The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Open accessAbstract
BACKGROUNDNivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma.We now report 5-year outcomes in the trial. METHODSWe randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo.The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTSAt a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 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, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63).Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone.No new late toxic effects were noted. CONCLUSIONSAmong patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab.(Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.govnumber, NCT01844505.
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“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 [133]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In many cancers, nivolumab in combination with ipilimumab improves response rates compared to either agent alone, but the combination has not been evaluated in childhood cancer.”
From A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412 (2022) · cites this paper as [12]
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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 [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While immune checkpoint inhibitors (ICIs) have greatly enhanced clinical outcomes across multiple cancer types,1, 2, 3”
From irAE-GPT: leveraging large language models to identify immune-related adverse events in electronic health records and clinical trial datasets (2026) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In unresectable or metastatic melanoma, overall survival at 5 years is 52% following nivolumab plus ipilimumab compared to 44% for nivolumab alone and 26% for ipilimumab alone12,13.”
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In the citing paper
“Melanomas and urothelial carcinomas that are intrinsically resistant to anti-PD-1/PD-L1 therapy show elevated TGF-β signaling, particularly in the stromal compartment of immune excluded tumors21,77,228,361.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [361]
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In the citing paper
“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.”
From A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412 (2022) · cites this paper as [12]
Experimental — accuracy not yet measuredIn the citing paper
“Multiple clinical trials with combined blockade of CTLA4 and PD-1/PD-L1 demonstrated higher response rates than either monotherapy, in different cancer types including melanoma ( 54, 55 ), hepatocellular carcinoma ( 56 ), renal cell carcinoma (RCC; refs.57, 58 ), NSCLC ( 59 ), malignant pleural mesothelioma ( 60 ), and colorectal cancer (MSI-H/dMMR; ref. 61 ).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [55]
In the citing paper
“Long-term follow-up has demonstrated durable survival benefi t for a subset of patients with melanoma and RCC, and combination therapy with ICT is under active investigation for a number of tumor types ( 55,58 ).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [55]
In the citing paper
“Anti-PD-1/PD-L1 agents pared with chemotherapy have also improved response rates and survival in many diseases including lung cancer, triple negative breast cancer, head and neck squamous cell carcinoma, and others.12–14”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [13]
In the citing paper
“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 [133]
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Citations
Cites
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157
Self-citationOverall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
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., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709684 · Cited by 5,357
Self-citation(1997) · doi:10.1097/00005650-199711000-00002 · Cited by 4,544
Hodi, F. S., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Cowey, C. L., Lao, C. D., Schadendorf, D., Wagstaff, J., Dummer, R., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30700-9 · Cited by 1,399
Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma
Robert, C., Grob, J. J., Stroyakovskiy, D., Karaszewska, B., Hauschild, A., Levchenko, E., Chiarion Sileni, V., Schachter, J., Garbe, C., Bondarenko, I., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1904059 · Cited by 1,389
Self-citationCombined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain
Tawbi, H. A., Forsyth, P. A., Algazi, A. P., Hamid, O., Hodi, F. S., Moschos, S. J., Khushalani, N. I., Lewis, K. D., Lao, C. D., Postow, M. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1805453 · Cited by 1,336
Self-citationLong, G. V., Atkinson, V. G., Lo, S., Sandhu, S. K., Guminski, A. D., Brown, M. P., Wilmott, J. S., Edwards, J. J., Gonzalez, M., Scolyer, R. A., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30139-6 · Cited by 1,001
