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Cutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant-and more recently neoadjuvant-with targeted therapy-BRAF and MEK inhibitors-and immunotherapy-anti-PD-1-based therapies-offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis-clinical, pathological, and molecular-staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process., (© 2024. The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics., Methods: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm 2 (median) vs ≥5 per mm 2 ), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present)., Results: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm 2 and 0.57 (0.40 to 0.80) for ≥5 per mm 2 ; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS., Conclusions: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma., Trial Registration Number: ClinicalTrials.gov, NCT03553836., Competing Interests: Competing interests: DS reports being an invited speaker for BMS, Merck Serono, MSD, Novartis, Roche, and Sanofi; having advisory board roles with BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, and Sanofi/Regeneron; research grants from BMS and MSD; being a steering committee member for BMS, MSD, and Novartis; being a coordinating PI for BMS, MSD, Novartis, and Pierre Fabre; being a local PI for Philogen and Sanofi; and being member of the board of directors for EORTC-MG (non-financial). JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; having two provisional patents (serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)); participating on a data safety monitoring board or advisory board for AbbVie, Immutep, and Evaxion; having leadership or a fiduciary role in the Society for Immunotherapy of Cancer; and having stock or stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest. PAA reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, and Bayer; support for attending meetings and/or travel from Pfizer, Bio-Al Health, and Replimmune; and participating on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, and Erasca. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, and Regeneron. PR reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicine; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, AstraZeneca, Philogen and Blueprint Medicine. AK reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing or educational events from MSD and support for attending meetings and/or travel from MSD. MDV reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore. LdlC-M reports grants or contracts from Roche, Celgene, and MSD; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, MSD-Merck, Novartis, Roche, AstraZeneca, Incyte, and Gilead; and support for attending meetings and/or travel from Gilead. JM reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; support for attending meetings and/or travel from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; and participation on a data safety monitoring board or advisory board for MSD, Bristol Myers Squibb, and Novartis. VCS reports consulting fees from Pierre Fabre, Novartis, Merck-Serono, and Bristol Myers Squibb; support for attending meetings and/or travel from Pierre Fabre and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for Merck Sharp and Dohme and Pierre Fabre. JMK reports consulting fees from Amgen Inc., Ankyra Therapeutics, Applied Clinical Intelligence LLC, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore LLC, iOnctura, Iovance Biotherapeutics, Istari Oncology, Jazz Pharmaceuticals Inc., Magnolia Innovation LLC, Merck, Natera Inc, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc, PathAI Inc, Pfizer Inc, Regeneron Pharmaceuticals Inc, Replimune Inc, Scopus BioPharma Inc, SR One Capital Management LP, and Takeda; research trial support to institution from Amgen Inc, Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co, Immunocore Ltd, Iovance Biotherapeutics, Lion Biotechnologies Inc, Novartis Pharmaceuticals, Takeda, and Verastem Inc; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS; support for attending meetings and/or travel from Checkmate Pharmaceuticals, BMS, Regeneron, Ankyra Therapeutics, and Iovance Biotherapeutics; and participation on a data safety monitoring board or advisory board for Axio Research and IQVIA. CR reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Merck, MSD, Sun Pharma, and AstraZeneca; participation on a data safety monitoring board or advisory board for BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck, MSD, and AstraZeneca; and stock or stock options in Ribonexus. J-JG reports grants or contracts from Pierre Fabre (institution); consulting fees from Novartis, BMS, MSD, Pierre Fabre, Amgen, Sanofi, and Philogen; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, Novartis, and Pierre Fabre; support for attending meetings and/or travel from BMS, Novartis, MSD, and Pierre Fabre; and participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Philogen. RD reports consulting fees from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and TouchIME; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME. MSC reports consulting fees from MSD, BMS, Novartis, Amgen, Eisai, Ideaya, Nektar, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, BMS, and Novartis. YZ reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. MK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. CK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. AE reports consulting fees from Agenus, BioInvent, BioNTech, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GenOway, IO Biotech, IQVIA, ISA Pharmaceuticals, MSD, Pierre Fabre, Pfizer, Scorpion Pharmaceuticals, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS and MSD; support for attending meetings and/or travel from BMS; participation on a data safety monitoring board or advisory board for BioNTeck, IQVIA, and Pfizer; and stock or stock options in IO Biotech, Sairopa, and SkylineDX. RAS reports