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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).)

Purpose: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy., Patients and Methods: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy)., Results: Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS., Conclusion: Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

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.)

Background: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods., Patients and Methods: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted., Results: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06)., Conclusions: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings., Patients and Methods: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS., Results: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value., Conclusions: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253., (©2023 The Authors; Published by the American Association for Cancer Research.)

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.

Purpose: Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136)., Methods: Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review., Results: A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count)., Conclusion: Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

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.)

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported., Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment., Results: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms., Conclusions: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MK has no conflicts of interest to declare. JJL reports advisory/consultancy roles with AbbVie, Immutep, Evaxion, 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, STipe, Tempest, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Day One, Duke St, EMD Serono, Endeavor, Flame, Genentech, Gilead, Glenmark, HotSpot, Kadmon, Janssen, Ikena, Immunocore, Incyte, IO Biotech, Macrogenics, Merck, Nektar, Novartis, Partner, Pfizer, Regeneron, Roivant, Servier, STINGthera, Synlogic, and Synthekine; stock ownership in Actym, AlphamabOncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, STipe, and Tempest; research grants/funding to their institution 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, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; travel, accommodation, and/or expenses from Castle; and the following provisional patents: Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. PAA reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, and Medicenna.Bio-Al Health; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, AstraZeneca, Immunocore, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, and iTeos. PR reports advisory/consultancy roles with MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines, and Philogen; speaker bureau for BMS, MSD, Novartis, Pierre Fabre, Merck, and Sanofi; research grant/funding to their institution from Pfizer; and officer/board of director roles with ASCO, ESMO, and the Polish Oncological Society. DS reports advisory/consultancy roles with 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; speaker bureau for BMS, Merck/MSD, Merck Serono, Novartis, Roche, Sanofi, and Sun Pharma; research grant/funding to their institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; travel, accommodation, and/or expenses from BMS, Merck Serono, MSD, Novartis, and Sanofi; officer/board of director role with WTZ; and the following nonremunerated activities: EORTC-MG, member of board of directors; coordinating PI for 4SC, BMS, MSD, Nektar, Novartis, and Pierre Fabre; local PI for Philogen, Roche, and Sanofi. CR worked in a consulting/advisory role for BMS, Roche, Amgen, Novartis, Pierre Fabre, MSD, Sanofi, Biothera, CureVac, and Merck. MAP worked in a consulting/advisory role for BMS, Merck, Eisai, Novartis, Incyte, NewLink Genetics, Aduro, and Pfizer; received research/grant support from BMS, Merck, Novartis, Array BioPharma, RGenix, Infinity, and AstraZeneca. JJG reports advisory/consultancy roles with BMS, MSD, Novartis, Roche, Philogen, Pierre Fabre, Sanofi, Amgen, Merck, and Pfizer; and travel, accommodations, and/or expenses from BMS and Pierre Fabre. LDLCM reports advisory/consultancy roles with Roche, BMS, and MSD-Merck; research grant/funding to their institution from Roche, Celgene, and MSD; and travel, accommodation, and/or expenses from Gilead. MDV reports honoraria and advisory/consultancy roles with Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. FS reports honoraria from BMS, Novartis, MSD, Pierre Fabre, Sanofi, Sun Pharma, Merck; and advisory/consultancy roles with Novartis, MSD, Pierre Fabre, Sun Pharma, and Philogen. JM reports honoraria from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, Novartis; advisory/consultancy roles with MSD and Bristol Myers Squibb; and travel, accommodations, and/or expenses from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis. VCS reports travel, accommodation, and/or expenses from Pierre-Fabre and Novartis; and nonremunerated activities for BMS, Pierre-Fabre, and Merck-Serono. MSC reports honoraria from Bristol Myers Squibb, MSD, and Novartis; and advisory/consultancy roles with Amgen, Bristol Myers Squibb, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, and Roche. PM reports honoraria and advisory/consultancy roles with Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, and Immunocore; research grant/funding from BMS, Novartis, and MSD; and travel, accommodation, and/or expenses from Pierre Fabre, MSD, Merck Germany, and Roche. FDG reports advisory/consultancy roles with BMS and Novartis; and research grant/funding to their institution from Novartis. MR reports advisory/consultancy roles with MSD; and travel, accommodation, and/or expenses from MSD. ZE reports advisory/consultancy roles with Pfizer, Novartis, Genentech, Regeneron, OncoSec, Natera, and Eisai; and research grant/funding to their institution from Pfizer and Novartis. KC is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA. RJ, MFK, and CK are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA, and are stockholders of Merck & Co., Inc., Rahway, NJ USA. AE reports honoraria from Agenus, Biocad, BioInvent, BioNTech, Brenus, CatalYm, Clover, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Merck/MSD, Nektar, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDx, TigaTx, and TTxDiscovery; advisory/consultancy roles with Agenus, Biocad, BioInvent, BioNTech, Brenus, CatalYm, Clover, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Merck/MSD, Nektar, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDx, TigaTx, and TTxDiscovery; speaker bureau for Biocad, BMS, and Merck/MSD; a leadership role with the European Academy of Cancer Sciences; stock ownership in IO Biotech and SkylineDx; and nonremunerated activities for the European Academy of Cancer Sciences (EACS) and the Fondation Cancer (FOCA). JMK reports advisory/consultancy roles with Applied Clinical Intelligence LLC, Amgen Inc., Ankyra Therapeutics, Axio Research/Instil Bio, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore LLC, Intellisphere LLC/Cancer Network, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Millennium Pharmaceuticals/Takeda Pharmaceutical, Natera Inc, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc., Pfizer, Replimune, Scopus BioPharma, and SR One Capital Management; and research grant/funding to their institution from Amgen Inc., Bristol Myers Squibb, Castle Biosciences Inc, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore LLC, Iovance Biotherapeutics, Merck, Novartis Pharmaceuticals, Schering-Plough, Takeda, and Verastem Inc., (Copyright © 2022 The Author(s), Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc.,. Published by 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.)

