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