Search

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, brain 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 (11 [18%]). 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 who received triplet therapy in the BRAF V600 mutation-positive cohort and two (13%) of 15 in the BRAF V600 wild-type cohort. No treatment-related deaths occurred., Interpretation: Atezolizumab plus vemurafenib and cobimetinib provided 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. PGD, 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 © 2023 Elsevier Ltd. All rights reserved.)

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

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 [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<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: 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: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1)., Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1., Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis., Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma., Funding: None., Competing Interests: Declaration of interests IPdS reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche, outside the submitted work. ABW reports personal fees from Shanghai Jo'Ann Medical Technology, Nanobiotix, Novartis, LG Chem Life Sciences, and Iovance, outside the submitted work. CA reports personal fees from Roche, Amgen, and Bristol Myers Squibb, outside the submitted work. JM reports grants, personal fees, and travel grants from Bristol Myers Squibb and Merck Sharp & Dohme; personal fees from Merck Sharp & Dohme, Pfizer, Sanofi, Amgen, and Novartis; personal fees and travel grants from Pierre Fabre; and travel grants from Ultrasun and Loreal, outside the submitted work. LZ reports personal fees, advisory board participation, and travel grants from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Roche, and Novartis; and advisory board participation and travel grants from Sanofi and Amgen, outside the submitted work. ML reports personal fees from Bristol Myers Squibb, Novartis, Roche, and Merck Sharp & Dohme, outside the submitted work. OK and AH report personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. OM reports grants and personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre-Fabre, and Amgen; personal fees from Roche, Novartis, and GlaxoSmithKline; and grants from Merck Sharp & Dohme, outside the submitted work. PAA reports grants and personal fees from Bristol Myers Squibb, Roche, Array BioPharma, and Sanofi; personal fees from Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, and Lunaphore; and uncompensated consultant service from Takis, outside the submitted work. MSC reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Sanofi, Merck Serono, Pierre Fabre, Roche, Ideaya, Regeneron, Nektar, Eisai, Qbiotics, and Oncosec, outside the submitted work. CL reports grants and personal fees from Bristol Myers Squibb and Roche; personal fees from Merck Sharp & Dohme, Novartis, Amgen, Avantis Medical Systems, Pierre Fabre, Pfizer, Incyte, Merck Serono, and Sanofi, outside the submitted work. PL reports personal fees and support for travel from Merck Sharp & Dohme and Novartis; personal fees from Amgen, Nektar, and Pierre Fabre; and grants, personal fees, and support for travel from Bristol Myers Squibb, outside the submitted work. DBJ reports being part of advisory boards and consulting for Array Biopharma, Catalyst, Iovance, Jansen, Merck Sharp & Dohme, Novartis, and Oncosec; grants and other research funding from Bristol Myers Squibb; and grants from Incyte, outside the submitted work. SS reports grants from Novartis, AstraZeneca, Merck Sharp & Dohme, and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb, outside the submitted work. CUB reports grants from an advisory role in Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; research funding from Bristol Myers Squibb, Novartis, and NanoString; stock ownership in Uniti cars; and is a cofounder of Immagene, outside the submitted work. AMM reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and QBiotics, outside the submitted work. GVL reports personal fees from Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharp & Dohme, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and Specialised Therapeutics Australia, outside the submitted work. TA, ILMR, AMW, JRP, PS-B, KN, CT, DS, CLG, and SNL declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results., Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73])., Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AMME reports being the study chair of the EORTC 18071/CA-029 phase 3 clinical trial (Bristol Myers Squibb [BMS]) and of the EORTC 1325/KEYNOTE-054 phase 3 trial (Merck Sharp & Dohme), and has worked in a consulting or advisory role and received honoraria from Biocad, Biotech, BioInvent, BMS, CatalYm, GlaxoSmithKline (GSK), IO Biotech, ISA Pharmaceuticals, Merck, Novartis, Regeneron Pharmaceuticals, Sellas, and SkylineDx. CUB reports receiving grants from BMS, NanoString Technologies, Novartis, and Third Rock Ventures and personal fees from AstraZeneca, BMS, GenMab, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, and Roche during the conduct of the study; he owns stocks in Unity Cars, and is co-founder of Immagene BV. MM reports receiving grants from