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Cited by 5,519Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

Nivolumab in Previously Untreated Melanoma without BRAF Mutation

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Robert, Caroline, Long, Georgina V., Brady, Benjamin, Dutriaux, Caroline, Maio, Michele, Mortier, Laurent, Hassel, Jessica C., Rutkowski, Piotr +20 more·2015·New England Journal of Medicine
DOI 10.1056/nejmoa1412082
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Abstract

BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

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Crossref · 10.1056/nejmoa1412082

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  • Responses to immune checkpoint inhibitors in melanoma and other cancers are heterogeneous and often not durable.

    “however responses to these therapies are often heterogeneous and not durable (1–3).”

    From Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients (2018) · cites this paper as [3]

    The Discussion reports varied outcomes with nivolumab, including a 40% objective response rate, but describes the responses as durable—not often short-lived. Its Figure 2 discussion says 12 of 84 nivolumab responders did not have a durable response; the median response duration had not been reached. The study concerns melanoma without a BRAF mutation, not other cancers. (LLM, conf=0.85)

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  • Treatment with immunotherapy targeting checkpoint inhibitors PD-1 or CTLA-4 significantly increases survival in patients with metastatic melanoma over other standards of care.

    “Treatment with immunotherapy targeting checkpoint inhibitors PD-1 or CTLA-4 significantly increases survival in patients with metastatic melanoma over other standards of care [1, 2]”

    From Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients (2019) · cites this paper as [1]

    The Results and Conclusions report significantly better survival with the PD-1 inhibitor nivolumab than with dacarbazine, but the trial was limited to previously untreated patients with metastatic melanoma without a BRAF mutation. The Conclusions and Discussion also report survival benefits for ipilimumab in other trials. The claim omits those population and comparator limits and implies a broader benefit over standards of care than this paper establishes. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Immune checkpoint inhibitors greatly enhance clinical outcomes across multiple cancer types.

    “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 [2]

    The Conclusions (page not available in our copy) report significantly improved overall and progression-free survival with nivolumab versus dacarbazine in previously untreated metastatic melanoma without a BRAF mutation. The paper also mentions promising activity in patients with solid tumors, but it does not establish greatly enhanced clinical outcomes across multiple cancer types. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Responses to ICI treatment have still been observed in those with low or undetectable levels of PD-L1 expression.

    “Nevertheless, the responses to ICI treatment have still been observed in those with low or undetectable levels of PD-L1 expression.9”

    From The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC (2019) · cites this paper as [9]

  • Anti-PD-1 therapy gives long-term clinical benefit to about 40% of patients with advanced melanoma.

    “Immune checkpoint blockade with monoclonal antibodies (mAbs) targeting programmed cell death protein 1 (PD-1) provides long-term clinical benefits to nearly 40% of patients with advanced melanoma (1–5).”

    From Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients (2021) · cites this paper as [3]

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Authors
Robert, C., Long, G. V., Brady, B., Dutriaux, C., Maio, M., Mortier, L., Hassel, J. C., Rutkowski, P., McNeil, C., Kalinka-Warzocha, E., Savage, K. J., Hernberg, M. M., Lebbé, C., Charles, J., Mihalcioiu, C., Chiarion-Sileni, V., Mauch, C., Cognetti, F., Arance, A., Schmidt, H., Schadendorf, D., Gogas, H., Lundgren-Eriksson, L., Horak, C., Sharkey, B., Waxman, I. M., Atkinson, V., & Ascierto, P. A.
Affiliations
  • Inserm (FR)
  • The University of Sydney (AU)
  • Cabrini Hospital (AU)
  • Centre Hospitalier Universitaire de Bordeaux (FR)
  • University of Siena (IT)
  • Hôpital Claude Huriez (FR)
  • University Hospital Heidelberg (DE)
  • The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
  • Royal Prince Alfred Hospital (AU)
  • The authors' affiliations are listed in the Appendix.
  • BC Cancer Agency (CA)
  • Helsinki University Hospital (FI)
  • Royal Victoria Hospital (CA)
  • Centrum für Integrierte Onkologie (DE)
  • Instituto Nazionale Tumori Regina Elena (IT)
  • Hospital Clínic de Barcelona (ES)
  • Aarhus University Hospital (DK)
  • University of Duisburg-Essen (DE)
  • National and Kapodistrian University of Athens (GR)
  • Bristol-Myers Squibb (United States) (US)
  • Greenslopes Private Hospital (AU)
  • Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2015-01-22
Volume
372
Issue
4
Pages
320-330
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1412082
OpenAlex
W2128035403
Semantic Scholar
6a8a53c7f9fd79ff959c6101698e58d58ff6123e
Cited by
5,519
References
25
Citations by year
2026: 154 · 2025: 230 · 2024: 293 · 2023: 335 · 2022: 430 · 2021: 516 · 2020: 601 · 2019: 586 · 2018: 642 · 2017: 715 · 2016: 614 · 2015: 373 · 2014: 15 · 2013: 2 · 2012: 3
FWCI
274.51
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Use Siena air (University of Siena) (submittedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
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
nivolumab, metastatic melanoma, BRAF wild-type melanoma, dacarbazine, immune checkpoint inhibitors, PD-1 inhibitors, overall survival, progression-free survival, objective response rate, PD-L1 expression, treatment-naive patients, adverse events, immunotherapy versus chemotherapy, subgroup analysis
MeSH terms
Nivolumab, Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Dacarbazine, Double-Blind Method, Female, Humans, Male, Melanoma, Middle Aged, Survival Rate, Disease-Free Survival, Proto-Oncogene Proteins B-raf, Young Adult, Programmed Cell Death 1 Receptor

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