Self-citationEstimation of minimally important differences in EQ-5D utility and VAS scores in cancer
Pickard, A. S., Neary, M. P., & Cella, D. F. (2007) · Health and Quality of Life Outcomes · doi:10.1186/1477-7525-5-70 · Cited by 932
Lebbé, C., Meyer, N., Mortier, L., Marquez-Rodas, I., Robert, C., Rutkowski, P., Menzies, A. M., Eigentler, T., Ascierto, P. A., Smylie, M., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01998 · Cited by 408
Self-citationKhair, D. O., Bax, H. J., Mele, S., Crescioli, S., Pellizzari, G., Khiabany, A., Nakamura, M., Harris, R. J. C., French, E., Hoffmann, R. M., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00453 · Cited by 252
Regan, M. M., Werner, L. L., Rao, S. A., Gupte-Singh, K., Hodi, F. S., Kirkwood, J. M., Kluger, H. M., Larkin, J., Postow, M. A., Ritchings, C., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.00345 · Cited by 80
Self-citationTarhini, A. A., McDermott, D. F., Ambavane, A., Gupte-Singh, K., Ribero, V. A., Ritchings, C., Benedict, Á., Rao, S. A., Regan, M. M., & Atkins, M. B. (2018) · Immunotherapy · doi:10.2217/imt-2018-0168 · Cited by 35
Tarhini, A. A., Benedict, Á., McDermott, D. F., Rao, S. A., Ambavane, A., Gupte-Singh, K., Sabater, J., Ritchings, C., Ribero, V. A., Regan, M. M., et al. (2018) · Immunotherapy · doi:10.2217/imt-2018-0085 · Cited by 26
Schadendorf, D., Larkin, J., Wolchok, J. D., Chiarion‐Sileni, V., Taylor, F. C., Lawrance, R. M., Moreno‐Koehler, A., Lord‐Bessen, J., Rizzo, J. I., Moshyk, A., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.15_suppl.9551 · Cited by 2
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Nivolumab plus ipilimumab in advanced non-small-cell lung cancer
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., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1910231 · Cited by 2,823
Thai, A. A., Solomon, B., Sequist, L. V. D., Gainor, J. F., & Heist, R. S. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00312-3 · Cited by 2,753
Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma
Tawbi, H. A., Schadendorf, D., Lipson, E. J., Ascierto, P. A., Matamala, L., Gutiérrez, E. C., Rutkowski, P., Gogas, H. J., Lao, C. D., Menezes, J. J. D., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2109970 · Cited by 1,994
Self-citationA decade of immune-checkpoint inhibitors in cancer therapy
Robert, C. (2020) · Nature Communications · doi:10.1038/s41467-020-17670-y · Cited by 1,608
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445
Metadata
- Authors
- Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., Ferrucci, P. F., Smylie, M., Hogg, D., Hill, A., Márquez-Rodas, I., Haanen, J., Guidoboni, M., Maio, M., Schöffski, P., Carlino, M. S., Lebbé, C., McArthur, G., Ascierto, P. A., Daniels, G. A., Long, G. V., Bastholt, L., Rizzo, J. I., Balogh, A., Moshyk, A., Hodi, F. S., & Wolchok, J. D.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- From the Royal Marsden NHS Foundation Trust, London (J.L.), and the College of Medicine, Swansea University, Swansea (J.W.) — both in the United Kingdom; the Oncology Institute of Veneto IRCCS, Padua (V.C.-S.), the European Institute of Oncology, IRCCS, Milan (P.F.F.), Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and the Center for Immuno...
- University of Siena (IT)
- The University of Sydney (AU)
- ORCID
- Larkin, James
- Gonzalez, Rene
- Grob, Jean-Jacques
- Rutkowski, Piotr
- Schadendorf, Dirk
- Wagstaff, John
- Dummer, Reinhard
- Ferrucci, Pier F.
- Smylie, Michael
- Hogg, David
- Haanen, John
- Guidoboni, Massimo
- Maio, Michele
- Schöffski, Patrick
- Carlino, Matteo S.
- McArthur, Grant
- Ascierto, Paolo A.
- Daniels, Gregory A.
- Long, Georgina V.
- Bastholt, Lars
- Moshyk, Andriy
- Hodi, F. Stephen
- Wolchok, Jedd D.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-10-17
- Volume
- 381
- Issue
- 16
- Pages
- 1535-1546
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3043703771
- Cited by
- 3,723
- References
- 14
- Citations by year
- 2026: 257 · 2025: 366 · 2024: 560 · 2023: 656 · 2022: 693 · 2021: 712 · 2020: 453 · 2019: 18
- FWCI
- 195.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Lirias (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
- Use Siena air (University of Siena) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Array BioPharma
- Regeneron Pharmaceuticals
- Massachusetts Medical Society
- Les Laboratories Pierre Fabre
- Incyte
- Syndax Pharmaceuticals
- National Institute for Health and Care Research
- Eisai
- Ipsen
- Plexxikon
- EUSA Pharma
- LEO Pharma
- Genentech
- EMD Serono
- Sanofi Genzyme
- Pharmacyclics
- 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
- ipilimumab, advanced melanoma, combination immunotherapy, immune checkpoint inhibitors, five-year survival, overall survival, progression-free survival, long-term outcomes, health-related quality of life, CheckMate 067, PD-1 inhibitors, CTLA-4 inhibitors, immune-related adverse events
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