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Nivolumab plus ipilimumab in advanced non-small-cell lung cancer
Open accessAbstract
BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a 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 alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more. RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy. CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).
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In the citing paper
“Nivolumab, a PD-1 inhibitor, in combination with ipilimumab, a CTLA-4 inhibitor, has shown favourable efficacy outcomes and manageable safety profiles across multiple tumour types.”
From Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial (2025) · cites this paper as [11]
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“Evidence for benefit of nivolumab plus ipilimumab compared to single agent ICI has also been demonstrated in patients with advanced renal cell cancer, microsatellite high/deficient mismatch repair (MSI-hi/dMMR) metastatic colorectal cancer12,14,15, hepatocellular carcinoma16, and non-small cell, EGFR/ALK wild type lung cancer17–19.”
In the citing paper
“Third, many of these studies utilized ICIs as monotherapy in a heavily pretreated population whereas current standard first-line therapy often includes a combination of ICIs or ICI with chemotherapy for multiple tumor types (35–40).”
From A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors (2021) · cites this paper as [39]
In the citing paper
“First-line nivolumab + ipilimumab treatment also produced longer OS than chemotherapy in patients with advanced NSCLC10.”
From Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial (2021) · cites this paper as [10]
In the citing paper
“First-line nivolumab + ipilimumab resulted in a longer duration of OS than chemotherapy in patients with metastatic NSCLC, irrespective of the PD-L1 expression10,28.”
From Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial (2021) · cites this paper as [10]
In the citing paper
“most notably the combination of pembrolizumab and axitinib (an inhibitor of vascular growth factor inhibitor) in renal cell carcinoma.15”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [15]
In the citing paper
“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 [136]
In the citing paper
“Moreover, the data of CheckMate-214, CheckMate-227, and CheckMate-743 indicated the superior efficacy of ipilimumab plus nivolumab over the standard targeted therapy or chemotherapy [135–137].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [136]
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Metadata
- Authors
- Hellmann, M. D., Paz-Ares, L., Bernabe Caro, R., Zurawski, B., Kim, S.-W., Carcereny Costa, E., Park, K., Alexandru, A., Lupinacci, L., de la Mora Jimenez, E., Sakai, H., Albert, I., Vergnenegre, A., Peters, S., Syrigos, K., Barlesi, F., Reck, M., Borghaei, H., Brahmer, J. R., O’Byrne, K. J., Geese, W. J., Bhagavatheeswaran, P., Rabindran, S. K., Kasinathan, R. S., Nathan, F. E., & Ramalingam, S. S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Universidad Complutense de Madrid (ES)
- From the Memorial Sloan Kettering Cancer Center, New York (M.D.H.); Hospital Universitario Doce de Octubre, Centro Nacional de Investigaciones Oncológicas, Universidad Complutense, and Centro de Investigación Biomédica en Red de Cáncer, Madrid (L.P.-A.), Hospital Universitario Virgen Del Rocio, Seville (R.B.C.), and the Catalan Institute of Oncology–Germans Trias i Pujol Hospital, Badalona (E.C.C.) — all in Spain; Ambulatorium Chemioterapii, Bydgoszcz, Poland (B.Z.); the Asan Medical Center (S.-W.K....
- Fox Chase Cancer Center (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-11-21
- Volume
- 381
- Issue
- 21
- Pages
- 2020-2031
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2976744492
- Cited by
- 2,823
- References
- 26
- Citations by year
- 2026: 183 · 2025: 316 · 2024: 399 · 2023: 448 · 2022: 516 · 2021: 570 · 2020: 368 · 2019: 18
- FWCI
- 154.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- 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
- ipilimumab, non-small cell lung cancer, PD-L1 expression, immune checkpoint inhibitors, combination immunotherapy, overall survival, chemotherapy, PD-1, CTLA-4, long-term benefits, PD-L1-negative tumors, stage IV lung cancer, recurrent lung cancer, immune-related adverse events, immune-related pneumonitis
- MeSH terms
- Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Survival Analysis, B7-H1 Antigen
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