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Background: Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non-responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing anti-tumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent., Methods: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS)., Results: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301)., Conclusion: Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JK has received honoraria from Bristol-Myers Squibb and Sanofi Genzyme and has received travel support from SUN Pharma and Pierre Fabre, outside the submitted work. GG has received honoraria from Bristol-Myers Squibb and has research funding from Sanofi Genzyme, outside the submitted work. IsH has received honoraria from Bristol-Myers Squibb and Sysmex, outside the submitted work. 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; outside the submitted work. UL declares research support from Merck Sharp & Dohme; speakers and advisory board honoraria from Sanofi, Regeneron, Sun Pharma, Merck Sharp & Dohme, Allmiral and Novartis; and meeting and travel support from Pierre Fabre, and Sun Pharma; outside the submitted work. CB declares honoraria as speaker and/or advisory board member from Almirall Hermal, Bristol-Myers Squibb, Delcath, Immunocore, InflaRx, Leo Pharma, MSD, Novartis, Pierre Fabre, Regeneron, and Sanofi, outside the submitted work. RG received honoraria for lectures/ advisory boards from Bristol Myers Squibb, Merck Sharp Dohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/ Regeneron; Meeting support SUN Pharma, Boehringer Ingelheim, PierreFabre; Research support (to institution) Novartis, Sanofi/ Regeneron, Merck Serono, Amgen, SUN Pharma, Kyowa Kirin, Almirall Hermal. DS Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Sandoz. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron. 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. 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. IvW received honorairia as speaker from Novartis, BMS, MSD, Sanofi, Stemline, Kyowa Kirin and as consultant or advisory from BMS, MSD, Sanofi; travel, accommodations and expenses from Novartis, BMS, MSD, Sanofi, Stemline and Kyowa Kirin. FriM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, BMS, MSD, Pierre Fabre, Sanofi and Immunocore. SH declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Immunocore, Novartis, Pierre-Fabre, Sanofi, Sun Pharma outside the submitted work. KD received financial support (speaker’s honoraria, advisory boards, travel expense reimbursements or grants) from Abbvie, Bristol-Myers-Squib, Novartis, and Pierre-Fabre. 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. SAW received honoria from Bristol Myers Squibb, Novartis and Sun Pharma, outside the submitted work. CP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sunpharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Kyowa Kirin, L′Oréal, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. JeU is on the advisory board or has received honoraria and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi and SUN Pharma outside the submitted work. FraM 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, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. JW has received honoraria and travel support from Abbvie, Almirall, BMS, Boehringer Ingelheim, Janssen, Infectopharm Leo, Lilly, Mibe, MSD, Novartis, Pfizer and Sanofi. BS received honoraria from SUN Pharma, Allmiral, Novartis; Advisory Board for Pierre Fabre Pharma, Sanofi, Immunocore; travel support from Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre-Fabre, Sanofi, Sun Pharma outside the submitted work. AK received honoraria as speaker from InfectoPharm, Paul-Ehrlich-Gesellschaft für Chemotherapie e.V., Almirall Hermal, MSD Sharp & Dohme, Boehringer Ingelheim, Janssen-Cilag. LH declares speaker and advisory board honoraria from BMS, Immunocore, Novartis and Therakos. CL received honoraria for advisory board from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Boehriner Ingelheim; speakers fee from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Lilly and travel reimbursement from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Pfizer. GS has received honoraria from Bristol-Myers Squibb and Kyowa Hakko Kirin Co. Ltd. outside the submitted work. SG declares honoraria for advisory boards, oral presentations and/ or travel expenses from Roche, Novartis, MSD, BMS, Sun Pharma, Klinge Pharma, Kyowa Kirin, Pierre Fabre, Guidepoint Global and UCB and research funds from Novartis and Pierre Fabre outside the submitted work. ND received honoraria from BMS and MSD outside the submitted work. RH and IK are employee of Helios Klinikum Erfurt GmbH. CS reports support from Kyowa Kirin, BMS, Novartis, Roche, SunPharma in context of dermatooncology as well as from Boehringer Ingelheim, Biotest AG and Janssen Cilag in other medical fields. AE is on advisory board or has received honoraria from Agenus, BioInvent, BioNTech, Boeringer Ingelheim GmbH, Brenus, CatalYm, Eurobio. IO Biotech, IQVIA, Merck&Co, MSD, Pfizer, Pierre Fabre, Sairopa BV, SkylineDX BV, Trained ImmunoTherapeutics Discovery and has Equity in IO Biotech, Sairopa BV and SkylineDX BV. MVH received honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Immunocore, InfectoPharm. CG 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, Regeneron, Roche, Sanofi Genzyme, SUN Pharma and Sysmex, research funding from Bristol-Myers Squibb, Novartis, Regeneron and Sanofi, outside the submitted work. C.G. is co-founder of Dermagnostix and Dermagnostix R&D. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

