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Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF -mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1-9.3) and the median OS was 18.3 months (14.9-21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9-7.2)) compared with those not requiring corticosteroids (5.9 months (4.8-6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3-11.6)) compared to those who did not (11.9 months (9.6-19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators' upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.

Background: Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment)., Methods: In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78)., Findings: Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported., Interpretation: Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests JCB reports grants from Alcedis, Bristol Myers Squibb, HTC Molecular Diagnostics, IQVIA, Merck Serono, and Alcedis; consulting fees from Almirall Hermal, Boehringer Ingelheim, InProTher, Merck Serono, Pfizer, and Sanofi–Regeneron; and honoraria from Amgen, Pfizer, Recordati, and Sanofi. JCB participated on a data safety monitoring or advisory board from ICON Clinical Research and 4SC. SU reports grants or contracts from Bristol Myers Squibb and Merck Serono and support for attending meetings and travel from Bristol Myers Squibb, MSD, and Pierre Fabre. SU participated on a data safety monitoring or advisory board from Bristol Myers Squibb, MSD, Merck Serono Novartis, and has a leadership role in the German dermato-oncology working group also known as the German dermatologic cooperative group (ADO/DeCOG). UL reports research support from MSD and honoraria and participation on a data safety monitoring or advisory board from Almirall Hermal, MSD, Novartis, Roche, Sanofi, and Sun Pharma. FM reports consulting fees and honoraria and participation on a drug safety monitoring or advisory board for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, and Sanofi, and support for attending meetings or travel grants from Bristol Myers Squibb, MSD, Pierre Fabre, and Sanofi. RG reports consulting fees, personal fees, and support for attending meetings or travel grants from Bristol Myers Squibb, Merck Serono, Pierre Fabre, Roche, and Sun Pharma; consulting and personal fees from Almirall Hermal, Amgen, Immunocore, MSD, Novartis, and Sanofi; and institutional research funding from Almirall Hermal, Amgen, Johnson & Johnson, Kyowa-Kirin, Merck Serono, Novartis, Pfizer, and Sanofi, in addition to an unpaid leadership role (ADO/DeCOG). SH reports personal fees and honoraria and participation on a drug safety monitoring or advisory board for Bristol Myers Squibb and MSD. LZ reports institutional payments from Novartis and Bristol Myers Squibb; personal fees and support for attending meetings or travel grants from Bristol Meyers-Squibb, MSD, Pierre Fabre, Novartis, Sanofi, and Sun Pharma; and participation on drug safety monitoring or advisory boards for the same companies. EL reports personal fees, honoraria, and support for attending meetings or travel grants from Bristol Myers Squibb, Medac, Novartis, Pierre Fabre, and Sun Pharma, and honoraria from MSD, Recordati, and Sanofi. EL participated on a drug safety monitoring or advisory board for Bristol Myers Squibb, Novartis, Sanofi, and Sun Pharma. TKE reports consulting fees from Almirall Hermal, Bristol Myers Squibb, Immunocore, Novartis, Pierre Fabre, and Sanofi outside the submitted work, and an unpaid leadership or fiduciary role for ADO/DeCOG. AH reports grants and personal fees for Amgen, Bristol Myers Squibb, Eisai, Immunocore, Merck Pfizer, MSD, Novartis, Pierre Fabre, Philogen, Regeneron, Replimune, Roche, Seagen, and Sanofi-Genzyme. JCH reports honoraria and personal consulting fees from GSK, MSD, Pierre Fabre, and Sun Pharma; further honoraria from Amgen, Bristol Myers Squibb, Immunocore, Novartis, and Sanofi; travel support from Bristol Myers Squibb and Sun