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

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 +16 more·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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  • Limited biomarkers such as PD-L1 expression and tumor mutation load are clinically used to predict immunotherapy benefit.

    “Currently, limited biomarkers, such as PD-L1 expression (88) and tumor mutation load (TMB) (89–91), are clinically used to predict the immunotherapy benefit.”

    From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [89]

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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
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
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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