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: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only., Methods: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022., Results: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug., Conclusions: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. LJA received honoraria from Novartis, Sunpharma, and Bristol-Myers Squibb and travel support from Sunpharma, Takeda Pharmaceuticals, and Sanofi, outside the submitted work., FD receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre and Sun Pharma., PG has received conference support from Pierre Fabre., JCH received honoraria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi, Sunpharma and travel support from BMS, Iovance and Sunpharma., ME declares honoraria and travel support from Bristol Myers Squibb, Immunocore, Novartis, Pierre Fabre and Sanofi, outside the submitted work., AF reports honoraria for presentations for BMS, MSD, Novartis, Pierre-Fabre; Travel support and congress participation support from BMS, Pierre-Fabre, Novartis; Advisory Boards from MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional funding from BMS Stiftung Immunonkologie, outside the submitted work., 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., GL received travel support from Sun Pharma, Pierre Fabre, research funding from Novartis, JMP 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., FK received travel support for participation in congresses and / or (speaker) honoraria from Novartis, Almirall and Boehringer Ingelheim, outside the submitted work, AZ received travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work., 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, AR reports grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Novartis, Bristol Myers Squibb, and Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb and Teva, outside the submitted work., CB has received honoraria for advisory and/or speaker functions from Almirall Hermal, BMS, Delcath, Immunocore, InlaRx, Leo Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, and Sanofi, outside the submitted work., CP receives/received honoraria from AstraZeneca und Roche Pharma, outside the submitted work., AMM has served as a consultant for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics., 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, 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., 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, DS declares research support from Amgen, Bristol Myers Squibb, Merk Sharp & Dome, Novartis and Roche (all to institution); speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, PamGene, Neracare, Replimune, InFlarx, Immocore, Erasca, Philogen, BioAlta, Astra Zeneca, Daiichi-Sanyco, Formycon, Innovent Biologics, Agenus, Array Pharma, Pierre Fabre, Pfizer, Regeneron, Immatics, Curevac, Haystack Oncology, NoviGenix, Seagen, BionTech, SunPharma, UltimoVacs, and Novartis; and meeting and travel support from Pierre Fabre, 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, All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. 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.)

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: 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.)

Background: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised., Methods: We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age 41-70 and ≥ 71 years)., Results: A total of 676 patients were included: 190 patients (28%) aged ≤40 years, 313 (46%) between ages 41-70, and 173 patients (26%) aged ≥71. Patients ≤40 years had higher response rates (53% vs 38%, p = 0.035) and improved progression-free survival (median 13.7 vs 4.0 months, p = 0.032) with combination ICI compared to monotherapy. Progression-free survival was similar among groups while overall survival was inferior in patients >70 years, who had low response rates to combination therapy (28%). ICIs had a similar incidence of severe toxicities, though hepatotoxicity was particularly common in younger patients vs. patients >40 with monotherapy (9% vs. 2%, p = 0.007) or combination ICI (37% vs. 10%, p < 0.001)., Conclusions: ICIs had comparable efficacy between younger and older patients, although outcomes were superior with combination ICI compared to monotherapy in patients aged ≤40 years. Toxicity incidence was similar across age groups, though organs affected were substantially different., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, and Targovax, and has received research funding from BMS and Incyte. RJS has served on advisory boards or as a consultant for BMS, Eisai, Iovance, Merck, Novartis, Oncosec, and Pfizer, and has received research funding from Merck. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion, Hexal AG, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, and Regeneron. MSC is a consultant advisor for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, and Roche; honoraria: Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics. IMR has served on advisory boards or as a consultant for Amgen, BMS, GSK, Novartis, MSD, Roche, Celegene, Pierre Fabre, Highlight Therapeutics (formerly Bioncotech), Regeneron, Sanofi, Merck Serono, Astra Zeneca, BiolineRx, and Sun Pharma. EMC has served on advisory boards or as a consultant for Amgen, BMS, GSK, Novartis, MSD, Roche, Celegene, Pierre Fabre, Regeneron, Sanofi, Merck Serono, Astra Zeneca, and Sun Pharma. LZ (MGH) has served on advisory boards or as a consultant for Merck. 