Pharma; institutional fees for consultancy from Bristol Myers Squibb, Immunocore, Nektar Therapeutics, Novartis, Philogen, and Sanofi; participation on drug safety monitoring or advisory boards for NEC OncoImmunity and several pharmaceutical companies (GSK, MSD, Pierre Fabre, Sunpharma, Bristol Myers Squibb, Immunocore, Nektar, Novartis, Philogen, and Sanofi); and an unpaid leadership or fiduciary role for ADO/DeCOG. PM reports institutional grants from Bristol Myers Squibb, MSD, and Novartis; personal fees and honoraria from Amgen, Bristol Myers Squibb, GSK, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; and travel support from Bristol Myers Squibb. PM participated on a data safety monitoring or advisory board from Almirall Hermal, Amgen, Beiersdorf, Bristol Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, and received travel support from Bristol Myers Squibb and Sun Pharma. MF reports payment or honoraria (for presentations and participation on advisory boards) from Bristol Myers Squibb, Pierre Fabre, Roche, and Sanofi. IT reports institutional grants or contracts from Kartos Therapeutics, 4SC, and Incyte; consulting fees and honoraria from Bristol Myers Squibb outside the submitted work; and honoraria and travel support from Pierre Fabre. MG reports honoraria and travel support from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, and Sanofi. IG reports payment or honoraria from Bristol Myers Squibb, Kyowa Kirin, MSD, Novartis, Pierre Fabre, Sanofi-Genzyme, and Sun Pharma; travel support from Bristol Myers Squibb and Kyowa Kirin; and participation on drug safety monitoring or advisory boards for Almirall Hermal, Bristol Myers Squibb, MSD, Novartis, Roche, and Sanofi. ANS and SE are employees of Alcedis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Basal cell carcinoma (BCC), the most common type of skin cancer, is characterized by aberrant activation of the hedgehog molecular pathway. Systemic therapy is indicated when local approaches, such as surgery and radiation, are inappropriate. In this article, a group of clinical experts recommends the long-term management strategy for advanced BCC patients treated with systemic therapy. The hedgehog inhibitors sonidegib and vismodegib are first-line treatments for advanced BCC with a long-lasting response, but long-term treatment with hedgehog inhibitors is often challenged by tolerability issues. However, several strategies for adverse effect management are available, such as dose interruptions, on-label alternate-day dosing and supportive medications. In conclusion, although BCC shows a high tumor mutational burden that favors a response to immunotherapy, experts recommend keeping patients on hedgehog inhibitors limiting immunotherapy to those who developed resistance during hedgehog inhibitor therapy or in case of persisting toxicity despite long-term management of adverse events., Competing Interests: Declaration of Competing Interest The authors declare the following conflicts of interest. Pietro Quaglino: advisory boards and speaker fees from Sanofi, SUNPharma, Roche. Ralf Gutzmer: research support to Pfizer, Johnson&Johnson, Novartis, Amgen, Sanofi, Merck-Serono, Kyowa-Kirin, Almirall; honoraria for lectures from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi; honoraria for advice from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Sanofi, Immunocore; support for participation in meetings from Roche Pharma, Bristol-MyersSquibb, Pierre-Fabre, Merck-Serono, SUN, Merck-Serono. Brigitte Dreno: personal fees for board meetings from Roche, Regeneron and Sun Pharma. Paolo Ascierto: consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Roland Kaufmann: institutional grants outside the submitted talk and entirely linked to clinical trials from Novartis and Roche, and grants from AbbVie, Amgen, Astra Zeneca, Biontech, BMS, Celgene, Galderma, Incyte, Janssen, Leo, Lilly., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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

