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Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Open accessAbstract
BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).
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“with anti-PD-1 and anti-PD-1/CTLA-4 combination therapy emerging as most effective [3, 4].”
From Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients (2019) · cites this paper as [4]
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“3-year overall survival rates were 58%, 52%, and 34% in combination therapy, anti-PD-1, and anti-CTLA-4 groups, respectively [4].”
From Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients (2019) · cites this paper as [4]
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“These chemokines have been identified as the dominant mediators for the recruitment of CXCR3+ and CCR5+ tumor-specific T lymphocytes into the tumors and their intratumoral expression correlated with favorable clinical outcomes in patients with melanoma30–32.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [30]
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“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 [36]
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“By contrast, ICB has shown promise in the adjuvant setting in patients with melanoma or NSCLC57–59”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [59]
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A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients
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“5 months.(2) This important achievement in survival follows the improvements in therapeutic strategies, mainly targeted therapies and immune-therapy: selective inhibitors of the mitogen-activated protein (MAP) kinase pathway and blockers of immune checkpoint molecules result in a major survival benefits for patients w…”
BackgroundSelf-citationImmune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma
Abu‐Sbeih, H., Ali, F. S., Qiao, W., Lü, Y., Patel, S. P., Diab, A. K., & Wang, Y. (2019) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-019-02303-1 · Cited by 88
Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors
Simon, S. C. S., Hu, X., Panten, J., Grees, M., Renders, S., Thomas, D., Weber, R., Schulze, T. J., Utikal, J. S., & Umansky, V. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1727116 · Cited by 88
“A clinical response to the combination of nivolumab and ipilimumab was observed in 58% of the patients as compared to 44% for nivolumab monotherapy.(2) Because of limited response rates and”
BackgroundResultMelanoma classification and management in the era of molecular medicine
Rashid, S., Shaughnessy, M., & Tsao, H. (2022) · Dermatologic Clinics · doi:10.1016/j.det.2022.07.017 · Cited by 92
Melanoma Treatments and Mortality Rate Trends in the US, 1975 to 2019
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ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
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Exploiting temporal aspects of cancer immunotherapy
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“presenting cells [54] suggests a direct regulation of PD-L1 gene expression by STAT3 at the transcriptional level.”
BackgroundPoels, K., van Leent, M. M. T., Reiche, M. E., Kusters, P. J. H., Huveneers, S., de Winther, M. P. J., Mulder, W. J. M., Lutgens, E., & Seijkens, T. T. P. (2020) · Cells · doi:10.3390/cells9091987 · Cited by 87
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“Beyond T cells and NK cells, ICIs have also been used to engage macrophages by interfering with the CD47-SIRPα axis [23].”
BackgroundInfluentialOrganoid Models for Precision Cancer Immunotherapy
Sun, C., Lan, H., Fang, X., Yang, X., & Jin, K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.770465 · Cited by 90
The oligometastatic spectrum in the era of improved detection and modern systemic therapy
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Aggressive Pituitary Tumors and Pituitary Carcinomas: From Pathology to Treatment
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“In other types of cancers, simultaneous inhibition of CTLA-4 and PD-1 pathways resulted in superior effects compared to monotherapy (160).”
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“Nevertheless, a consistent signature (if one exists) of dysbiosis associated with ICI resistance distinct from that of response (overall survival rate 50% for melanoma 61 and 40% for non-small cell lung cancer 62,63 (NSCLC)) remains undefined.”
Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma
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Melanoma of the lower genital tract: Prognostic factors and treatment modalities
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“Some major challenges remain in the clinical deployment of CPIs for metastatic skin cancers: (1) The response rate for PD-1 inhibitor monotherapy tops out at around 40%, and while in a recent phase 3 trial combination therapy with PD-1 and CTLA-4 blockade found the response rate closer to 60%, it carries a significant…”
BackgroundOptimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma
Choi, C., Yoo, G. S., Cho, W. K., & Park, H. C. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i20.2416 · Cited by 85
Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma
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BRAF in malignant melanoma progression and metastasis: potentials and challenges.