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; outside the submitted work. LZ (Essen) reports personal fees and other (advisory board participation, travel grants) from Bristol-Meyers-Squibb, MSD, Pierre Fabre, Roche, and Novartis; other (advisory board participation and/or travel grants) from Sanofi and Amgen; all outside the submitted work. EL reports personal fees and other (advisory board participation and/or travel grants) from Amgen, BMS, MSD, Novartis, Roche, and medac; personal fees from Janssen; other fees from Actelion and Pierre-Fabre; all outside the submitted work. DS reports research finding to the institution for clinical studies or research from BMS, MSD, Novartis, Amgen, Array; patient fees to the institution from BMS, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, SunPharma, Sandoz, and UltimoVacs; reimbursement for travel from BMS, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; non-financial support from BMS, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, SunPharma, and Sandoz; all outside the submitted work. SMB has served as a consultant for Two River Consulting and Third Rock Ventures and reports equity holdings in Kronos Bio and 76Bio. All remaining authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis., Methods: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre., Results: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43)., Conclusions: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LMJ, JMV, WB, PH, RM, AC, TH, FM, LR, PB, JAS, TE, MT, CH, LvB, THu, declare no conflicts of interest. SZ declares speaker's fees or travel grants from Bristol-Myers Squibb (BMS), Sun Pharma and Merck Sharp & Dohme (MSD). ME received funding from DFG under Germany's Excellence Strategy – EXC-2049 – 390688087, BMBF, DZNE, DZHK, EU, Corona Foundation, and Foundation Leducq. ME reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. CUB received compensation (all paid to the institute except TRV) for advisory roles for BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre Pharmaceuticals, Third Rock Ventures, received research funding (all paid to the institute) from BMS, Novartis, NanoString, and declares stockownership in Immagene BV, where he is co-founder. AG received speaker's honoraria from Allmiral, BMS, MSD and Roche; AG has intermittent advisory board relationships with Amgen, BMS, Novartis, MSD, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from BMS, MSD, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, BMS, GSK, Novartis, Merck, MSD, Pfizer, and Roche. MS received speaker's honoraria and travel grants from Abbvie, BMS, Merck, MSD, Novartis, Pfizer, and Sanofi. JCH has served as a consultant for GSK, MSD, Pierre Fabre Pharmaceuticals, Sunpharma (personal) and BMS, Immunocore, Nektar, Novartis, Philogen (institution); received speaker's honoraria from Almirall, Amgen, BMS, GSK, MSD, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, Roche, Sanofi (personal); a scientific grant from BMS and Sunpharma (institution) and clinical trial honoraria for BioNTech, BMS, Genentech, Immunocore, Iovance, MSD, Novartis, Philogen, Pierre Fabre Pharmaceuticals, Regeneron, Roche, Sanofi, 4SC (institution). SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, MSD, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, MSD, and Pierre Fabre Pharmaceuticals. LZ served as consultant and/or has received honoraria from BMS, MSD, Novartis, Pierre-Fabre Pharmaceuticals, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from MSD, BMS, Amgen, Pierre-Fabre Pharmaceuticals, Sunpharma, Sanofi and Novartis, outside the submitted work. LS declares advisory and speaker honoraria from Bristol Myers Squibb. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre Pharmaceuticals, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre Pharmaceuticals, Medac and Novartis. RSB has served as consultant for and/or received honoraria from Amgen, AstraZeneca, BMS, Celgene, Jansen-Cilag, MSD, Merck Seono, Novartis, Pfizer, and Roche. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, MSD, Novartis Pharma AG, OncoSec, PHMR Limited, Pierre Fabre Pharmaceuticals, Provectus, Qbiotics, Regeneron. FS has received an honorarium from Gilead for an advisory board meeting. MS received speaker's honoraria and participated in advisory boards of BMS, Novartis, MSD, Roche, Pierre Fabre Pharmaceuticals, Kyowa Kirin, Immunocore, Recordati and Sanofi-Genzyme. MS received travel accommodation and expenses by Novartis, Pierre Fabre Pharmaceuticals, and Sun Pharma. LEF has served as consultant for Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, Abbvie, UCB, Biotest, and InflaRx. SK received compensation for advising roles for Biogen. LH has served as consultant for Amgen, BMS, Biome-dx, EMA, Immunocore, Kyowa Kirin, MSD, Novartis, Pierre Fabre Pharmaceuticals, Roche, and Sanofi., (Copyright © 2022 The Author(s). Published by 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: MEK inhibitors (MEKi) have shown clinical efficacy for