Background: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAF V600-mutant ( BRAF mut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy., Methods: For this multicenter cohort study, we identified 515 BRAF mut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments., Results: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004)., Conclusions: BRAF mut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are: PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. KCK declareds speakers and advisory board Honoria from Novartis and BMS, as well as travel support from Novartis, Pierre Fabre, Kyowa Kirin and Sun Pharma. FMeier 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. GL has received travel support for congress participation by Sun Pharma, Pierre-Fabre and research funding from Novartis. 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 Roche, BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. RG served as consultant or/and has received Honoria from Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Pierre Fabre, Merck-Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, 4SC, Delcath, received travel support from Sun Pharma, Pierre Fabre, and Boehringer-Ingelheim. AH received consultancy and advisory board fees from Agenus Bio, Almirall Hermal, Amgen, Beiersdorf, BMS, Dermagnostix, Eisai, Highlight Therapeutics, Incyte, IO Biotech, Immunocore, MSD/Merck, MerckPfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme, Seagen and Xenthera. UL served as consultant to Roche, Novartis, MSD, Almirall Hermal, Sanofi and Sun Pharma; received travel support from Sun Pharma and Pierre-Fabre, received speaker fees from Roche, Novartis, MSD, Sun Pharma and Sanofi, outside the submitted work. She reports institutional research grants from MSD. 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. DD has been on the advisory board or has received honoraria from BMS, MSD, Novartis, Pierre Fabre. IvW declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. JCH received research grants from BMS, Sanofi and Sunpharma and served as a consultant and/or received honoria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi and Sunpharma, outside of the submitted work. MVH reports honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Pierre Fabre, Immunocore. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre Pharmaceuticals, and travel support from Novartis, Roche, Bristol-Myers Squibb and Pierre Fabre Pharma, outside the submitted work. 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. 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. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. FZ served as consultant and/or has received honoria from BMS, MSD, Novartis, Pierre-Fabre, Sanofi, Sun Pharma. AF 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, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FMeiss served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. SG declares honoraria for advisory boards, oral presentations, and travel expenses from Roche, Novartis, MSD, and BMS outside the submitted work. CL declares speakers, advisory board honoraria, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Pierre Fabre, Sun Pharma, Kiowa Kirin, Sanofi, Biontech, and Almirall Hermal outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The effect of mogamulizumab in cutaneous T-cell lymphoma (CTCL) on T cells (TC) in the peripheral blood and its potential role to navigate treatment intervals are explored., Methods: We investigated within a retrospective monocentric analysis the effect of mogamulizumab on the CD3 + TC and the aberrant T cell population (TCP), i.e., the CD4 + /CD7 - and the CD4 + /CD26 - TC, analyzed by flow cytometry., Results: Thirteen patients with CTCL were included. After four cycles there was a mean reduction of 57% in CD3 + TC, 72% in the CD4 + /CD7 - and 75% in the CD4 + /CD26 - TCP compared to the individual baseline of each patient. The reduction in CD4 + /CD7 + and CD4 + /CD26 + TC was lower, averaging 54% and 41%. A significant decrease in aberrant TCP was already evident after the first administration. A median plateau of TCP already occurred during the IP. Progressive disease occurred in 5/13 patients without a clear correlation to aberrant TCP., Conclusions: Already after one dose of mogamulizumab, aberrant TCP and, to a lesser extent, normal TC decrease. We did not observe a clear correlation between TCP and the efficacy of mogamulizumab, but further studies with larger numbers of patients are needed., (© 2023 Deutsche Dermatologische Gesellschaft (DDG).)

