Elsevier

The Lancet Oncology

Volume 21, Issue 11, November 2020, Pages 1465-1477
The Lancet Oncology

Articles
Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(20)30494-0Get rights and content

Summary

Background

Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB–C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.

Methods

This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB–C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906.

Findings

Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6–52·7) with nivolumab and 50·9 months (36·2–52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8–56·3) in the nivolumab group and 41·2% (36·4–45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60–0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7–81·5) with nivolumab and 76·6% (72·2–80·3) with ipilimumab (HR 0·87 [95% CI 0·66–1·14]; p=0·31). Late-emergent grade 3–4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.

Interpretation

At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab.

Funding

Bristol Myers Squibb and Ono Pharmaceutical.

Introduction

Checkpoint inhibitors and targeted therapy are approved in the USA and Europe for adjuvant treatment of high-risk resected melanoma. The first checkpoint inhibitor to be approved by the US Food and Drug Administration for adjuvant treatment of melanoma was ipilimumab, a human antibody against CTLA-4, in 2015 at 10 mg/kg for resected melanoma with involvement of lymph nodes larger than 1 mm, on the basis of proven recurrence-free survival benefit versus placebo.1 Ipilimumab was subsequently shown to demonstrate an overall survival benefit compared with placebo.2 The PD-1 checkpoint inhibitor nivolumab was approved for adjuvant treatment of resected melanoma with lymph node involvement in 2017 on the basis of an improvement in recurrence-free survival versus the active comparator, ipilimumab.3 Another PD-1 inhibitor, pembrolizumab, was approved in 2019 for adjuvant treatment based on an improvement in recurrence-free survival versus placebo.4 The targeted therapy combination of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib was approved in 2018 on the basis of an improvement in recurrence-free survival versus placebo.5

Research in context

Evidence before this study

We searched PubMed and congress abstracts, including the annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the Society for Melanoma Research, for articles published in English up to May 31, 2020. We searched for studies that evaluated immune checkpoint inhibitors or targeted therapies approved for the adjuvant treatment of advanced melanoma, in which recurrence-free survival was a study endpoint, with particular attention to studies that also reported overall survival. We used the search terms “adjuvant melanoma treatment” and the US Food and Drug Administration-approved therapies of “nivolumab”, “pembrolizumab”, “ipilimumab”, “dabrafenib”, and “trametinib”. Before the current report, recurrence-free survival results were reported for nivolumab and pembrolizumab at a follow-up of 3 years, ipilimumab at 5 years, and dabrafenib plus trametinib at 5 years. In these reports, pembrolizumab, ipilimumab, and dabrafenib plus trametinib showed a recurrence-free survival benefit compared with placebo, and nivolumab showed a benefit compared with the active agent, ipilimumab. Among checkpoint inhibitors, an overall survival benefit was reported for ipilimumab 10 mg/kg compared with placebo (European Organisation for Research and Treatment of Cancer 18071) and ipilimumab 3 mg/kg compared with high-dose interferon (E1609). In addition, an improvement in overall survival was reported for dabrafenib plus trametinib compared with placebo at an interim overall survival analysis, but the improvement did not cross the prespecified threshold for significance.

Added value of this study

To our knowledge, this is the first report of overall survival results for a PD-1 inhibitor in the adjuvant melanoma setting. In addition, compared with longer-term reports published for recurrence-free survival in this setting, this report includes data on patients with American Joint Committee on Cancer (7th edition) stage IIIB–C melanoma with in-transit metastases, as well as patients with resected stage IV melanoma. Moreover, we provide a recurrence-free survival analysis of patients with BRAF-mutated stage IIIB and IIIC disease, a population that resembles one treated with the approved targeted therapy dabrafenib plus trametinib. Voluntary reports of late-emergent treatment-related adverse events were few in number.

Implications of all the available evidence

Updated recurrence-free survival and distant metastasis-free survival results with longer follow-up show that nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, including multiple patient subgroups and, notably, patients with in-transit metastases who have traditionally not been enrolled in such trials. Additional support for the continued use of nivolumab in this patient population is derived from the high 4-year overall survival observed in patients in the nivolumab group, albeit not significant when compared with patients in the ipilimumab group, who received effective approved subsequent therapies; comparison of these results with a watch-and-wait strategy is warranted.

