclusion: SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common., Methods & Results: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAF V600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1B high cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death., Conclusion: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy., Methods: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised., Results: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases., Conclusion: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Anti-programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immunotherapy is now routinely used to treat several cancers. Clinical trials have excluded several populations, including patients with solid organ transplant, HIV infection and hepatitis B/C infection. We examined the safety outcomes of these populations treated with anti-PD-1/PD-L1 treatment in a multicentre retrospective study., Methods: Patients from 16 centres with advanced cancer and solid organ transplant, HIV infection or hepatitis B/C infection were included. Demographic, tumour, treatment, toxicity and outcome data were recorded., Results: Forty-six patients were included for analysis, with a median age of 60 years, and the majority of patients diagnosed with melanoma (72%). Among six patients with solid organ transplants, two graft rejections occurred, with one resulting in death, whereas two patients achieved partial responses. There were four responses in 12 patients with HIV infection. In 14 patients with hepatitis B, there were three responses, and similarly, there were three responses in 14 patients with hepatitis C. There was no unexpected toxicity in any viral infection group or an increase in viral load., Conclusion: Patients with HIV or hepatitis B/C infections treated with anti-PD-1/PD-L1 immunotherapy may respond to treatment without increased toxicity. Given the risk of graft rejection in solid organ transplant patients and also the potential for response, the role of anti-PD-1/PD-L1 immunotherapy needs to be carefully considered., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Advanced cutaneous squamous cell carcinoma (aSCC) is an area of unmet medical need and no treatment standards are established. Recently, an anti-PD-1 inhibitor received FDA breakthrough therapy designation. The aim of the study was to describe the clinical course, therapeutic management and prognosis of aSCC under real-life conditions., Patients and Methods: In a retrospective study performed in 24 German and Austrian hospitals and doctor's offices, patient and tumour characteristics of patients diagnosed with aSCC between January 1, 2010 and December 31, 2011 and their disease course was documented. Advanced SCC comprised either locally advanced SCCs (laSCC) or metastatic SCCs (mSCC) with any kind of metastatic spread., Results: Data of 190 patients with aSCC were analysed. Median age at time of diagnosis of aSCC was 78 years. LaSCC was diagnosed in 76 patients (40%), 114 patients (60%) had mSCC. Once diagnosed with laSCC, most patients (59%) did not receive any therapy, whereas in 92% of mSCC patients at least one type of therapy was performed. Only 32 patients (29 mSCC, 3 laSCC) received systemic antitumour therapies, mostly EGFR inhibitor-based regimens. Mean duration of response was short (17-months laSCC patients, 3-months mSCC patients). Only 2 patients achieved a complete response, 27% had a partial response, 43% disease stabilisation. At diagnosis of aSCC, ECOG status was 0-1 in most patients. Non-malignant comorbidities influenced the decision on SCC-specific therapy in 39 patients (21%)., Conclusions: Our data show the high medical need for efficient and tolerable antitumour therapies and demonstrate that despite older age and comorbidities, most patients can be expected to be fit for treatment. This study provides a historical context for emerging aSCC treatments., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients., Patients and Methods: We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues. The oligocentre cohort 1 included 83 patients whose tumour tissues were analysed retrospectively with the anti-PD-L1 antibody clone E1L3N. The multicentre cohort 2 included 58 patients whose tumour tissues were analysed prospectively within the framework of the "Registry of the Arbeitsgemeinschaft Dermatologische Onkologie" (ADOREG) and "Tissue Registry in Melanoma" (TRIM) project using the anti-PD-L1 antibody clone 28-8., Results: PD-L1 expression in pre-treatment tumour tissue did not correlate with response or survival to BRAFi-based therapies in both MM patient cohorts. This finding was not influenced by retrospective versus prospective immunohistochemistry analyses, oligocentre versus multicentre cohorts or the different anti-PD-L1 antibody clones used. In cohort 1, PD-L1 positivity was detected in tumour tissue of 41.0% and 18.1% of patients (cut-off 1% and 5%, respectively). In cohort 2, 58.6% and 39.7% of patients showed PD-L1 positivity (cut-off 1% and 5%, respectively)., Conclusion: In two independent cohorts including a total of 141 MM patients, PD-L1 expression in tumour tissue did not correlate with the outcome of BRAFi-based treatment. Therefore, PD-L1 cannot be recommended for the use as a predictive biomarker of BRAFi-based therapy in BRAF V600-mutated MM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM., Patients and Methods: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis., Results: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001)., Conclusion: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited., Patients and Methods: Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy., Results: In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity., Conclusion: While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)