The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Open accessAbstract
BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
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In the citing paper
“A direct comparison between the two checkpoint inhibitors in a Phase III clinical trial found better response (44%) and survival rates (6.9 months progression-free survival) among patients treated with the anti-PD-1 antibody nivolumab than among those treated with the anti-CTLA-4 antibody ipilimumab (19% and 2.8 months).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In the citing paper
“Combined administration of both nivolumab and ipilimumab resulted in even higher response rates (58%) and survival (11.5 months) (67).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In the citing paper
“Even more patients were affected when treated with a combination of both (55%) (67).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In the citing paper
“Clinical trials that directly compared different types of immune checkpoint inhibitors and their combination noted that more patients experienced side effects when treated with anti-CTLA-4 (27.3%) compared to anti-PD-1 (16.3%).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In the citing paper
“Although PD-L1 expression on tumor cells was correlated with treatment efficacy in melanoma patients (67, 108), it was not in patients with squamous cell carcinoma, non-small cell lung cancer and Merkel cell carcinoma (70, 72, 74).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In the citing paper
“Severe adverse reactions include severe diarrhea, colitis, increased alanine aminotransferase levels, inflammation pneumonitis, and interstitial nephritis (67, 73, 99).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [67]
In 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 [54]
In the citing paper
“Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival.”
From Microbiota-centered interventions to boost immune checkpoint blockade therapies (2025) · cites this paper as Larkin et al., 2015
In the citing paper
“treatment-limiting toxicity with anti-PD-1 (16%), anti-CTLA-4 (27%), and combination therapies (65%)”
From The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy (2018) · cites this paper as Larkin et al., 2015
In the citing paper
“At the end of the trial, progression-free survival was highest in patients who received the combination therapy, followed by patients treated with nivolumab alone, and was lowest in patients treated with ipilimumab alone (59).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [59]
In the citing paper
“In patients with untreated melanoma, treatment with anti-CTLA-4 led to grade 3 or 4 irAEs in 27.3% of patients and treatment with anti-PD-1 led to such severe irAEs in only 16.3% of patients (59).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [59]
In the citing paper
“Combination treatment of advanced melanoma with both anti-CTLA-4 and anti-PD-1 led to a marked increase in both the incidence and the severity of irAEs, with 55% of those patients exhibiting high-grade irAEs (59).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [59]
In the citing paper
“Although the immune checkpoint inhibitors have success in treating various malignancies, there is still a significant number of patients that can use such therapy only for a limited amount of time, given the occurrence of strong toxic side effects, including gut inflammation, due to the subsequent immune-dysregulation (i.e., autoimmunity) [177].”
From Gut Microbiota and Cancer: From Pathogenesis to Therapy (2019) · cites this paper as [177]
In the citing paper
“Therefore, ipilimumab is commonly administrated at a reduced dose [154], which might weaken the efficacy of combination therapy.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [154]
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Citations
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Metadata
- Authors
- Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., Ferrucci, P. F., Hill, A., Wagstaff, J., Carlino, M. S., Haanen, J. B., Maio, M., Marquez-Rodas, I., McArthur, G. A., Ascierto, P. A., Long, G. V., Callahan, M. K., Postow, M. A., Grossmann, K., Sznol, M., Dreno, B., Bastholt, L., Yang, A., Rollin, L. M., Horak, C., Hodi, F. S., & Wolchok, J. D.
- Affiliations
- University of Siena (IT)
- From the Department of Medical Oncology, Royal Marsden Hospital, London (J.L.), and South West Wales Cancer Institute, Singleton Hospital, Swansea (J.W.) — both in the United Kingdom; Melanoma Oncology Unit, Veneto Region Oncology Research Institute, Padua (V.C.-S.), Oncology of Melanoma Unit, European Institute of Oncology, Milan (P.F.F.), University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) — all in Italy; Division of Medical Oncology, University...
- ORCID
- Larkin, James
- Gonzalez, Rene
- Grob, Jean Jacques
- Cowey, C. Lance
- Schadendorf, Dirk
- Dummer, Reinhard
- Smylie, Michael
- Rutkowski, Piotr
- Ferrucci, Pier F.
- Wagstaff, John
- Carlino, Matteo S.
- Haanen, John B.
- Maio, Michele
- McArthur, Grant A.
- Ascierto, Paolo A.
- Long, Georgina V.
- Callahan, Margaret K.
- Postow, Michael A.
- Grossmann, Kenneth
- Sznol, Mario
- Bastholt, Lars
- Hodi, F. Stephen
- Wolchok, Jedd D.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-07-02
- Volume
- 373
- Issue
- 1
- Pages
- 23-34
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5698905
- OpenAlex
- W2166662937
- Semantic Scholar
- f1d33462f43c22bfc0b6d687ce5866eacb6b188e
- Cited by
- 8,157
- References
- 22
- Citations by year
- 2026: 295 · 2025: 388 · 2024: 530 · 2023: 626 · 2022: 689 · 2021: 827 · 2020: 925 · 2019: 867 · 2018: 925 · 2017: 1039 · 2016: 837 · 2015: 190
- FWCI
- 435.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (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)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- 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
- ab, ipilimumab, metastatic melanoma, PD-1 inhibitors, CTLA-4 inhibitors, immune checkpoint inhibitors, combination immunotherapy, PD-L1 expression, progression-free survival, overall survival, treatment-related adverse events, immune-related adverse events, immune-related pneumonitis, immune-related colitis, immune-related endocrinopathy, immune-related hepatitis
- MeSH terms
- Ipilimumab, Nivolumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Female, Humans, Male, Melanoma, Middle Aged, Skin Neoplasms, Disease-Free Survival, Tumor Burden, Intention to Treat Analysis
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