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Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade
Nair, S., Mazzoccoli, L., Jash, A., Govero, J., Bais, S. S., Hu, T., Fontes-Garfias, C. R., Shan, C., Okada, H., Shresta, S., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.144619 · Cited by 93
“Despite the 260 success of immunotherapies for solid tumors such as melanoma (48, 70) and non-small cell lung 261 cancer (71), the treatments have largely failed in GBM (50-54).”
BackgroundChimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead
Soltantoyeh, T., Akbari, B., Karimi, A., Chalbatani, G. M., Ghahri-Saremi, N., Hadjati, J., Hamblin, M. R., & Mirzaei, H. R. (2021) · Cells · doi:10.3390/cells10061450 · Cited by 89
“However, this combination is associated with high levels of toxicity [233].”
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“The enhancement in the overall response rate by combining anti-CTLA4 and anti-PD1 therapies is associated with increased prevalence of drug-related toxicity, with 53% of patients experiencing grade 3 or 4 irAEs compared to 18% in the monotherapy group (57).”
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Self-citationSystematic review of combinations of targeted or immunotherapy in advanced solid tumors
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“There may also be heterogeneity in the relative contribution of Box 1 What is specifically learned about combinations of novel–novel agents?”
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Metadata
- Authors
- Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Cowey, C. L., Lao, C. D., Wagstaff, J., Schadendorf, D., Ferrucci, P. F., Smylie, M., Dummer, R., Hill, A., Hogg, D., Haanen, J., Carlino, M. S., Bechter, O., Maio, M., Marquez-Rodas, I., Guidoboni, M., McArthur, G., Lebbé, C., Ascierto, P. A., Long, G. V., Cebon, J., Sosman, J., Postow, M. A., Callahan, M. K., Walker, D., Rollin, L., Bhore, R., Hodi, F. S., & Larkin, J.
- Affiliations
- University of Siena (IT)
- From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.); Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.),...
- ORCID
- Wolchok, Jedd D.
- Gonzalez, Rene
- Rutkowski, Piotr
- Grob, Jean-Jacques
- Cowey, C. Lance
- Wagstaff, John
- Schadendorf, Dirk
- Ferrucci, Pier F.
- Smylie, Michael
- Dummer, Reinhard
- Hogg, David
- Haanen, John
- Carlino, Matteo S.
- Bechter, Oliver
- Maio, Michele
- Guidoboni, Massimo
- McArthur, Grant
- Ascierto, Paolo A.
- Long, Georgina V.
- Cebon, Jonathan
- Sosman, Jeffrey
- Postow, Michael A.
- Callahan, Margaret K.
- Bhore, Rafia
- Hodi, F. Stephen
- Larkin, James
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-10-05
- Volume
- 377
- Issue
- 14
- Pages
- 1345-1356
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5706778
- OpenAlex
- W2753432434
- Semantic Scholar
- 23dbeed54cde655fb6a12697b02c9ff303515da7
- Cited by
- 5,357
- References
- 18
- Citations by year
- 2026: 159 · 2025: 282 · 2024: 569 · 2023: 705 · 2022: 746 · 2021: 947 · 2020: 900 · 2019: 578 · 2018: 428 · 2017: 37
- FWCI
- 234.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Use Siena air (University of Siena) (submittedVersion, other-oa)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Lirias (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- 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, immune checkpoint inhibitors, PD-1 inhibitors, CTLA-4 inhibitors, overall survival, progression-free survival, treatment-related adverse events, immune-related adverse events, PD-L1 expression, BRAF mutation, long-term follow-up
- MeSH terms
- Ipilimumab, Nivolumab, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Humans, Melanoma, Middle Aged, Neoplasm Staging, Skin Neoplasms, Survival Rate, Disease-Free Survival, Kaplan-Meier Estimate
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