Abstract
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.
| Original language | English |
|---|---|
| Journal | The Lancet |
| Volume | 395 |
| Issue number | 10236 |
| Pages (from-to) | 1558-1568 |
| Number of pages | 11 |
| ISSN | 0140-6736 |
| DOIs | |
| Publication status | Published - 16.05.2020 |
Funding
LZ reports personal fees, advisory board participation, and travel grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Roche, and Novartis; and advisory board participation and travel grants from Sanofi and Amgen, all outside the submitted work. EL reports personal fees, advisory board participation, and travel grants from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Medac; personal fees from Janssen; and other fees from Actelion and Pierre Fabre, all outside the submitted work. JCH reports investigator fees paid by Bristol-Myers Squibb to her institution during the conduct of the study outside the submitted work; personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Pfizer, Sanofi, and Pierre Fabre; and grants from Bristol-Myers Squibb. TE reports personal fees from Bristol-Myers Squibb, Roche, Novartis, Pierre Fabre, Sanofi Genzyme, Leo Pharma, and Merck Sharp & Dohme, all outside the submitted work. CL reports personal and travel fees from Bristol-Myers Squibb and Pierre Fabre; personal fees from Merck Sharp & Dohme, Roche, Merck, Novartis, Sanofi, and Amgen; and travel support from Kyowa Kirin, all outside the submitted work. SH reports grants, personal fees, and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Merck Sharp & Dohme, Amgen, Roche, and Novartis, all outside the submitted work. RG reports personal fees and non-financial support from Almirall Hermal, Bristol-Myers Squibb, Pierre Fabre, Roche, Sanofi Regeneron, and Merck Serono; grants, personal fees, and non-financial support from Amgen and Novartis; personal fees from AstraZeneca, 4CS, Leo Pharma, Merck Sharp & Dohme, and SUN Pharma; grants and personal fees from Pfizer; and a research grant from Johnson & Johnson, all outside the submitted work. PM reports personal fees, non-financial support, and advisory board roles from Pierre Farbre, GlaxoSmithKline, Merck Sharp & Dohme, Merck Germany, Roche, Bristol-Myers Squibb, Novartis, and Sanofi; personal fees, non-financial support, and honoraria for speaker roles from Pierre Farbre, GlaxoSmithKline, Merck Sharp & Dohme, Merck Germany, Roche, Bristol-Myers Squibb, Novartis, and Sanofi, all outside the submitted work. AH reports grants and personal fees from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme/Merck, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi Genzyme, and Novartis; personal fees from OncoSec and SUN Pharma, all outside the submitted work. BS reports grants and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; and personal fees from Incyte, Novartis, Pfizer, and Roche, all outside the submitted work. AR reports grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, all outside the submitted work. J-CS reports personal and institutional honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Roche. CG reports grants and personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen, Merck Sharp & Dohme, and Philogen; and grants and personal fees from NeraCare, Novartis, Roche, and Sanofi, all outside the submitted work. JCB reports personal fees from Amgen, Merck Serono, Sanofi, Pfizer, 4SC, Amgen, CureVac, eTheRNA, Lytix, Novartis, ReProTher, and Rigontec; grants from Alcedis, Bristol-Myers Squibb, IQVIA, and Merck Serono; non-financial support from 4SC and Incyte, all outside the submitted work. DS reports a research grant from Bristol-Myers Squibb for translational research; cooperation and payment of patient fees as part of clinical study to his institution (the University Hospital Essen); honoraria from Bristol-Myers Squibb; personal fees from Amgen, Array, Boehringer Ingelheim, 4SC, Incyte, InFlarX, NeraCare, Pierre Fabre, Pfizer, and Sanofi; personal fees and other fess from Roche, Regeneron, Merck Serono, Merck Sharp & Dohme, and Philogen; and grants, personal fees, and other fees from Novartis, all outside the submitted work; and personal fees from Bristol-Myers Squibb during the conduct of the study. All other authors declare no competing interests. The funder of the study provided nivolumab and ipilimumab free of cost and also provided third-party funding for trial coordination, documentation, monitoring, and data management. Writing assistance for the initial manuscript draft was provided by Ecc-Oncology (Trier, Germany) and funded by the University Hospital Essen. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
