Elsevier

The Lancet

Volume 395, Issue 10236, 16–22 May 2020, Pages 1558-1568
The Lancet

Articles
Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial

https://doi.org/10.1016/S0140-6736(20)30417-7Get rights and content

Summary

Background

Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced—ie, unresectable or metastatic—melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.

Methods

We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.

Findings

Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7–36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3–33·3) in the nivolumab group and 6·4 months (3·3–9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12–0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33–0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0–84·9) and at 2 years was 70% (55·1–81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1–63·9) and at 2 years was 42% (28·6–54·5); and in the placebo group, this rate was 32% (19·8–45·3) at 1 year and 14% (5·9–25·7) at 2 years. Treatment-related grade 3–4 adverse events were reported in 71% (95% CI 57–82) of patients in the nivolumab plus ipilimumab group and in 27% (16–40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.

Interpretation

Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3–4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.

Funding

Bristol-Myers Squibb.

Introduction

Cutaneous melanoma has the potential to spread to distant organs, causing more than 60 000 deaths annually worldwide.1, 2 Surgical excision of the primary tumour along with adjuvant therapy reduces the risk of disease recurrence and distant metastasis.2 Adjuvant immunotherapy with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (10 mg/kg) showed consistent clinical benefit in stage III melanoma when compared with placebo.3, 4, 5 Treatment-related toxicity, however, was high.3, 4 Recently, dabrafenib plus trametinib as well as the programmed cell death 1 (PD-1) blocking agents nivolumab and pembrolizumab showed practice-changing clinical efficacy in resected stage III melanoma, leading to the registration for adjuvant treatment.6, 7, 8 The EORTC 1325 trial of patients with stage III melanoma, which compared pembrolizumab with placebo,8 showed significantly improved recurrence-free survival in favour of pembrolizumab, and similarly the CheckMate-238 trial, which tested nivolumab head to head with ipilimumab, resulted in significantly improved recurrence-free survival in favour of nivolumab.7, 9, 10 The CheckMate-238 trial included not only patients with resected stage IIIB–C melanoma (according to the American Joint Committee on Cancer 2009 7th edition11), but also approximately 20% of patients with fully resected stage IV melanoma.

For metastatic melanoma, PD-1 inhibitors,12, 13 CTLA-4 inhibitor ipilimumab,14 the combination of nivolumab and ipilimumab,15, 16 and—for BRAF-mutated melanoma—combinations of BRAF and MEK inhibitors17, 18, 19 have been approved for several years. Patients with stage IV melanoma with no evidence of disease, however, were excluded from these phase 3 trials, as they required measurable tumour lesions. Patients with stage IV melanoma with no evidence of disease have a great therapeutic need, since their survival outcome is worse than in patients with stage III disease.3, 6, 8, 9, 20, 21, 22

Data for recurrence-free survival and overall survival of patients with stage IV melanoma with no evidence of disease is scarce.21, 22, 23 Recurrence-free survival was reported to range between 5 and 7 months and overall survival between 20 and 24 months in small case series.20, 21, 22, 24 In this study, we aimed to report the safety and efficacy data for a prespecified interim analysis of the combination of nivolumab and ipilimumab, as well as of nivolumab monotherapy, in comparison with a placebo in patients with stage IV melanoma with no evidence of disease.

Section snippets

Study design and participants

We did a randomised, double-blind, placebo-controlled, phase 2 trial (IMMUNED) in Germany at 20 academic medical centres. Eligible patients were aged 18–80 years and had stage IV cutaneous or unknown primary melanoma with no evidence of disease after surgery or radiotherapy. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, known BRAF status, and tumour tissue from the resected site available for immunohistochemical assessment of programmed cell

Results

Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to a treatment group, of whom 162 received treatment. The characteristics of the patients at baseline were similar in all three groups with some minor discrepancies for ECOG score and previous adjuvant therapies (table 1; appendix p 3). In the nivolumab plus ipilimumab group, patients had a better ECOG performance status when compared with the placebo group and, for the exploratory analyses, with the nivolumab group.

At

Discussion

IMMUNED is the first double-blind, randomised, placebo-controlled study in patients with stage IV melanoma with no evidence of disease, which showed a statistically significant and clinically meaningful prolongation of recurrence-free survival for the adjuvant use of nivolumab plus ipilimumab. In this phase 2 trial of patients with stage IV melanoma with no evidence of disease after surgery or radiation therapy, nivolumab plus ipilimumab resulted in a significantly higher rate of

Data sharing

The IMMUNED trial is currently ongoing, until the last patient off treatment is followed up for 2 years. Data sharing procedures will be described once all secondary outcomes variables are analysed and the results of that final analysis will be published.

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