ArticlesNivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial
Introduction
The recent evolution in the treatment landscape for advanced melanoma has been accompanied by continuously improving survival outcomes for these patients in the past 10 years. Historically, patients with advanced melanoma had a median overall survival of around 8 months and a 5-year overall survival of approximately 10%.1 Survival outcomes began to improve in 2011 with the regulatory approval of ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, in the USA; survival follow-up of 1861 patients with advanced melanoma who had received ipilimumab in clinical and observational studies showed that approximately 20% of patients survived to 5 years or more.2 Additionally, targeted monotherapy treatments have had a survival impact on patients with BRAF-mutated melanoma, with a 4-year overall survival of 17% reported with vemurafenib and a 5-year overall survival of 24% reported with dabrafenib.3, 4
Newer agents that target the programmed death 1 receptor (PD-1) within the tumour microenvironment, thus blocking interaction with its ligands PD-L1 and PD-L2 on tumour cells,5 have shown that overall survival times can be extended beyond those achieved with ipilimumab alone. In the phase 3 CheckMate 0676 and KEYNOTE-0067 trials, the anti-PD-1 agents nivolumab and pembrolizumab, respectively, have demonstrated significantly improved overall survival compared with ipilimumab monotherapy in patients with advanced melanoma. At a minimum follow-up of 36 months, 3-year overall survival was 52% with nivolumab and 34% with ipilimumab in the CheckMate 067 study.6 In the KEYNOTE-006 study, at a median follow-up of 45·9 months (range 0·3–50·0), the proportions of previously untreated patients alive at 3 years and 4 years when treated with pembrolizumab were 51% and 44%, respectively, compared with 41% and 36%, respectively, of those treated with ipilimumab.8
Several combination therapies have been evaluated for advanced melanoma in recent years, and patient follow-up time is now sufficient in some of these studies to suggest that these combination therapies might provide a greater long-term overall survival benefit than approved monotherapies. In the phase 3 COMBI-d trial,9 the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib led to a 3-year overall survival of 44% (95% CI 36–51), compared with 32% (25–38) with dabrafenib alone, in patients with BRAF-mutant metastatic melanoma.9 More recently, the results of the phase 3 COLUMBUS trial10 in patients with BRAF-mutant metastatic melanoma showed a 3-year overall survival of 47% with the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib versus 32% with vemurafenib alone. In the CheckMate 067 trial,6 involving previously untreated patients with BRAF wild-type or BRAF-mutant advanced melanoma, we previously reported a 3-year overall survival of 58% with the combination of nivolumab and ipilimumab, 52% with nivolumab alone, and 34% with ipilimumab alone. Along with a numerically higher 3-year overall survival, patients in the combination group had a longer time to subsequent therapy and a higher percentage were free of subsequent therapy at 3 years compared with patients in either of the two monotherapy groups. Moreover, in a pooled analysis of data from the phase 2 CheckMate 069 trial11 and the CheckMate 067 trial, efficacy outcomes in patients who discontinued nivolumab plus ipilimumab early because of treatment-related adverse events were similar to those in patients who did not discontinue treatment for treatment-related adverse events.12
In the present Article, we provide a 4-year update of efficacy and safety data from the CheckMate 067 trial, including analyses of time without subsequent therapy, patients free of subsequent therapy, and efficacy outcomes for those who discontinued nivolumab plus ipilimumab early because of treatment-related adverse events.
Section snippets
Study design and participants
In this multicentre, randomised, controlled, double-blind, phase 3 trial, we recruited patients from 137 cancer centres in 21 countries (appendix pp 22–24). The study protocol is available in the appendix, and the methods have been published previously.6 Eligible patients were aged 18 years or older and had histologically confirmed, unresectable stage III or stage IV metastatic melanoma with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and known BRAFV600 mutation
Results
Between July 3, 2013, and March 31, 2014, we enrolled 1296 patients at 137 sites in 21 countries and randomly assigned 945 patients to study treatment: 314 to combination nivolumab plus ipilimumab, 316 to nivolumab alone, and 315 to ipilimumab alone (efficacy population for the primary and secondary endpoints; figure 1). The safety population consisted of 313 patients in the combination group and in the nivolumab group and 311 patients in the ipilimumab group (figure 1). Patient demographics
Discussion
This 4-year analysis of the CheckMate 067 trial showed similar overall survival benefit with the combination of nivolumab and ipilimumab to the 3-year update with matured progression-free survival results and no new safety concerns. Median overall survival was not reached in the nivolumab plus ipilimumab group and 36·9 months in the nivolumab group versus 19·9 months in the ipilimumab group. Median progression-free survival was 11·5 months in the nivolumab plus ipilimumab group, 6·9 months in
Data sharing
Bristol-Myers Squibb's policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
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