NRAS-mutated, metastasized melanoma in randomised controlled trials, yet their clinical use is currently restricted to advanced, pre-treated patients, which is a different situation compared to previous trials. Data on their efficacy in the current real-world use are scarce., Methods: In this retrospective, multi-centre study, we evaluated the clinical course of disease of patients treated with MEKi with at least one previous treatment line in five German cancer centres., Results: Thirty-three patients were included, 19 males (58%) and 14 females (42%), with a median age of 64 years. Ninety-one percent of patients were pre-treated with immune checkpoint inhibitors, 90% of patients had elevated serum lactate dehydrogenase (LDH) levels at treatment initiation, 33% suffered from cerebral metastases and 30% had an Eastern Cooperative Oncology Group performance status of 2 or higher. The response rate was 18.2%; the disease control rate was 48.5%. Median progression-free survival was 2.8 months (95% confidence interval (CI): 1.6-3.9 months), and median overall survival was 7.1 months (95% CI: 5.8-8.3 months). In subgroup analysis, clinical efficacy was similar also in patients with high LDH levels and cerebral metastases, and there was a better outcome in males and in patients treated with trametinib vs. other MEKi, which may be based on selection bias. Overall, the clinical efficacy was similar compared to previous clinical trials in earlier treatment lines., Conclusions: MEKi fulfil the need for an in-between treatment to stabilise the course of disease in advanced NRAS-mutated melanoma, but expectations regarding ongoing tumour response should be tempered., Competing Interests: Conflict of interest statement MS: honoraria and/or travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer and Sanofi. JP: No conflict of interest to declare. CL: Advisory board: BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, Novartis; speakers fee and travel reimbursement: BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal, Kiowa Kirin, Novartis. DRS: served as consultant and/or has received honoraria from Novartis, Roche, Bristol-Myers Squibb and travel support from Novartis, Sunpharma and Sanofi Genzyme, outside the submitted work. FraM: 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. FriM: 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. 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. DS: declares relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). AHE: advisory honoraria from Biotest AG, MSD Oncology, Galderma, Janssen Cilag, AbbVie as well as speaker’s honoraria from Roche Pharma. JCH: honoraria for talks from BMS, MSD, Roche, Novartis; advisory board member for MSD, Pierre Fabre; scientific grant support from BMS; travel grants from BMS, Pierre Fabre., (Copyright © 2022 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: Combination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF) V600 -mutated melanoma (IMMU-TARGET, NCT02902042)., Methods: The dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1 and 200 mg QD and 30 mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose of the triplet combination, DLT and safety. As per the sponsor's decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD,NCT04657991)., Results: Fifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n = 1) and gamma glutamyl transferase (GGT) increase (n = 1). No DLT was observed in further 3 + 3 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III-IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12-45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35-87). At a median follow-up of 25 months (IQR, 9-28), progression-free survival at 12 months was 41% (95% CI, 13-68)., Conclusions: Triplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Forty to 60% of patients with advanced or metastatic melanoma respond to first-line immune checkpoint inhibitors (ICI) and half of all patients in the metastatic setting eventually progress. This review evaluated the latest long-term data from clinical trials. It also considered data from recent retrospective studies, as these address important questions for clinical practice. 'Retreatment' defined as 'repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended' and showed activity in selected patients with recurrence after regular completion of adjuvant PD-1 treatment. In melanoma patients with adjuvant PD-1 monotherapy who recur during adjuvant treatment, further treatment with PD-1 monotherapy seems to have no clinical utility, indicating the need for a therapy switch or escalation in these patients. Targeted therapy with BRAF/MEK inhibitors and ipilimumab-based therapy (alone or combined with PD-1 blockade) show clinical activity in patients who recur during and after adjuvant treatment. 