consulting fees from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen Inc., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up., Methods: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment., Findings: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [&lt;1%]), rash (seven [1%] vs two [&lt;1%]), autoimmune hepatitis (seven [1%] vs two [&lt;1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported., Interpretation: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests GVL reports research funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co; fees for consulting or advisory roles for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion Biotech, Hexal (Sandoz Company), Highlight Therapeutics, MSD (Australia), Novartis, Oncosec Medical Australia, Pierre Fabre, Provectus, Qbiotics, and Regeneron Pharmaceuticals; and honoraria for speaker's bureau from Bristol-Myers Squibb (BMS) and Pierre Fabre. JJL reports research funding to the institution for clinical studies from MSD, AbbVie, Agios, Array, Astellas, AstraZeneca, BMS, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; membership on data safety monitoring board for AbbVie and Immutep; membership on scientific advisory boards for 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, and Xilioo; stocks for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, and Tempest; compensation for consultancy with AbbVie, Alnylam, Bayer, BMS, CheckMate, Codiak, Crown, Cstone, Day One, Eisai, EMD Serono, Flame, Genentech, Gilead, HotSpot, Kadmon, KSQ, Janssen, Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rublus, Silicon, Synlogic, Synthekine, TRex, Werewold, and Xencor; and patents (provisional) for cancer immunotherapy (PCT/US18/36052; microbiome biomarkers for Anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof). MAK, J-JG, FdG, and CHY report research funding to their institution for clinical studies from MSD. LdlCM reports research funding to their institution for clinical studies from Celgene, MSD, and Roche; reimbursement for travel expenses from Roche; and consultant or advisory roles for BMS, MSD, Novartis, and Roche. MDV reports research funding to their institution for clinical studies from MSD and honoraria as a consultant or advisor for Novartis, BMS, MSD, and Pierre Fabre. PR reports research funding to their institution from MSD and Pfizer; honoraria for lectures and advisory board participation for MSD, BMS, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. FS reports research funding to their institution for clinical studies from MSD; and fees for consulting and honoraria for speakers bureaus from MSD, Novartis, Pierre Fabre, Philogen, Sun Pharma, Merck, and BMS. JM reports research funding to their institution for clinical studies from MSD; honoraria from BMS, MSD, Roche, Novartis, and Pierre Fabre; and consultant or advisory roles for BMS and MSD. VC-S reports research funding to their institution for clinical studies from MSD; reimbursement for travel and accommodation for medical congress from Novartis and Pierre Fabre; and honoraria for advisory board participation for Novartis, Pierre Fabre, BMS, and Merck-Serono. JMK reports research funding to their institution from MSD, Amgen, BMS, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapies, Novartis Pharmaceuticals, Castle Biosciences, and Merck; fees from Amgen, Ankyra Therapeutics, Axios Research Instil Bio, BMS, Checkmate Pharmaceuticals, DermTech, Elsevier, Harbour BioMed, Immunocore, Iovance Biotherapies, Istari Oncology, Millenium Pharmaceuticals or Takeda Pharmaceuticals, Natera, Novartis Pharmaceutical, OncoCyte Corporation, OncoSec Medical, Pfizer, Scopus BioPharma, and Merck. CR reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor for Amgen, AstraZeneca, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. DS reports research finding to their institution for clinical studies from BMS, MSD, Novartis, Amgen, and Array; patient fees to their institution from BMS, MSD, Novartis, Merck–EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, Sun Pharma, Sandoz, and UltimoVacs; reimbursement for travel from BMS, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; and non-financial support from BMS, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, Sun Pharma, and Sandoz. MSC reports research funding to their institution for clinical studies for MSD and honoraria for consulting from BMS, Eisia, IDEAYA Biosciences, Merck Serono, MSD, Novartis, Oncosec, Pierre Fabre, Qbiotics, Roche, and Sanofi. PM reports research funding to their institution for clinical studies from MSD, Amgen, Johnson & Johnson, Merck Serono, Novartis, Pfizer, Sanofi, and Sun Pharma; honoraria from Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Genentech (Roche Group), and Sanofi; consulting or advisory roles for Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; fees for speakers bureau from Amgen, BMS, MSD, Novartis, Roche, and Sanofi; and reimbursement for travel, accommodations, and expenses from Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma. RD reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, BMS, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX, Pfizer, and touchIME. JEG reports research funding to their institution for clinical studies from Merck; royalties for content contribution to UpToDate; consulting or advisory roles for Merck, Regeneron, Syndax, and Bristol-Myers Squibb; fees for speakers bureau for Banner MD Anderson Phoenix; reimbursement for travel to meetings from American Joint Committee on Cancer (AJCC), American College of Surgeons, Melanoma Research Alliance, and Bridges Melanoma meeting; and leadership roles for AJCC and Melanoma Research Alliance. XLW, MF-K, and CK are employees of and own stock in MSD. AMME reports research funding to their institution for clinical studies from MSD; fees for advisory board membership for Merck, Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck, MSD, Nektar, Novartis, Pfizer, Sellas, SkylineDX, TigaTx, and