Cited by 3,063Cancer Immunotherapy and BiomarkersLung Cancer Treatments and MutationsLung Cancer Diagnosis and Treatment

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Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

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Hellmann, Matthew D., Ciuleanu, Tudor-Eliade, Pluzanski, Adam, Lee, Jong Seok, Otterson, Gregory A., Audigier-Valette, Clarisse, Minenza, Elisa, Linardou, Helena, Burgers, Sjaak, Salman, Pamela, Borghaei, Hossein, Ramalingam, Suresh S., Brahmer, Julie, Reck, Martin, O’Byrne, Kenneth J., Geese, William J., Green, George, Chang, Han, Szustakowski, Joseph, Bhagavatheeswaran, Prabhu, Healey, Diane, Fu, Yali, Nathan, Faith, Paz-Ares, Luis·2018·New England Journal of Medicine

DOI 10.1056/nejmoa1801946PMC PMC7193684

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Abstract

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .). CONCLUSIONS: Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

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Authors: Hellmann, M. D., Ciuleanu, T.-E., Pluzanski, A., Lee, J. S., Otterson, G. A., Audigier-Valette, C., Minenza, E., Linardou, H., Burgers, S., Salman, P., Borghaei, H., Ramalingam, S. S., Brahmer, J., Reck, M., O’Byrne, K. J., Geese, W. J., Green, G., Chang, H., Szustakowski, J., Bhagavatheeswaran, P., Healey, D., Fu, Y., Nathan, F., & Paz-Ares, L.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
From Memorial Sloan Kettering Cancer Center Hospital, New York (M.D.H.); Prof. Dr. Ion Chiricuta Institute of Oncology and Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-Napoca, Romania (T.-E.C.); Centrum Onkologii–Instytut im. Marii Sklodowskiej-Curie, Warsaw, Poland (A.P.); Seoul National University Bundang Hospital, Seoul, South Korea (J.S.L.); Ohio State University, Columbus (G.A.O.); Hôpital Sainte Musse, Toulon, France (C.A.-V.); Ospedale Santa Maria della Misericordia, Perugia,...
Fox Chase Cancer Center (US)
ORCID: Hellmann, Matthew D.
Ciuleanu, Tudor-Eliade
Lee, Jong Seok
Otterson, Gregory A.
Audigier-Valette, Clarisse
Linardou, Helena
Burgers, Sjaak
Salman, Pamela
Borghaei, Hossein
Ramalingam, Suresh S.
Brahmer, Julie
Reck, Martin
Geese, William J.
Green, George
Szustakowski, Joseph
Fu, Yali
Paz-Ares, Luis
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2018-05-31
Volume: 378
Issue: 22
Pages: 2093-2104
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1801946
PMC: PMC7193684
OpenAlex: W2797675588
Cited by: 3,063
References: 22
Citations by year: 2026: 100 · 2025: 184 · 2024: 222 · 2023: 289 · 2022: 419 · 2021: 499 · 2020: 559 · 2019: 542 · 2018: 247
FWCI: 174.31
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Bristol-Myers Squibb, Inc.
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: nivolumab, ipilimumab, non-small cell lung cancer, tumor mutational burden, PD-L1 expression, immune checkpoint inhibitors, progression-free survival, chemotherapy comparison, stage IV lung cancer, treatment-related adverse events, treatment response biomarkers, objective response rate, immunotherapy biomarkers, safety and tolerability
MeSH terms: Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Biomarkers, Tumor, Disease-Free Survival, Kaplan-Meier Estimate, B7-H1 Antigen

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Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

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