'Rechallenge', defined as 'repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease', with pembrolizumab at progression in the advanced setting achieving additional disease control. If possible, 'escalation' (PD-1 inhibitors combined with additional agents) should be preferred to PD-1 inhibitor monotherapy rechallenge as higher response rates were demonstrated. The combination of PD-1 plus CTLA-4 was found to be more effective but not more toxic than CTLA-4 alone. Promising antitumor activity was observed for escalation to lenvatinib plus pembrolizumab, entinostat plus pembrolizumab, and relatlimab plus nivolumab. Retreatment, rechallenge and escalation are available options for patients with melanoma who relapse in the adjuvant or advanced setting., Competing Interests: Conflict of interest statement AZ reports receiving travel support from Novartis, Sanofi Genzyme, and Bristol-Myers Squibb, outside the submitted work. AMME reports a consultant or advisor role for Ellipses Pharma, GlaxoSmithKline, ISA Pharmaceuticals, MSD, Novartis, Pfizer, Sellas Life Sciences, Skyline Diagnostics, BioInvent, IO Biotech, CatalYm and Nektar, serving on the speaker's bureau for MSD and BIOCAD, receiving travel funding from Bristol Myers Squibb and received honoraria from Ellipses Pharma, GlaxoSmithKline, ISA Pharmaceuticals, MSD, Novartis, Pfizer, Sellas Life Sciences, Skyline Diagnostics, BIOCAD, CatalYm, BioInvent, IO Biotech, and Nektar, providing expert testimony for Novartis and having stock and other ownership interest with RiverD, Skyline Diagnostics, and Theranovir, all outside the submitted work. CR reports participation in advisory boards for Roche; Pierre Fabre; Merck; Novartis; Amgen; Bristol-MyersSquibb; Novartis; Merck Sharp & Dohme Corp., asubsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD); and Sanofi. RD reports having 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 and touchIME outside the submitted work. 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 and Merck Sharp & Dohme. EL reports serving as a consultant and/or receiving 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. PAA reports 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, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, and iTeos. He also reports receiving research funding from Bristol Myers Squibb, Roche-Genentech, Array, and Sanofi and travel support from MSD. GVL reports being a 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., and Specialised Therapeutics Australia Pty Ltd. DS 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, and personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. LZ reports being a consultant and/or receiving honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; research funding to institution from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work., (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.)

Background: Radiological imaging such as computed tomography (CT) is used frequently for disease staging and therapy monitoring in advanced skin cancer patients. Detected lesions of unclear dignity are a common challenge for treating physicians. The aim of this study was to assess the frequency and outcome of CT-guided biopsy (CTGB) of radiologically unclear, suspicious lesions and to depict its usefulness in different clinical settings., Methods: This retrospective monocentric study included advanced skin cancer patients (melanoma, Merkel cell carcinoma, squamous cell carcinoma, angiosarcoma, cutaneous lymphoma) with radiologically unclear lesions who underwent CTGB between 2010 and 2018., Results: Of 59 skin cancer patients who received CTGB, 47 received CTGB to clarify radiologically suspicious lesions of unclear dignity. 32 patients had no systemic therapy (cohort A), while 15 patients received systemic treatment at CTGB (cohort B). In both cohorts, CTGB revealed skin cancer metastasis in a large proportion of patients (37.5%, 40.0%, respectively), but benign tissue showing inflammation, fibrosis or infection in an equally large percentage (37.5%, 46.7%, respectively). Additionally, a significant number of other cancer entities was found (25.0%, 13.3%, respectively). In patients receiving BRAF/MEK inhibitors, CTGB confirmed suspicious lesions as skin cancer metastasis in 83.3%, leading to treatment change. In immune checkpoint inhibitor-treated patients, skin cancer metastasis was confirmed in 11.1% of patients only, whereas benign tissue changes (inflammation/fibrosis) were found in 77.8%., Conclusions: Our results highlight the relevance of clarifying radiologically unclear lesions by CTGB before start or change of an anti-tumour therapy to exclude benign alterations and secondary malignancies., Competing Interests: Conflict of interest statement All conflict of interest listed in the manuscript have been outside the submitted work and do not influence the submitted work. Therefore, the authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. CF has been on the advisory board of or received honoraria from BMS and Novartis and received travel grants from BMS, Novartis and Pierre Fabre outside the submitted work. EL served as consultant or/and 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. JT served as a consultant or/and has received honoraria from Roche and Boston Scientific outside the submitted work. EH received honoraria for consulting and travel expenses from Biotest outside the submitted work. LZ: Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre; Consultant or Advisory Role: BMS, Novartis, Pierre Fabre, Sun Pharma, Sanofi, MSD; Research funding to institution: Novartis; Travel support: BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sun Pharma. All fundings were outside the submitted work. DS declares advisory board and speakers honoraria from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, Sanofi, Nektar, Amgen, Hexal, InFlaRx, Array, Pierre Fabre, Immunocore, Philogen Sun Pharma, Regeneron and Ultimovacs, as well as grant and travel support from Roche, Novartis, Bristol-Myers-Squibb, MSD, Merck-Serono, and Sanofi outside the submitted work. 