TxDiscovery; fees for independent data monitoring committee for Biocad, GSK, Pfizer, and Novartis;fees for speakers bureau from Biocad, BMS, and Merck; and equity in IO Biotech and SkylineDX. PAA reports research funding to their institution for clinical studies by MSD, BMS, Genentech (Roche Group), Sanofi, and Pfizer or Array BioPharma; fees as a consultant or advisor from BMS, Genentech (Roche Group), MSD, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Nektar, Italfarmaco, Pfizer or Array BioPharma, Lunaphore, Medicenna, Bio-Al Health, and ValoTx; and participation on data safety monitoring boards or advisory boards for BMS, Genentech (Roche Group), MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, and ITeos., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8., Patients and Methods: In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8., Results: Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS)., Conclusions: CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JLa has worked in a consulting/advisory role for iOnctura, Apple Tree, Merck, Bristol Myers Squibb (BMS), Eisai, Debipharm, and Incyte; has received honoraria from AstraZeneca, BMS, Eisai, EUSA Pharma, GlaxoSmithKline (GSK), Incyte, Ipsen, Merck, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Merck Sharp & Dohme (MSD), Novartis, Aptitude, Pierre Fabre, Pfizer, Roche, Seagen, Inselgruppe, eCancer, Ultimovacs, Calithera, and Goldman Sachs; and has received research/grant support from Achilles Therapeutics, BMS, Immunocore, Aveo, Pharmacyclics, MSD, Nektar Therapeutics, Covance, Novartis, Pfizer, and Roche. JW has worked in a consulting/advisory role for, received honoraria from, and received institutional research/grant support from BMS; and is named on a patent for a PD-1 biomarker not used in the current trial. MDV has worked in a consulting/advisory role for and received honoraria from BMS, MSD, Novartis, and Pierre Fabre. HG has worked in a consulting/advisory role for Amgen, BMS, MSD, and Replimune; has received honoraria from BMS, MSD, Novartis, Sanofi, and Pierre Fabre; and has received research/grant support from Amgen, BMS, Iovance, MSD, Pfizer, and Replimune. AMA has worked in a consulting/advisory role for, and received honoraria from Pierre Fabre, Novartis, BMS, Merck, Roche, MSD, and Sanofi; and has served as a speaker/provided expert testimony for BMS, Merck, Pierre Fabre, Novartis, MSD, Sanofi, and Roche. SD has received research/grant support from BMS and MSD; has received travel/congress support from BMS; and has worked in an advisory role for MSD. CLC has worked in a consulting/advisory role for Merck, Novartis, Pfizer, Sanofi, and Eisai. MS has received research/grant support from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, BeiGene, Bioven, Clovis Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Tesaro. J-JG has worked in a consulting/advisory role for Amgen, BMS, MSD, Novartis, Philogen, Pierre Fabre, Roche, and Sanofi. VC-S has received honoraria from Pierre Fabre, Novartis, and BMS; and has received travel/congress support from Novartis and Pierre Fabre. IM-R has worked in a consulting/advisory role for AstraZeneca, Amgen, BMS, Incyte, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Highlight Therapeutics, Regeneron, and Sanofi; has received honoraria from BMS, MSD, Roche, Pierre Fabre, Novartis, and Sun Pharma; and has received travel/congress support from BMS, MSD, Novartis, Pierre Fabre, Roche, and Sun Pharma. MOB has worked in a consulting/advisory role for BMS, GSK, Immunocore, Merck, Novartis, Pfizer, Adaptimmune, Sun Pharma, Instil Bio, IOVANCE, Medison, LaRoche Possey, and Sanofi; has received research/grant support from Merck, Takara Bio, and Novartis; has received honoraria from Sanofi, BMS, Merck, and Novartis; and has served on the safety review board for Adaptimmune, and GSK. AMDG has worked in a consulting/advisory role for BMS, MSD, Pierre Fabre, Novartis, and Sanofi; has received honoraria from BMS, MSD, Pierre Fabre, and Sanofi; and has received travel/congress support from Pierre Fabre. MRM has worked in a consulting/advisory role for Novartis, BioLineRx, BMS, Immunocore, Kineta, Merck, and Silicon Therapeutics; and has received institutional research/grant support from Roche, Astrazeneca, GSK, Immunocore, BioLineRx, Pfizer, Regeneron, Replimune, and GRAIL. LDlC-M has received honoraria from BMS, Merck, MSD, Roche, AstraZeneca, and Gilead; and has received travel/congress support from Gilead. VA has worked in a consulting/advisory role for BMS, MSD, Nektar Therapeutics, Novartis, Pierre Fabre, and Q Biotics; has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Nektar Therapeutics, and Q Biotics; and has given expert testimony for BMS. AH is an employee of Tasman Oncology; has received honoraria from BMS; has received travel/congress support from BMS and Merck; and holds stock in Tasman Oncology. LAF has worked in a consulting/advisory role for Elsevier, and Via Oncology; has received cooperative group research/grant support from Array BioPharma and Pfizer; has received institutional research/grant support from Array BioPharma, BMS, EMD Serono, Incyte, Kartos Therapeutics, Merck, and Pfizer; has received honoraria from ASCO, and the Michigan Society of Hematology and Oncology; and has served on the data and safety monitoring board of the Hoosier Cancer Research Network. MMi has worked in a consulting/advisory role for BMS, Novartis, Roche, MSD, The Limbic, Takeda, Guardant Health, Beigene, Amgen, Merck, and Lilly; has received honoraria from BMS, Roche, and The Limbic; has received travel/congress support from AstraZeneca; and has served in a leadership position for Melanoma and Skin Cancer Trials Australia. NIK has received institutional research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience, Merck, Novartis, Regeneron, and Replimune; had received honoraria from Novartis and Replimune; holds