BMS, MSD, and Roche Novartis and has worked in a consulting or advisory role for BMS, MSD, and Pierre Fabre. GVL has worked in a consulting or advisory role and received honoraria from Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim, BMS, Highlight Therapeutics, MSD, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and SkylineDX. VGA has worked in a consulting or advisory role and received speaking fees or travel support, or both, from BMS, Merck, MSD, Nektar, Novartis, OncoSec, Pierre Fabre, and Roche. SD reports receiving grants from BMS and MSD. AMH reports receiving personal fees from BMS, MSD, and Novartis. AM has worked in a consulting or advisory role and received honoraria from Amgen, AstraZeneca, Aventis, Bayer, BIOCAD, BMS, Eisai, Eli Lilly, Merck, Sanofi, SERVIER, and Takeda Pharmaceuticals. AK reports grants and personal fees from MSD. MSC has worked in a consulting role and received honoraria from BMS, Eisia, IDEAYA Biosciences, Merck Serano, MSD, Novartis, Oncosec, Pierre Fabre, Q biotics, Roche, and Sanofi. SSa reports receiving grants from Amgen, AstraZeneca, BMS, Endocyte, and MSD. JL reports receiving grants from Achilles Therapeutics, AVEO Pharmaceuticals, BMS, Covance, Genentech/Roche, Immunocore, MSD, Nektar, Novartis, Pharmacyclics, and Pfizer and has worked in a consulting role and received honoraria from Achilles Therapeutics, AstraZeneca, Boston Biomedical, BMS, Covance, Eisai, EUSA Pharma, Genentech/Roche, GSK, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Secarna Pharmaceuticals, and Vitaccess. SP received grants from Abbie, Almirall, AMLO Biosciences, Castle Biosciences, La Roche Posay, Leo Pharma, Melagenix, and Sun Pharma, has worked in a consulting role and received honoraria from Almirall, ISDIN, La Roche-Posay, Leo Pharma, Regeneron, Sanofi, and Sun Pharma, and speaker's bureau from Bioderma, BMS, La Roche Posay, Pierre Fabre, Roche, and Sanofi. PAA received grants and research funds from Array BioPharma, BMS, and Genentech/Roche and has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, BMS, Genentech/Roche Genmab, Idera Pharmaceutials, Immunocore, Incyte, MedImmune, Merck Serono, MSD, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax Pharmaceuticals, and Ultimovacs. PR has worked in a consulting or advisory role and received honoraria from Blueprint Medicines, BMS, MSD, Novartis, Pfizer, and Pierre Fabre. DS has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, Incyte, Pierre Fabre, and Pfizer. RK has worked in a consulting role and received honoraria from BMS, MSD, Novartis, Pierre Fabre, and Roche. LH-A reports that his institution received fees to conduct clinical trials from Merck, Amgen, BMS, Corvus, Genentech, Immunocore, Merck-EMD, Novartis, Polynoma, Regeneron, and Roche. AMDG has worked in a consulting or advisory role and received fees from BMS, GSK, Pierre Fabre, and Sanofi. AJMvdE has worked in a consulting or advisory role and received fees from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre and grants from BMS, Sanofi, and Roche. J-JG has worked in a consulting or advisory role or received speaker fees, and received fees from Amgen, BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. RG has worked in an advisory role and received fees from 4SC, Almirall, Amgen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and Sun Pharma and received grants from Amgen, Johnson & Johnson, Novartis, and Pfizer. RJ reports receiving grants and patient fees from MSD during the conduct of the study and receiving grants from BMS and Iovance and fees to conduct clinical trials for his institutions from Roche, GSK, AstraZeneca, and Novartis. PCL has worked in a consulting or advisory role and his institution received honoraria and grants from 4SC, Amgen, BMS, Merck, and Novartis. ACJvA reports receiving grants from 4SC, Amgen, BMS, Merck, MSD, Novartis, Pfizer, and Sanofi. CK and NI are employees and shareholders of Merck. MK and SSu report receiving grants from Merck during the conduct of the study. CR has worked in a consulting or advisory role and received honoraria from Amgen, Biothera, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. SM declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint., Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant., Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AMME reports non-financial support from BMS and Merck & Co during the conduct of the study; personal fees from Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, GSK, IO Biotech, ISA pharmaceuticals, Merck, Novartis, Regeneron, Sellas, SkylineDx, Novartis, and Pfizer, outside the submitted work. AMH reports personal fees from Merck Sharp and Dohme (MSD); and personal fees from Novartis and BMS, outside the submitted work. AJMvdE reports grants and personal fees from BMS; grants from Roche and Idera; and personal fees from MSD, Amgen, Pierre Fabre, and Novartis, outside the submitted work. AM reports personal fees from Lilly Pharma, AstraZeneca Pharmaceuticals, Merck, BMS, and Sanofi-Aventis Group, outside the submitted work AMDG reports advisor or consultant roles from BMS, Pierre Fabre, Sanofi, and MSD, outside the submitted work. ACJvA reports grants and personal fees from Amgen and Merck-Pfizer; and personal fees from BMS, Novartis, MSD-Merck, Sanofi, Sirius Medical, and 4SC, outside the submitted work. CUB reports grants and personal fees from BMS and Novartis; personal fees from Roche, MSD, Pfizer, Lilly, Pierre Fabre, and GenMAb; grants from NanoString and Third Rock Ventures; stock ownership of Unity Cars; and is a cofounder of Immagene, outside the submitted work. CR participated in advisory boards for Roche, Pierre Fabre, Merck, Novartis, Amgen, BMS, Novartis, MSD, Sanofi, Biothera, and Ultimovacs. DS reports personal fees consulting or advisory role, honorarium, speakers bureau, travel, accommodations, and expenses from MSD during the conduct of the study; personal fees and non-financial support from Roche/Genentech, Merck Serono, and Merck; grants, personal fees, non-financial support, consulting or advisory role, honoraria, speakers bureau, travel, accommodations, expenses, and research funding from Novartis and Amgen; grants, personal fees, consulting or advisory role, honoraria, speakers bureau, travel, accommodations, expenses, and research funding from BMS; and personal fees from Immunocore, Incyte, 4SC, Pierre Fabre, Sanofi, Array BioPharma, Pfizer, Philogen, Regeneron, Nektar, and Sandoz, outside the submitted work. GVL reports personal fees from Aduro Biotech, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Highlight Therapeutics, MSD, Novartis Pharma, QBiotics, Rhegeneron Pharmaceuticals, and SkylineDX, outside the submitted work. NI and CK report personal fees from Merck & Co during the conduct of the study. J-JG reports personal fees from BMS, MSD, Novartis, Roche, Amgen, Pierre Fabre, and Sanofi; and personal fees from Merck and Pfizer, outside the submitted work. JL reports grants and personal fees from BMS, MSD, Pfizer, Novartis, Roche, Immunocore, Achilles therapeutics, and Nektar; personal fees from Eisai, GSK, Kymab, Secarna, AstraZeneca, Boston Biomedical, EUSA Pharma, Ipsen, Imugene, Incyte, iOnctura, Merck Serono, Pierre Fabre, Vitaccess, and Covance; and grants from Aveo and Pharmacyclics, outside the submitted work. LH-A reports personal fees from Merck during the conduct of the study; and personal fees from BMS, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, and Genentech, outside the submitted work. MM reports grants from BMS, MSD, and Roche; and advisory board from Pierre Fabre, BMS, and MSD, outside the submitted work. MSC reports personal fees from MSD, BMS, Novartis, Roche, Pierre Fabre, and Sanofi; and personal fees from Merck Serono, Nektar, Eisia, and Ideaya, outside the submitted work. PAA reports grants and personal fees from BMS, Roche-Genentech, and Array; personal fees, advisory or consultant role, and travel support from MSD; personal fees from Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, and Boehringer Ingelheim, outside the submitted work. PCL reports personal fees and advisory, speaker, and trials roles for BMS, Novartis, Amgen, GSK, and Chugai; and personal fees from Merck, outside the submitted work. PR reports personal fees from MSD, BMS, Novartis, Pierre Fabre, Blueprint Medicines, and Pfizer outside the submitted work. RG reports documentation fees to institution from MSD during the conduct of the study; personal fees and non-financial support from BMS, Roche Pharma, Merck Serono, Pierre Fabre, and Sanofi Regeneron; fees from MSD, Almirall Hermal, SUN Pharma, and 4SC; grants, personal fees, and non-financial support from Amgen and Novartis; grants and personal fees from Pfizer; and grants from Johnson & Johnson, outside the submitted work. RJ reports grants, fees paid to institution for the conduct of studies in melanoma, and grant for Investigator Initiated Trial in metastatic melanoma from BMS during the conduct of the study; grants, per patients fees paid to the institution for the conduct of the study, and grant for Investigator Initiated Trial in metastatic melanoma from Merck; fees paid to the institution for the conduct of studies in melanoma from Roche/Genentech, GSK, AstraZeneca, and Novartis; and grants from Iovance, outside the submitted work; and has acted as a presenter or as a consultant in advisory boards for both BMS and Merck but has not received any monetary compensation for those roles. SD acts as principal investigator in clinical trials promoted by BMS and MSD and has received institutional research grants from BMS and MSD. SP reports grants from Leo Pharma, Almirall, Castle Bioscience, AMLO Bioscience, and Melagenics; personal fees from Amirall, Leo Pharma, Isdin, Sanofi, La Roche Posay, Regeneron, and Pfizer; speaker bureau from La Roche Posay, Roche, Pierre Fabre, BMS, Bioderma, and Sanofi, outside the submitted work. SSa reports personal fees from BMS and MSD outside the submitted work. SSu, MK, CC, and AK report grants from MSD during the conduct of the study. VGA reports personal fees and non-financial support from BMS; personal fees from Merck, MSD, Novartis, Pierre Fabre, Roche, and Nektar; and travel support from Onco-sec, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.)

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF V600 -mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival., Methods: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF V600E or BRAF V600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38., Findings: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment., Interpretation: The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF V600 -mutant melanoma., Funding: Array BioPharma, Novartis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF V600 -mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAF V600 -mutant melanoma., Methods: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF V600E or BRAF V600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38., Findings: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator., Interpretation: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma., Funding: Array BioPharma, Novartis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma., Methods: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419., Findings: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug., Interpretation: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population., Funding: F Hoffman-La Roche Ltd., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg., Methods: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189., Findings: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events., Interpretation: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment., Funding: Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma., Methods: NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m 2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51., Findings: Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group., Interpretation: Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy., Funding: Array BioPharma and Novartis Pharmaceuticals Corporation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial., Methods: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168., Findings: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19])., Interpretation: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events., Funding: Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.)

Background: Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens., Methods: The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394., Findings: Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis., Interpretation: Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC., Funding: Bristol-Myers Squibb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma., Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients., Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy., Interpretation: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma., Funding: Merck Sharp & Dohme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up., Methods: In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing., Findings: Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses)., Interpretation: This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially., Funding: F Hoffmann-La Roche., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence., Methods: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168., Findings: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome., Interpretation: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value., Funding: Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746., Findings: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred., Interpretation: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need., Funding: Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options., Methods: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397., Findings: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively)., Interpretation: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug., Funding: F Hoffmann-La Roche., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials., Methods: We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose., Findings: After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0·71 (95% CI 0·29-0·90) with a random-effects assumption, 0·85 (0·59-0·95) with a fixed-effects assumption, and 0·89 (0·68-0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81-0·99), which decreased to 0·93 (0·74-0·98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0·55, 0·03-0·84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0·85 (0·51-0·96)., Interpretation: PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups., Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980., Findings: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events., Interpretation: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation., Funding: F Hoffmann-La Roche-Genentech., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma., Methods: In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment)., Findings: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes., Interpretation: To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments., Funding: Novartis Pharmaceuticals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain., Methods: We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01266967., Findings: Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%])., Interpretation: Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed., Funding: GlaxoSmithKline., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases., Methods: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m(2) intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692., Findings: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase., Interpretation: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases., Funding: Bristol-Myers Squibb., (Copyright © 2012 Elsevier Ltd. All rights reserved.)