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, and Merck Sharp & Dohme outside the submitted work. AW, HAB, JH, IC, IS, JK, J-MP, GL declare no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients., Methods: We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019., Results: In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0-91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7-4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4-4.9)., Conclusions: Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor., Competing Interests: Conflict of interest statement E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, outside the submitted work. T.K. received travel support from Novartis, Amgen, Celgene, Lilly, and Pierre-Fabre, outside the submitted work. A.Z. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. F.R. received travel support from Pierre-Fabre, Merck Sharp & Dohme, and Novartis, outside the submitted work. S.Kn. received travel support from Bristol-Myers Squibb and Amgen, outside the submitted work. E.G. received travel support from Pierre-Fabre, 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. 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. 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 or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, Sanofi, and Sun Pharma; and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sun Pharma, and Novartis, outside the submitted work. M.G. reports work as a consultant/independent contractor with Roche Pharma, Janssen, Novartis, AbbVie Inc, Novocure Inc, and Daiichi-Sankyo; honorarium from Novartis, UCB Inc, TEVA Pharmaceuticals, Bayer Corp, Novocure Inc, Medac, Merck Sharp & Dohme Corp, and Kyowa Kirin Group; grants from Novocure and Medac and travel fees from Novocure Inc and Medac, outside the submitted work. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; research funding to institution from Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. Other authors declare no conflict of interest., (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.)

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes., Patients and Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres., Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis)., Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Rafaela Kramer: NoneZaremba Anne: Received travel support from Novartis, Genzyme and Bristol-Myers Squibb. Alvaro Moreira: Speaker's honoraria from AbbVie, Novartis, Bristol-Myers Squibb, Pfizer and Roche; consultant's honoraria from Almirall. Selma Ugurel: Selma Ugurel declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp and Dohme. Douglas Johnson: Advisory boards for Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis, and research funding from BMS and Incyte. Jessica C. Hassel: honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi; consultant's honoraria from Pierre Faber, MSD, Sunpharma; science grant from BMS. Martin Salzmann: honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Novartis and Pfizer. Anja Gesierich: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp and Dohme and Roche; Consultant's honoraria from Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp and Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel support from Bristol-Myers Squibb, MSD Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp and Dohme, Pfizer and Roche. Alisonn Weppler: none. Lavinia Spain: Honoraria from Bristol-Myers Squibb for Advisory Boards Carmen Loquai: Advisory board, speakers fee, travel reimbursement: Roche, Pierre Fabre, Novartis, BMS, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma, Sanofi Milena Dudda: none. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO. Clinical studies: Novartis, BMS. Adriana Hepner: AH is employee of AstraZeneca with stock options in the company, has received honoraria from Novartis and travel expenses from Roche. Georgina V. Long: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe and Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. Alexander Menzies: advisory board BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics Matteo S. Carlino: MSC has served on advisory boards for Bristol-Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai and honoraria from Bristol-Myers Squibb, MSD, Novartis Michael M. Sachse: Speaker fees: Roche, MSD, Novartis Céleste Lebbé: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Sanofi, Incyrte, Roche, Amgen, GSK, Curevac, Genentech and Novartis Barouyr Baroudjian: Consultancy, speaker fees, travel grants: BMS, MSD, Novartis, Pierre Fabre Tomohiro Enokida: none. Makoto Tahara: reports grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD, grants and personal fees from BMS, during the conduct of the study; grants and personal fees from Bayer, grants and personal fees from Eisai, grants and personal fees from Merck serono, personal fees from LOXO, grants and personal fees from Pfizer, grants and personal fees from Rakuten Medical, personal fees from Celgene, personal fees from Amgen, grants and personal fees from Novartis, outside the submitted work. Max Schlaak: Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma Kinan Hayani: none. Paul Bröckelmann: PJB declares honoraria and non-financial support by Bristol-Myers Squibb and research funding by Bristol-Myers Squibb and MSD Sharp and Dohme. Friedegund Meier: F.