Background: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases., Methods: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAF V600 wild-type cohort and a BRAF V600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, CNS metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAF V600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAF V600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAF V600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141., Findings: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF V600 mutation-positive cohort; the BRAF V600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAF V600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAF V600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAF V600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAF V600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAF V600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAF V600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients in the BRAF V600 mutation-positive cohort and two (13%) of 15 in the BRAF V600 wild-type cohort. One death in the BRAF V600 mutation-positive cohort (limbic encephalitis) was considered to be related to atezolizumab treatment., Interpretation: Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAF V600 -mutated melanoma with CNS metastases., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests RD reports consulting fees and honoraria from Alligator, Amgen, Bristol Myers Squibb, Catalym, Merck Sharp & Dohme, MaxiVAX, Novartis, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Second Genome, Sun Pharma, T3 Pharma, Takeda, and touchIME, and research funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. PQ reports consulting fees and honoraria from Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, and travel, accommodations, or other expenses from Merck Sharp & Dohme and Sanofi. AMAG reports former employment with F Hoffmann-La Roche, current employment with Daiichi-Sankyo, and stock or other ownership with Daiichi-Sankyo. YH and DW report employment with Roche. SJdA reports research funding from Roche-Genentech. CR reports consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. PAA reports consulting fees from 4SC, Bio-Al Health, Bristol Myers Squibb, Idera, Italfarmaco, Lunaphore, Medicenna, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pfizer/Array, Pierre-Fabre, Roche-Genentech, Sandoz, Sanofi, and Sun Pharma; research funding from Bristol Myers Squibb, Pfizer/Array, Roche-Genentech, and Sanofi; and participation on a data safety monitoring board or advisory board for AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Immunocore, iTeos, Merck Sharp & Dohme, Nouscom, Novartis, Oncosec, Regeneron, Roche-Genentech, and Seagen. VC-S reports consulting fees from Bristol Myers Squibb, Merck-Serono, Novartis, and Pierre Fabre; honoraria from Bristol Myers Squibb and Novartis; and travel, accommodations, or other expenses from Bristol Myers Squibb and Pierre Fabre. FS reports honoraria from Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, and consulting fees from Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre, and Sun Pharma. GL reports consulting fees, honoraria, and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi; research funding from Roche, Clinical Excellence Program, establishment of The National Tumor Biology Laboratory, and Investment of the Future; and a leadership role with College of Dermatology, Hungarian Medical Research Council, and CEEAO. LdlCM reports consulting fees from Bristol Myers Squibb, Gilead, Incyte, Merck Sharp & Dohme, Novartis, and Roche, and research funding from Celgene, Merck Sharp & Dohme, and Roche. HT reports consulting fees from Boxer Capital, Bristol Myers Squibb, Eisai, Genentech, Iovance, Jazz Pharmaceuticals, Karyopharm, Medicenna, Merck, and Novartis, and research funding from Bristol Myers Squibb, Celgene, Dragonfly, Eisai, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, and RAPT Therapeutics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival., Methods: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual., Findings: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred., Interpretation: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA., Competing Interests: Declaration of interests JJL reports research funding to their institution for clinical studies from Merck Sharp & Dohme (MSD), AbbVie, Agios, Array, Astellas, AstraZeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; membership on data safety monitoring boards for AbbVie and Immutep; membership on scientific advisory boards with no stock ownership or stock options for 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, Xilioo, and with stock for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, and Tempest; compensation for consultancy with AbbVie, Alnylam, Bayer, Bristol-Myers Squibb, CheckMate, Codiak, Crown, Cstone, Day One, Eisai, EMD Serono, Flame, Genentech, Gilead, HotSpot, Kadmon, KQS, Janssen Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rublus, Silicon, Synlogic, Synthekine, TRex, Werewold, and Xencor; and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof). PR reports research funding to their institution from MSD and Pfizer and honoraria for lectures and advisory board participation from MSD, Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. PQ reports research finding to their institution for clinical studies from MSD, and honoraria as consultant or advisor role from Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Sun Pharma, Sanofi-Regeneron, and Roche. MDV reports research finding to their institution for clinical studies from MSD and honoraria as consultant or advisor for Novartis, Bristol Myers Squibb, MSD, and Pierre Fabre. JM reports research funding to their institution for clinical studies from MSD; honoraria from Bristol Myers Squibb, MSD, Roche, Novartis, and Pierre Fabre; and consultant or advisor roles for Bristol Myers Squibb and MSD. VC-S reports research funding to their institution for clinical studies from MSD; reimbursement for travel and accommodation for medical congress from Bristol Myers Squibb and Pierre Fabre; and honoraria for advisory board participation from Novartis and Pierre Fabre. LdlCM reports research funding to their institution for clinical studies from Celgene, MSD, and Roche; reimbursement for travel expenses from Roche; and consultant or advisor roles for Bristol Myers Squibb, MSD, Novartis, and Roche. MAK reports research funding to their institution for clinical studies from MSD and MSD Australia; fees as speaker from Bristol Myers Squibb, Novartis, Merck Serono, and MSD Australia; and reimbursement for travel from Bristol Myers Squibb and Roche. DS reports research funding to their institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Amgen, and Array; grants paid to their institution from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, SunPharma, Sandoz, and UltimoVacs; reimbursement for travel from Bristol Myers Squibb, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; and non-financial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, SunPharma, and Sandoz. GVL reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor from Aduro Biotech, Amgen, Arrary Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S L, MSD, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group, Regeneron Pharmaceuticals, SkylineDX BV, and Specialised Therapeutics Australia. PAA reports research funding to their institution for clinical studies from MSD, Bristol Myers Squibb, Roche-Genentech, Sanofi, and Pfizer and fees as a consultant or advisor from Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Italfarmaco, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, and ITeos. MM reports research funding to their institution for clinical studies from MSD and personal fees from MSD, Pierre Fabre, Novartis, Bristol Myers Squibb, and Sanofi. FDG and J-JG report research funding to their institutions for clinical studies from MSD. AH reports research funding to their institution for clinical studies from MSD and fees for advisory board membership from Novartis, Bristol Myers Squibb, and MSD. RD reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, Bristol Myers Squibb, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME. CR reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor for Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. MSC reports research funding to their institution for clinical studies for MSD and honoraria for consulting from Bristol Myers Squibb, 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, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche/Genentech, and Sanofi; consulting or advisory roles for Amgen, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; fees for speakers bureau from Amgen, Bristol Myers Squibb, MSD, Novartis, Roche, and Sanofi; and reimbursement for travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma. AP reports research funding to their institution for clinical studies from MSD; fees for consulting or advisory roles from Novartis; and fees for speakers bureau from Bristol Myers Squibb. VKS reports research funding to their institution for clinical studies from MSD and Neogene Therapeutic and fees for participation in independent data safety monitoring committees and participation in advisory boards from Bristol Myers Squibb, Eisai, Novartis, Merck, Regeneron, and Replimune. RAS reports research funding to their institution from MSD and fees for professional services from F Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, AMGEN, Bristol Myers Squibb, Myriad Genetics, and GSK. RAS is supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1141295). JMK reports research funding to their institution from MSD, Amgen, Bristol Myers Squibb, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapies, Novartis Pharmaceuticals, Castle Biosciences, and Merck; personal fees from Amgen, Ankyra Therapeutics, Axio Research/Instil Bio, Bristol Myers Squibb, Checkmate Pharmaceuticals, DermTech, Elsevier, Harbour BioMed, Immunocore, Iovance Biotherapies, Istari Oncology, Millenium Pharm/Takeda Pharm, Natera, Novartis Pharmaceutical, OncoCyte Corporation, OncoSec Medical, Pfizer, Scopus BioPharma, Merck, Becker Pharmaceutical Consulting, Fenix Group International, Intellisphere LLC/Cancer Network, IQVIA, Replimune, and SR One Capital Managment. KC, SJD, SA, and NI 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, Bristol Myers Squibb, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck, MSD, Nektar, Novartis, Pfizer, Sellas, SkylineDX, TigaTx, and TxDiscovery; personal fees for independent data monitoring committee for Biocad, GSK, Pfizer, and Novartis; fees for participation in speakers bureau from Biocad, Bristol Myers Squibb, and Merck; and equity in IO Biotech, SkylineDX., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.)