Ipilimumab is the only checkpoint inhibitor that has been reported to show an overall survival benefit so far in the adjuvant treatment setting. 5-year follow-up results of the European Organisation for Research and Treatment of Cancer (EORTC) 18071 phase 3 trial showed that treatment with ipilimumab at a dose of 10 mg/kg resulted in longer overall survival than did placebo in patients with stage IIIA (>1 mm nodal involvement), IIIB, or IIIC melanoma (hazard ratio [HR] 0·72 [95·1% CI 0·58–0·88]; p=0·001), with 5-year overall survival of 65·4% (95% CI 60·8–69·6) in the ipilimumab group versus 54·4% (49·7–58·9) in the placebo group.2 In EORTC 18071, grade 3 or 4 immune-related adverse events occurred in 196 (41·6%) of 471 patients treated with ipilimumab, and five (1·1%) of 471 patients in the ipilimumab group died due to immune-related toxicities.

The CheckMate 238 study compared nivolumab 3 mg/kg with ipilimumab 10 mg/kg as adjuvant treatment for patients with high-risk resected stage IIIB–C or stage IV melanoma (enrolled as per the 2009 classification of the American Joint Committee on Cancer [AJCC], 7th edition). At a median follow-up of 19·5 months (minimum 18 months), nivolumab demonstrated longer recurrence-free survival than did ipilimumab (HR for disease recurrence or death 0·65; 97·56% CI 0·51–0·83; p<0·001), with 12-month recurrence-free survival of 70·5% (95% CI 66·1–74·5) in the nivolumab group versus 60·8% (56·0–65·2) in the ipilimumab group (3-year recurrence-free survival was subsequently reported at 58% vs 45%, respectively).3, 6 Nivolumab also demonstrated lower toxicity than ipilimumab: treatment-related grade 3 or 4 adverse events were reported in 65 (14·4%) of 452 patients treated with nivolumab versus 208 (45·9%) of 453 patients treated with ipilimumab. Moreover, treatment discontinuation due to treatment-related adverse events was reported in 35 (7·7%) of 452 patients who received nivolumab compared with 189 (41·7%) of 453 patients who received ipilimumab.

In this Article, we provide updated recurrence-free survival and distant metastasis-free survival results after a minimum follow-up of 4 years, including results across patient subgroups. We also report late-emergent treatment-related adverse events, and, to our knowledge, the first report of overall survival with a PD-1 inhibitor for the adjuvant treatment of patients with resected stage IIIB–C or stage IV melanoma.

Section snippets

Study design and participants

This multicentre, double-blind, randomised, controlled, phase 3, trial was done in 130 academic centres, community hosptials, and cancer centres across 25 countries (appendix pp 24–26). Detailed methods have previously been published.3 Patients aged 15 years or older with resected stage IIIB–C or IV melanoma according to AJCC (7th edition) criteria were included.7 Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and histologically

Results

Between March 30 and Nov 30, 2015, 906 patients were randomly assigned to receive nivolumab (n=453) or ipilimumab (n=453). 452 patients (one patient withdrew consent) in the nivolumab group and 453 patients in the ipilimumab group received treatment. Baseline patient characteristics are presented in table 1 and have been published previously.3 All patients had either completed or discontinued treatment at the time of the primary 18-month analysis, with a median number of doses of 24·0 (IQR

Discussion

In this 4-year update of CheckMate 238, nivolumab continued to show significantly improved recurrence-free survival versus the active comparator ipilimumab. In addition, nivolumab continued to show an improvement in the exploratory endpoint of distant metastasis-free survival compared with ipilimumab. In this first report of overall survival for CheckMate 238, 211 of the 302 anticipated overall survival events were observed at 4 years, resulting in an analysis with 73% of the planned 88% power

Data sharing

Bristol Myers Squibb's policy on data sharing can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

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