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. Lydia Reinhardt: none. Philip Friedlander: none. Thomas Eigentler: received fees for advisory boards from Roche, Novartis, MSD, BMS, Sanofi and Philogen 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. Lisa Zimmer: LZ has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol-Myers Squibb, Novartis, Pierre Fabre, Sunpharma, Sanofi, Merck Sharp and Dohme; travel support: Bristol-Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma Lucie Heinzerling: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis., (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: Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis., Case Presentation: Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32-70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12-17.6 months), two patients experienced melanoma relapse., Conclusions: In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment., Competing Interests: Conflict of interest statement E.C.: reports travel support from Bristol-Myers Squibb, MSD SHARP & DOHME and Novartis.T.K.: reports travel support from Novartis, Amgen, Celgene, Lilly and Pierre-Fabre. 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 travel support from MSD, BMS, Amgen, Pierre Fabre and Novartis. E.H.: reports no conflict of interest. S.U.: reports grants, personal fees and non-financial support from Novartis, grants and non-financial support from BMS, personal fees and non-financial support from Roche, personal fees from MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work. E.G.: reports travel support from Pierre-Fabre. A.R.: reports 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 MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work . F.B.: reports personal fees and non-financial support from Boehringer Ingelheim and Roche Pharma, personal fees from Galapagos, outside the submitted work. T.E.W: reports no conflict of interest. J.W.: reports no conflict of interest. D.T.: reports no conflict of interest. D.S: reports grants and other from 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 MSD, outside the submitted work. E.L.: served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Amgen, Pierre Fabre, Sunpharma and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking., Methods: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging., Results: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition., Conclusions: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials., Competing Interests: Conflict of interest statement Selma Ugurel: relevant financial activities (research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp, and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp, and Dohme). Joachim Röhmel: none. Paolo A. Ascierto: relevant financial activities (advisory board/consultant for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes; research funds from Bristol Myers-Squibb, Roche-Genentech, Array; travel support from Merck Sharp & Dohme). Jürgen C. Becker: relevant financial activities (speaker honoraria from Amgen, MerckSerono, Pfizer, Sanofi; advisory board honoraria from 4SC, Amgen, CureVac, eTheRNA, MerckSerono, Novartis and InProTher; research funding from Alcedis, Boehringer Ingelheim, Bristol-Myers Squibb, IQVIA, and MerckSerono; travel support from 4SC and Incyte). Keith T. Flaherty: relevant financial activities (consultant for Amgen, Array BioPharma, Bristol-Myers Squibb, Merck, Novartis, Pierre-Fabre, Roche). Jean Jacques Grob: relevant financial activities (Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche). Axel Hauschild: relevant financial activities (Amgen, Bristol-Myers Squibb, MerckSerono, Merck Sharp & Dohme, Novartis, Oncosec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche). James Larkin: relevant financial activities (Bristol-Myers Squibb, Merck, Novartis, Roche). Elisabeth Livingstone: relevant financial activities (served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, SunPharma, and Novartis). Georgina V. Long: relevant financial activities (consultant advisor to Aduro, Amgen, Array, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Oncosec, Pierre-Fabre, Roche). Paul Lorigan: relevant financial activities (Support for research: Bristol-Myers Squibb; Advisory work/speaker bureau: Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis, Amgen, Glaxo Smith Kline, Roche; Support for travel: Bristol-Myers Squibb and Merck Sharp & Dohme). Grant A. McArthur: relevant financial activities (Research funding for reimbursement of clinical trials from Array Biopharma and Genentech/Roche). ‘Antoni Ribas: relevant financial activities (Bristol-Myers Squibb, Merck, Novartis, Roche). Caroline Robert: relevant financial activities (Roche, Novartis, CureVac, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck, Sanofi, Amgen, Pierre Fabre, Biothera). Lisa Zimmer: relevant financial activities (consultant and/or honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Pierre Fabre, Sanofi, and Novartis). Dirk Schadendorf: relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). Claus Garbe: relevant financial activities (Roche, GSK, Novartis, Bristol-Myers Squibb, Merck Sharp & Dsohme)., (Copyright © 2020 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.)

