Elsevier

The Lancet Oncology

Volume 19, Issue 11, November 2018, Pages 1480-1492
The Lancet Oncology

Articles
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(18)30700-9Get rights and content

Summary

Background

Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.

Methods

In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.

Findings

Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44–0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53–0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7–19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1–10·2) in the nivolumab group, and 2·9 months (2·8–3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35–0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44–0·64; p<0·0001). Treatment-related grade 3–4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.

Interpretation

The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.

Funding

Bristol-Myers Squibb.

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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