stock in Amarin, Asensus, Bellicum, and Mazor Robotics; has served on the data and safety monitoring or advisory board of AstraZeneca, BMS, Castle Biosciences, Genzyme, Incyte, Instil Bio, Iovance, Merck, NCCN, Nektar Therapeutics, Novartis, and Regeneron; and has served in a leadership position for BMS, NCCN, Nektar Therapeutics, Regeneron, and Replimune. PQ has received honoraria from and served on the data safety monitoring board or advisory board of Novartis, Sun Pharma, Pierre Fabre, BMS, MSD, Merck, Sanofi, and Roche; and has received travel/congress support from MSD. GVL has worked in a consulting/advisory role for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG, Highlight Therapeutics, MSD, Novartis, OncoSec, Pierre Fabre, Provectus Australia, QBiotics, and Regeneron; and has received honoraria from BMS and Pierre Fabre. ML and MA are employees of BMS. PAA has worked in a consulting/advisory role for Array BioPharma, AstraZeneca, Boehringer Ingelheim, BMS, Idera Pharmaceuticals, Immunocore, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna, Bio-AI Health, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, 4SC, MSD, Merck Serono, Novartis, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, and Sun Pharma; and has received research/grant support from Array BioPharma, Pfizer, BMS, Sanofi, and Roche/Genentech. MMan has worked in a consulting/advisory role for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma; has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi, and Sun Pharma; and has received research/grant support from Novartis. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Skin tumours are among the cancer types most sensitive to immunotherapy, due to their unique immunogenic features including skin-associated lymphoid tissue, high mutational load, overexpression of tumour antigens, and high frequency of viral antigens. Despite this high immunotherapy response rate, however, ultimately most skin tumours develop similar treatment resistance to most other malignant tumours, which highlights the need for in-depth study of mechanisms of response and resistance to immunotherapy. A bibliographic review of the most recent publications regarding currently in use and emerging biomarkers on skin tumors has been done. Predictive biomarkers of treatment response, biomarkers that warn of possible resistance, and emerging markers, the majority of a systemic nature, are described. Including factors affecting not only genomics, but also the immune system, nervous system, microbiota, tumour microenvironment, metabolism and stress. For accurate diagnosis of tumour type, knowledge of its functional mechanisms and selection of a comprehensive therapeutic protocol, this inclusive view of biology, health and disease is fundamental. This field of study could also become a valuable source of practical information applicable to other areas of oncology and immunotherapy.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized., Patients and Methods: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily)., Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports., Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma., (©2021 The Authors; Published by the American Association for Cancer Research.)

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.

Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun-exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%-46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an uncommon aggressive skin cancer associated with advanced age, UV light exposure, and immunosuppression. Up to 80% are associated with Merkel cell polyomavirus. MCC is a chemosensitive disease, but tumor responses in the advanced setting are short-lived with no long-term survivors. Recent clinical trials with immune checkpoint inhibitors (i.e., pembrolizumab, avelumab, nivolumab) have shown promising results, with avelumab becoming the first drug to receive regulatory approval for this orphan indication. Further follow-up is needed, however, to define more adequately the long-term benefits of these drugs, and continued research is warranted to optimize immunotherapeutic strategies in this setting., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma., Methods: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8 + T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario., Results: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity., Conclusions: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Background: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600 -mutated melanoma treated in the Phase III coBRIM study., Methods: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms., Results: Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014)., Conclusions: Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600 -mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012.

Background: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF)., Materials and Methods: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes., Results: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines., Conclusions: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study., Methods: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS)., Results: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months., Conclusion: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

Background: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies., Methods: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants., Findings: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group., Interpretation: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma., Funding: F Hoffmann-La Roche-Genentech., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain., Patients and Methods: An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments., Results: In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups., Conclusions: Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior.