Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial.

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.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

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.