Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

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.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

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.