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial., Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups., Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm., Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident., Trial Registration Number: NCT02388906., Competing Interests: Competing interests: MM: Consulting or Advisory Role: Bristol Myers Squibb, Novartis, MSD Oncology, Pierre Fabre, Roche/Genentech; Honoraria: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, Roche/Genentech; Research Funding: Novartis, Roche/Genentech; JL: Grants: Achilles Therapeutics, Aveo, Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess, Covance, Immunocore; Personal Fees: Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, Imugen, Incyte, Ipsen, iOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess; PAA: Grant: Array, Bristol Myers Squibb, Roche/Genentech; Personal Fees: 4SC, Array, AstraZeneca, Bristol Myers Squibb, Idera, Immunocore, Incyte, Genmab, Medimmune, MSD, NewLink Genetics, Novartis, Merck Serono, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, Syndax, Sun Pharma, Ultimovacs; Advisory/consultant role and travel support: MSD; MDV: Consultant/Advisory Boards: Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, Sanofi; HG: Consulting or Advisory Role: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche, Pierre Fabre; Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche; Honoraria: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche; Research Funding: Bristol Myers Squibb, MSD Oncology, Roche, Novartis; CLC: Nothing to disclose; AA: Personal Fees: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; Travel Grant: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; SD: Consulting or Advisory Role: MSD; Research Funding: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Travel, Accommodations, Expenses: Bristol Myers Squibb; Stock Ownership/Employment: Sanofi Pasteur (immediate family member); MS Grant: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung; J-JG: Personal Fees: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sanofi, SunPharma; VC-S: Advisory Board: Incyte, Merck-Sorono, MSD; Meeting Expenses: Bristol Myers Squibb, Pierre Fabre; Speaker Fee: Novartis; IM: Grant: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Roche; Personal Fees: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Regeneron, Roche, Sanofi; Non-financial Support: BionCoTech, Bristol Myers Squibb, MSD, Roche; MOB: Consulting or Advisory Role: Adaptimmune, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Genzyme, Immunocore, Immunovaccine, Merck, Novartis; Expert Testimony: Merck; Honoraria: Bristol Myers Squibb, Merck, Novartis, Roche; Research Funding: Takara Bio, Merck; AMDG: Consulting or Advisory Role: Bristol Myers Squibb, Incyte, MSD, Pierre Fabre; JL: Consulting or Advisory Role: Array BioPharm, Bristol Myers Squibb, Novartis; Speakers’ Bureau: Array BioPharm, Novartis, Regeneron; Travel, Accommodations, and Expenses: Bristol Myers Squibb, Novartis, Pfizer; Research Funding: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Elios Pharmaceutical, Genentech/Roche, Incyte, Merck Seronon, Merck, Novartis, Pfizer, Viralytics; LDLC-M: Nothing to disclose; VA: Personal Fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec; PA: Nothing to disclose; AH: Nothing to disclose; LF: Grant: Bristol Myers Squibb, EMD Serono, Incyte, Kartos, Merck, Pfizer, Array; Consulting or Advisory Role: Elsevier/Via Oncology, Hoosier Cancer Research Network; MM: Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, MSD, Novartis, Pfizer, Roche; Travel, Accommodations, and Expenses: AstraZeneca, Bristol Myers Squibb, MSD, Roche; NIK: Consulting or Advisory Role: Array BioPharma, AstraZeneca, Bristol Myers Squibb, EMD Serono, Immunocore, HUYA Bioscience International, Genentech, Merck, Regeneron; Research Funding: Amgen, HUYA Bioscience International, GlaxoSmithKline, Merck, Novartis, Regeneron; Stock/Other Ownership Interests: Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, TransEnterix; VdP: Employee: Bristol Myers Squibb; Stock Ownership: Bristol Myers Squibb; ML: Employee: Bristol Myers Squibb; Stock Ownership: Advaxis Immunotherapies, Bristol Myers Squibb; JW: Consulting or Advisory Role: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Research Funding: Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte Corporation, Merck, Novartis, Roche; Travel, Accommodations, and Expenses: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, GlaxoSmithKline, Merck, Novartis, Pieris Pharmaceuticals, Inc, Roche; Honoraria: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Stock/Ownership Interests: Biond; Patents: Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker; named on a patent submitted from Biodesix for a PD-1 antibody biomarker., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Purpose: This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection., Methods: This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy., Results: A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values., Conclusions: Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.

Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results., Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906., Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported., Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab., Funding: Bristol Myers Squibb and Ono Pharmaceutical., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Intestinal dysbiosis has emerged as a biomarker of response to immune checkpoint inhibitors (ICIs). It can be caused by antibiotics, although it may also result from the use of other drugs that have been studied to a lesser extent. The objective of our study was to analyze the association between the use of potentially dysbiosis-related drugs and survival in patients treated with ICIs in the clinical practice., Materials and Methods: A retrospective, multicenter, cohort study was conducted. Clinicopathological variables were collected and the concomitant use of drugs was analyzed. A descriptive analysis of variables and overall survival, estimated by the Kaplan-Meier method, was performed, and association with various independent variables was assessed using Cox regression., Results: We included 253 patients, mainly with non-small cell lung cancer and melanoma. The most commonly used drugs were acid reducers, prescribed to 55.3% of patients, followed by corticosteroids (37.9%), anxiolytic drugs (35.6%), and antibiotics (20.5%). The use of acid reducers (9 vs. 18 months, P < .0001), antibiotics (7 vs. 15 months, P < .017), anxiolytic drugs (8 vs. 16 months, P < .015), and corticosteroids (6 vs. 19 months, P < .00001) was associated with poorer overall survival. Furthermore, the greater the number of drugs used concomitantly with ICIs, the higher the risk of death (1 drug: hazard ratio, 1.88; CI 95%, 1.07-3.30; 4 drugs: hazard ratio, 4.19; CI9 5%, 1.77-9.92; P < .001)., Conclusion: Response to ICIs may be influenced by the use of drugs that lead to intestinal dysbiosis. Although a confirmatory prospective controlled study is required, our findings should be taken into account when analyzing ICI efficacy.

