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Cited by 968Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

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

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Hodi, F Stephen, Chesney, Jason, Pavlick, Anna C, Robert, Caroline, Grossmann, Kenneth F, McDermott, David F, Linette, Gerald P, Meyer, Nicolas +13 more·2016·The Lancet Oncology
DOI 10.1016/s1470-2045(16)30366-7PMC PMC5630525
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Abstract

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 BRAF V600 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.

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  • Until now, the FDA has approved ipilimumab plus nivolumab for melanoma, RCC, MSI-H/dMMR colorectal cancer, HCC, PD-L1 positive NSCLC, and malignant pleural mesothelioma.

    “Until now, the FDA has approved the ipilimumab plus nivolumab for melanoma, RCC, MSI-H/dMMR colorectal cancer, HCC, PD-L1 positive NSCLC, and malignant pleural mesothelioma (Table 5) [132–138].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [132]

  • The results of CheckMate-069, CheckMate-067, and CheckMate-142 showed that ipilimumab plus nivolumab significantly improved the outcomes of patients, relative to ipilimumab or nivolumab monotherapies.

    “The results of CheckMate-069, CheckMate-067, and CheckMate-142 showed that ipilimumab plus nivolumab significantly improved the outcomes of patients, relative to ipilimumab or nivolumab monotherapies [132–134].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [132]

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Authors
Hodi, F. S., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K. F., McDermott, D. F., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., Shaheen, M., Ernstoff, M. S., Minor, D. R., Salama, A. K., Taylor, M. H., Ott, P. A., Horak, C., Gagnier, P., Jiang, J., Wolchok, J. D., & Postow, M. A.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • University of Louisville (US)
  • New York University (US)
  • Inserm (FR)
  • Huntsman Cancer Institute (US)
  • Beth Israel Deaconess Medical Center (US)
  • Washington University in St. Louis (US)
  • Prisma Health (US)
  • Temple University (US)
  • University of New Mexico (US)
  • Dartmouth–Hitchcock Medical Center (US)
  • California Pacific Medical Center (US)
  • Duke Medical Center (US)
  • Oregon Health & Science University (US)
  • Bristol-Myers Squibb (United States) (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Hodi, F Stephen
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2016-11
Volume
17
Issue
11
Pages
1558-1568
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(16)30366-7
PMC
PMC5630525
OpenAlex
W2519279652
Cited by
968
References
19
Citations by year
2026: 22 · 2025: 49 · 2024: 84 · 2023: 66 · 2022: 91 · 2021: 99 · 2020: 113 · 2019: 120 · 2018: 175 · 2017: 137 · 2016: 10 · 2015: 1
FWCI
79.47
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (P30CA008748)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
advanced melanoma, nivolumab, ipilimumab, combination immunotherapy, anti-PD-1, anti-CTLA-4, overall survival, BRAF mutation status, immune checkpoint inhibitors, objective response, progression-free survival, treatment safety, adverse events, immunotherapy
MeSH terms
Ipilimumab, Nivolumab, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Humans, Melanoma, Mutation, Proto-Oncogene Proteins B-raf

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