Study Aim: Melanomas arising in acral sites are associated with a poorer prognosis than other melanoma subtypes. The aim of this study was to evaluate clinical-pathological and genetic characteristics as well as therapeutic responses of a larger cohort of patients with melanomas arising in acral sites., Methods: Clinical data of 134 patients with melanomas arising in acral sites from the Dept. of Dermatology Essen were collected and analysed with regard to clinicopathological characteristics and treatment responses. Genetic analysis with targeted next-generation sequencing was done on 50 samples., Results: In our cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy)., Conclusion: Our data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Targeted therapy (TT) is an effective treatment for advanced BRAFV600-mutated melanoma, but most patients eventually acquire resistance and progress. Here, we evaluated the outcome of second-line immune checkpoint blockade (ICB) after progression on dual BRAF and MEK inhibition., Methods: Patients with metastatic melanoma progressing on combined BRAF + MEK inhibition and receiving second-line ICB between 2015 and 2019 in 9 tertiary referral centres were enrolled. Demographic and clinical data and blood counts of all patients were collected retrospectively., Results: We identified 99 patients with stage IV melanoma receiving ICB (nivolumab, pembrolizumab [n = 39] or ipilimumab plus nivolumab [n = 60]) after progression on combined TT. The median progression-free survival was similar in the PD-1 and ipilimumab plus nivolumab group (2.6 months [95% confidence interval {CI}, 2.0-3.1] vs. 2.0 [95% CI, 1.4-2.6], p = 0.15). The objective response rate was 18.0% in the PD-1 and 15.0% in the ipilimumab plus nivolumab group (p = 0.70). The disease control rate was 25.7% for monotherapy and 18.3% for combined ICB (p = 0.39). The median overall survival was 8.4 months (95% CI, 5.1-11.7) for patients receiving PD-1 monotherapy and 7.2 months (95% CI, 5.2-9.1) for patients receiving ipilimumab plus nivolumab (p = 0.86). The latter was associated with a higher rate of treatment-related adverse events (AEs). No significant association of laboratory values or clinicopathological characteristics with response to second-line ICB was observed., Conclusions: PD-1 monotherapy and combined ipilimumab plus nivolumab show similar activity and outcome in patients with melanoma resistant to BRAF + MEK inhibition. However, combined ipilimumab plus nivolumab was associated with a higher rate of treatment-related AEs compared with monotherapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma., Patients and Methods: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%)., Results: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma., Conclusions: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit., (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.)

The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials., (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.)

Background: Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies., Patients and Findings: Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of which one was a kidney-transplant recipient receiving immunosuppressive therapy with tacrolimus and prednisolone. The patient was initially treated with the anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk of allograft rejection. Upon disease progression, therapy was switched to the anti-PD-1 antibody nivolumab. The other three patients were treated with nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab., Results: The patients received a median of six doses (range 3-21) of anti-PD-1 antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable throughout the course of checkpoint blockade. In the kidney transplant recipient, neither ipilimumab nor nivolumab led to an allograft rejection. Responses to anti-PD-1 treatment were divergent with two patients showing disease progression, one achieving a mixed response and one experiencing a complete response., Conclusion: These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential., Methods and Findings: In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis., Conclusion: Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential., Methods and Findings: In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail., Conclusion: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity., (Copyright © 2016. Published by Elsevier Ltd.)

The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim of the Study: To describe the current management of patients diagnosed with cutaneous melanoma and melanoma in situ in Germany and assess for adherence with the existing German guideline in a first prospective population-based analysis., Methods: Prospective and longitudinal population-based study using online questionnaires. Registration by practitioners and hospitals was open for all patients diagnosed with melanoma between April and June 2008 in Germany. For data analysis, patients with melanoma stages 0-III (AJCC 2002) were included., Results: Data from 1081 patients registered by 106 different centres were available for analysis. Male patients were significantly older than female patients (61.4 years versus 55.8years, p<0.0001) and presented with thicker primary tumours (1.62 mm [median 0.9 mm] versus 1.48 mm [median 0.8 mm], p=0.01). Excessive safety margin excisions were most often applied in melanoma in situ and in small centres. Insufficient excision margins (6.9%) were associated with head and neck localisation, geographical region and implementation of further staging procedures. Decision on sentinel lymph node biopsy complied with the German guideline in >85% of cases and was dependent on age and tumour localisation. Only 60% of patients received a complete lymph node dissection (CLND) after a positive SLNB, the rate of CLND was lowest in older patients. Adjuvant treatments were initiated in only 34% of patients formally qualifying for adjuvant treatment based on guideline recommendations. Approximately half of all staging procedures were done in no-risk/low-risk tumour patients., Conclusions: Management of melanoma in Germany did not show great dependency on centre size, geographical area or treating physician but rather on patient and tumour characteristics. The low rate of adjuvant treatment initiations reflects the need of treatment options in this patient group. Excessive initial staging procedures generate significant costs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)