Elsevier

The Lancet Oncology

Volume 17, Issue 11, November 2016, Pages 1558-1568
The Lancet Oncology

Articles
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial

https://doi.org/10.1016/S1470-2045(16)30366-7Get rights and content

Summary

Background

Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.

Methods

In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients.

Findings

Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis.

Interpretation

Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients.

Funding

Bristol-Myers Squibb.

Introduction

Survival outcomes for patients with advanced melanoma have, historically, been very poor, with a median overall survival of about 8 months and 5-year overall survival from a diagnosis of metastatic disease of roughly 10%.1 Ipilimumab, which blocks CTLA-4, was the first agent to improve overall survival in a randomised controlled, phase 3 trial of patients with advanced melanoma.2 In this phase 3 trial, 2-year overall survival in ipilimumab-treated patients was 25%.3 A pooled analysis of data from 12 clinical trials of advanced melanoma, in which some ipilimumab-treated patients were followed up for up to 10 years, showed durable long-term overall survival, with 3-year overall survival of 22%.4 Newer immune checkpoint inhibitors, which block PD-1, include nivolumab and pembrolizumab. In a phase 3 trial (CheckMate 066),5 nivolumab monotherapy was shown to improve overall survival versus dacarbazine in previously untreated patients with BRAF wild-type tumours. Follow-up of patients in CheckMate 066 has shown 2-year overall survival of 58% with nivolumab and 27% with dacarbazine.6

Both nivolumab and pembrolizumab monotherapy have been shown to have superior efficacy outcomes compared with ipilimumab alone in phase 3 trials of advanced melanoma.7, 8 In a phase 2 trial of previously untreated patients with BRAF wild-type melanoma (CheckMate 069),9 the combination of nivolumab and ipilimumab was associated with a significantly greater proportion of patients achieving objective responses and significantly longer progression-free survival than with ipilimumab alone. More recently, the results of a phase 3 trial (CheckMate 067)7 also showed that nivolumab in combination with ipilimumab leads to longer progression-free survival and a greater proportion of patients achieving objective responses than does ipilimumab alone in previously untreated patients with advanced melanoma. In a phase 1 dose-finding study of nivolumab in combination with ipilimumab, follow-up over 33 months has shown 3-year overall survival of 68% in both previously treated and untreated patients with advanced melanoma.10 In the present study, we analysed 2-year overall survival data from the CheckMate 069 trial of nivolumab and ipilimumab in advanced melanoma.

Section snippets

Study design and participants

In this multicentre, randomised, controlled, double-blind, phase 2 study, we recruited patients from 19 specialist cancer centres in two countries (France and the USA; appendix p 15). 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 performance status of 0 or 1, and known BRAFV600 mutation status. Patients were also required to have measurable disease by CT or MRI, in

Results

Between Sept 16, 2013, and Feb 6, 2014, we enrolled 179 patients and randomly assigned 142 eligible patients (including 109 with BRAF wild-type tumours and 33 with BRAFV600 mutation-positive tumours) to receive either nivolumab and ipilimumab combination therapy (95 patients) or ipilimumab and placebo (ipilimumab monotherapy; 47 patients [figure 1]). Of these patients who were assigned to treatment, 72 in the nivolumab plus ipilimumab group and 37 in the ipilimumab plus placebo group had BRAF

Discussion

To the best of our knowledge, this analysis represents the longest follow-up so far of patients with advanced melanoma who received the combination of nivolumab and ipilimumab in a randomised, controlled trial. At a median follow-up of 2 years, the improved objective response outcomes and progression-free survival results in the combination therapy group compared with the ipilimumab alone group were maintained, but overall survival did not differ significantly between combination therapy and

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