Several regimens of immunotherapy have recently proven successful for multiple cancers, due to increased survival and quality of life. Rarely, immunotherapy with anti-programmed cell death protein 1 and programmed death-ligand 1 antibodies across cancer may cause immune-related pulmonary toxicity, with a low overall incidence, being particularly low among patients with melanoma and highest among individuals with lung cancer. In this vein, pulmonary toxicity is staged at 4 degrees according to the severity of the clinic and radiological findings, and its management is based on suppression of immunotherapy and administration of glucocorticoids. We report a case of pulmonary toxicity related to melanoma immunotherapy observed by F-FDG PET/CT.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF V600 -mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported., Methods: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful., Results: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment., Conclusions: In patients with advanced/metastatic BRAF V600 -mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy.

Metastatic or locally advanced unresectable melanoma carries a high morbidity and mortality. However, notable advances have been made in recent years in the systemic treatment of this disease, with the appearance of targeted therapy using tyrosine kinase inhibitors that block the mitogen activated protein kinase pathway, and of modern immunotherapy with immune-modulating monoclonal antibodies. In this paper, we provide an update of available data on new immune therapies and we review the clinical development that led to their approval for use in routine clinical practice., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

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.

Introduction: Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab., Materials and Methods: The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant "completely disagree" and 9 meant "completely agree"., Results: Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life., Conclusions: The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.

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.)

Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously.

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.

Background: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib., Methods: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival., Results: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy., Conclusions: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Background: Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits., Methods: A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used., Results: Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively., Conclusions: ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.