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.)

Purpose: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma., Methods: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype., Results: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup., Conclusion: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

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

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

Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.

Background: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland., Methods: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence., Results: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials., Conclusions: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences., Objective: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma., Methods: A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list., Results: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients., Conclusions: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

What Is This Summary About?: Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI ® ) and binimetinib (MEKTOVI ® ) are medicines used to treat a type of melanoma that has a change in the BRAF gene, called advanced or metastatic BRAF V600-mutant melanoma. Participants with advanced or metastatic BRAF V600-mutant melanoma took either encorafenib plus binimetinib together (COMBO group), compared with encorafenib alone (ENCO group) or vemurafenib (ZELBORAF ® ) alone (VEMU group)., What Were the Results?: In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time., What Do the Results Mean?: Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone. Clinical Trial Registration: NCT01909453 (ClinicalTrials.gov).

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.)

Melanoma is a highly aggressive skin tumor nicknamed "black cancer of the skin" because it originates from the pigment-forming cells (melanocytes). The tumors are prone to invasive growth and early lymphogenic and hematogenic metastasis. Known risk factors are UV radiation, light skin type, the presence of multiple atypical nevi, and a positive family history. Decisive for the course of the disease are a guideline-based diagnosis and therapy. In addition to complete excision of the primary tumor with an adequate safety margin, various systemic therapies are available. These are in particular BRAF-targeted therapy and PD-1-based immune checkpoint therapy. This mini-review does not claim to be exhaustive, but is intended to focus primarily on those aspects of the disease that are currently in clinical and scientific focus, and on which there are new developments to report. In particular, there are new therapeutic regimens for unresectable melanoma and studies of adjuvant treatments, as well as developments in diagnostics., (© 2023 Deutsche Dermatologische Gesellschaft (DDG).)

Background: Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing., Methods: A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed., Results: nAE of any grade were observed in 31% of the patients (n = 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05)., Conclusion: Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy., Methods: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS)., Results: Of 1704 patients, 916 were BRAF wild-type (BRAF wt ) and 788 were BRAF V600 mutant (BRAF mut ). Median follow-up time after start of 1L-therapy was 40.4 months. BRAF wt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAF mut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAF mut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAF mut patients. In BRAF wt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAF wt patients. For BRAF mut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK., Conclusions: In BRAF mut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAF wt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are as following: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol-Myers Squibb and Sun Pharma. 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. KK 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. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RG: 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, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. JU is on the advisory board or has received travel support from: Amgen, BMS, GSK, Immunocore, Leo Pharma, MSD, Novartis, Pierre Fabre, Sanofi, Roche. JU has received research support from Novartis; speakers and advisory board honoraria. PT has been on the advisory board or has received honoraria from Almirall, Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, and 4SC and received travel grants from Bristol Myers Squibb, and Pierre Fabre. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. 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. AF 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, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre Fabre and Sanofi Aventis. FraM (Frank Meiss) served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre and travel support from Novartis, Roche, BMS and Pierre Fabre. AK reports receiving lecture fees and fees for serving on advisory boards from MSD Sharp & Dohme, Almirall, Infectopharm, and Boehringer Ingelheim. JW has been on the advisory board, received honoraria and/or travel grants from Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono. CL has received speaker’s fees, advisory board honoraria and travel reimbursements from Merck, MSD, Roche, Almirall Hermal, Biontech, Sanofi, Sun Pharma, Kyowa Kirin, Immonocore, BMS, Pierre Fabre, Novartis. LH has received consultancy and speaker fees from Amgen, Biome Dx, BMS, Curevac, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi and SUN. SG has been on the advisory board and/or has received travel support from Bristol Myers Squibb, MSD, Sun Pharma and Novartis and received research support from Novartis and Pierre Fabre. DD has been on the advisory board or has received honoraria from BMS, Kyowa Kirin, MSD, Novartis, Pierre Fabre, Sanofi and received travel grants from Boehringer, Mylan, Pfizer. GS has received honoraria from BMS. GL has received travel support from Sun Pharma. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sunpharma, Sanofi and Novartis. 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, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis. JCB received speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board/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. 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). 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., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma.

Purpose: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma., Methods: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 10 6 plaque-forming unit (PFU) followed by ≤ 4 × 10 8 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis., Results: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm., Conclusion: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Purpose: Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma., Patients and Methods: In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup., Results: At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients., Conclusion: Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

Background: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis., Methods: The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672., Findings: Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib., Interpretation: Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAF V600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests PAA reports grants from Bristol Myers Squibb, Roche/Genentech, Pfizer/Array, and Sanofi; consulting fees from Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, and Replimmune; travel support from Pfizer; and advisory board member for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, and iTeos. HG reports honoraria from Bristol Myers Squibb, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron; research funding from Bristol Myers Squibb, Roche, MSD Oncology, Amgen, Novartis, and Iovance Biotherapeutics; travel, accommodation, and expenses from Bristol Myers Squibb, Merck Sharp & Dohme, Amgen, and Pfizer; and a consulting or advisory role for Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, and Sanofi/Regeneron. CR reports consulting fees from Roche, Novartis, Pierre Fabre, MSD, Bristol Myers Squibb, Sanofi, Pfizer, and AstraZeneca; and payment or honoraria from Roche, Novartis, Pierre Fabre, MSD, Bristol Myers Squibb, Sanofi, Pfizer, and AstraZeneca. KL reports honoraria from Array Biopharma and Iovance Biotherapeutics; a consulting or advisory role for Array Biopharma, Iovance Biotherapeutics, Merck, Nektar, Regeneron, Roche, and Sanofi; research funding from Alkermes, Amgen, Array Biopharma, Bristol Myers Squibb, Incyte, Iovance Biotherapeutics, Kartos Therapeutics, Merck, Nektar, Neon Therapeutics, OncoSec, Regeneron, Replimune, Roche/Genentech, Seagen, Senhwa Biosciences, and Ultimovacs; and travel, accommodations, or expenses from Alkermes, Merck, Neon Therapeutics, Regeneron, and Roche/Genentech. SP reports honoraria from Biocad, Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; speakers bureau for Biocad, Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; and research funding from Roche, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers Squibb, and Biocad. RPP reports speakers bureau for Roche and Bristol Myers Squibb and research funding from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Bayer, and AstraZeneca. TE reports a consulting or advisory role for Bristol Myers Squibb/Medarex, Sanofi/Regeneron, Novartis, and Pierre Fabre and speakers bureau for Almirall Hermal. PR reports honoraria from Bristol Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, and Merck; speaker's bureau for Pfizer, Novartis, and Pierre Fabre; consulting fee from Blueprint Medicines, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Philogen; research funding from Bristol Myers Squibb, Novartis, and Roche; and travel, accommodations, or expenses from Orphan Europe and Pierre Fabre. LD reports honoraria from Roche, Merck Sharp & Dohme, Bristol Myers Squibb, and Novartis and research funding from Roche, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, and Amgen. NZ reports honoraria from Roche, Novartis, Bristol Myers Squibb/Celgene, MSD Oncology, and AstraZeneca/Merck; consulting fees from Roche, MSD Oncology, Merck; and travel and accommodation expenses from MSD Oncology and Roche. JS reports a consultant or advisory role for Merck Sharp & Dohme and Bristol Myers Squibb. YY and IC report employment with Genentech and stock or other ownership with Roche/Genentech. CH and CX report employment with Roche. LK reports employment and ownership non-voting shares for Roche. GAM reports research funding to his institution from Genentech/Roche and Bristol Myers Squibb. RG reports honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, and Immunocore; a consulting or advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, and Immunocore; research funding from Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma, and Sanofi; and travel, accommodations, or expenses from Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, and Sun Pharma. DS declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453)., Methods: Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned., Results: Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard., Conclusion: In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma.

For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2-64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8-16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1-29) months. Response duration in the four responding patients was 2-29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option.

BACKGROUND: In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence- and distant metastasis-free survival than placebo in patients with resected high-risk stage III melanoma. To confirm the stability of these benefits, longer-term data were needed. METHODS: We randomly assigned 1019 patients to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) and had previously reported data with a 15-, 36-, and 42-month median follow-up. We now report data at a median follow-up of 4.9 years. We report a number of outcomes, including recurrence-free survival in the overall population and in the subgroup of patients with cancer who were positive for the programmed death-ligand 1 (PD-L1). Distant metastasis-free survival was a secondary end point. RESULTS: In the overall intention-to-treat population, pembrolizumab was still associated with longer recurrence-free survival than placebo (5-year rate of recurrence-free survival, 55.4% [95% confidence interval (CI), 50.8 to 59.8] vs. 38.3% [95% CI, 33.9 to 42.7]; hazard ratio for recurrence or death, 0.61 [95% CI, 0.51 to 0.72]) and a longer distant metastasis-free survival (5-year rate of distant metastasis-free survival, 60.6% [95% CI, 56.0 to 64.9] vs. 44.5% [95% CI, 39.9 to 48.9]; hazard ratio for distant metastasis or death, 0.62 [95% CI, 0.52 to 0.75]). Similar findings were obtained in the subgroup of 853 patients with PD-L1–positive tumors. CONCLUSIONS: The 5-year analysis of adjuvant therapy with pembrolizumab resulted in a sustained improvement in the long-term recurrence- and distant metastasis-free survival compared with placebo in patients with resected stage III melanoma. (Funded by Merck & Co., Inc.; ClinicalTrials.gov number, NCT02362594, and EudraCT number, 2014-004944-37.)

Background: The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data., Methods: IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete., Findings: Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths., Interpretation: Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease., Funding: Bristol-Myers Squibb., Competing Interests: Declaration of interests EL reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, Medac, MSD, Novartis, Sanofi, Sun Pharma, and Pierre Fabre; EL participated on a drug safety monitoring or advisory board for Bristol-Myers Squibb, Novartis, Sanofi, and Sun Pharma. LZ reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, MSD, Pierre Fabre, Novartis, Sanofi, and Sun Pharma; LZ participated on drug safety monitoring or advisory boards for Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. JCH reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Almirall Hermal, Amgen, GSK, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; medical writing support from Bristol-Myers Squibb outside the submitted work; and unpaid leadership or fiduciary roles for the Deutsche Krebshilfe charity and the German dermato-oncology working group. MF reports personal fees, honoraria, and other (support for attending meetings and/or travel grants), as well as participation on drug safety monitoring or advisory boards for Bristol-Myers Squibb, MSD, Novarts, Pierre Fabre, Roche, and Sanofi. TKE reports consulting fees from Bristol-Myers Squibb, Almirall Hermal, Immunocore, Novartis, Pierre Fabre, and Sanofi outside the submitted work, and an unpaid leadership or fiduciary role for DeCOG. CL reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Almirall Hermal, Biontech, BMS, Immunocore, Kyowa Kirin, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma outside the submitted work. SH reports personal fees and honoraria as well as participation on a drug safety monitoring or advisory board from/for Bristol Myers Squibb, MSD, Novartis, and Pierre Fabre, all outside the submitted work. RG reports consulting fees, personal fees, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, Merck Serono, Pierre Fabre, Roche, and Sun Pharma; consulting and personal fees from Almirall Hermal, Amgen, MSD, Novartis, and Sanofi; consulting fees from 4SC and Immuncore (all outside the submitted work); and participation on a drug safety monitoring or advisory board for Almirall Hermal, Amgen, Immunocore, 4SC, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, in addition to an unpaid leadership role (ie, chair) for the German dermato-oncology working group. FM reports personal fees and honoraria as well as participation on a drug safety monitoring or advisory board from/for Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Novartis, Roche, and Sanofi. PM reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from MSD, Novartis, and Pierre Fabre; personal fees and honoraria from Almirall Hermal, Amgen, Beiersdorf, Roche, and Sanofi; and travel support from Bristol-Myers Squibb. AH reports honoraria and personal fees as well as participation on a drug safety monitoring or advisory board from/for Eisai, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, Amgen, BMS, and MerckSerono; and additional participation on drug safety monitoring or advisory boards for Immunocore, Replimune, and Seagen. BS reports consulting fees from Almirall Hermal, Bristol-Myers Squibb, Immunocore, MSD and Sanofi; honoraria and personal fees from Bristol-Myers Squibb, Novartis, Pfizer, and Pierre Fabre; and support for attending meetings from Bristol-Myers Squibb and Pierre Fabre. CM reports grants and contracts from the German Research Fund (DFG, ME 5482/1-1) and the Society of MSK (June, 2018), as well as honoraria and personal fees from AstraZeneca, Bristol-Myers Squibb, and Recordati Rare Diseases. FK reports honoraria, consulting, and personal fees from Bristol-Myers Squibb, MSD, Novartis, and Sanofi; and honoraria from Pierre Fabre. AR reports honoraria, personal fees, and travel support from Novartis and honoraria from Bristol-Myers Squibb. MZ reports honoraria, personal fees, and travel support from Novartis; honoraria from MSD and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol-Myers Squibb and MSD. CG reports participation on drug safety monitoring or advisory boards for Bristol-Myers Squibb, CeCeVa, MSD, NeraCare, Novartis, Philogen, and Sanofi, and has a leadership role (ie, chair) for the European Association of Dermato-Oncology (EADO). JCB reports consulting fees from Almirall Hermal, Boehringer Ingelheim, InProTher, ICON Clinical Research, Merck Serono, Pfizer, Sanofi/Regeneron, and 4SC; and honoraria from Pfizer, Recordati, and Sanofi. 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, and Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi, and Sun Pharma; support for attending 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; and leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs, and EuMelaReg. CW-K and LS are employees of Alcedis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC.

Atopic dermatitis (AD) is maintained by a variety of cells and inflammatory mediators, including eosinophils and histamine. We recently reported that eosinophils from AD patients highly express the H 4 R. However, its immunomodulatory function in eosinophils is still largely unexplored. In this study, transcriptome analysis of blood eosinophils from AD patients stimulated with histamine and the H 4 R agonist ST-1006 revealed several regulated genes (e.g., IL-18R, IL-1RL1, PDE4B, CXCR4) involved in inflammation. Subsequently, the impact of histamine on one of the strongly regulated genes, the IL-18 receptor (IL-18Rα), was investigated in detail. Stimulation with histamine induced the upregulation of IL-18Rα at mRNA and at the protein level in human eosinophils, which was more pronounced in cells from AD patients than in cells from healthy controls. IL-18 was upregulated via histamine as well. After pre-incubation with histamine and IFN-γ, subsequent stimulation with IL-18 resulted in an increased ECP mRNA expression. The activation of eosinophils by histamine, in combination with IFN-γ and IL-5, was also accompanied by an upregulation of CD69. Thus, our results indicate a crucial role of histamine in the upregulation of the IL-18/IL-18R axis and in the activation of human eosinophils from AD patients.

Background: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM., Method: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS)., Results: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB., Conclusions: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS., Competing Interests: Competing interests: The authors declare no competing interests in reference to this work. For conflicts of interest outside the submitted work see list: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol Myers Squibb and Sun Pharma. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. 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. RH reports speakers and advisory board honoraria from Bristol Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma. 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. JUl has received research support from Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, and travel support from Bristol Myers Squibb and medac. PT 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. DN has received advisory and speaker honoraria from Merck Sharp & Dome, Bristol Myers Squibb, Novartis, Almirall and Sanofi. AF Advisory Board: Roche, Novartis, MSD, BMS, Pierre-Fabre; support for congress participation: Roche, Novartis, BMS, Pierre-Fabre; speaker honoraria: Roche, Novartis, BMS, MSD, CeGaT; institutional research support BMS Stiftung Immunonkologie. JUt 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 and Sanofi. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, and Merck-Serono. 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. JW received honoraria from Pierre Fabre, Novartis and Merck Sharp & Dohme. KS has been on the advisory board or has received honoraria from Bristol Myers Squibb, Roche, Merck Sharp & Dome, Pierre Fabre, Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. IH has been on the advisory board of Ymmunobio. AR reported grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Teva. 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, Sunpharma, Sanofi and Novartis. 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, Bristol Myers Squibb, Pierre Fabre, Sunpharma and Novartis. DS: relevant financial activities (Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, and Sandoz). SU declares research support from Bristol Myers Squibb and Merck Serona; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dome, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre. All other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 -mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy., Patients and Methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers., Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (