Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials
Abstract
IMPORTANCE: The anti-PD-1 therapeutic antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma. The activity of nivolumab in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset. OBJECTIVE: To evaluate the efficacy and safety of nivolumab in patients with wild-type BRAF and mutant BRAF metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of data pooled from 4 clinical trials of nivolumab in 440 adult patients with unresectable stage III or stage IV melanoma, who had been tested for BRAF mutational status while participating in one of the studies. INTERVENTION: The investigational drug, nivolumab, was administered intravenously to study participants over a 60-minute period, at doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks until disease progression, discontinuation owing to adverse events, withdrawal, or end of study. Most patients (83%) received nivolumab at a dosage of 3 mg/kg. MAIN OUTCOME AND MEASURE: Best overall response by modified World Health Organization or Response Evaluation Criteria In Solid Tumors criteria and safety profile. RESULTS: Of a total of 440 patients from 4 nivolumab clinical trials included in the analysis, 334 were BRAF wild-type and 106 were positive for BRAF V600 mutation. With the exception of prior BRAF inhibitor therapy, the demographics were well balanced between the 2 cohorts. In patients evaluable for response, the objective response rates were 34.6% (95% CI, 28.3-41.3) for the 217 patients with wild-type BRAF status and 29.7% (95% CI, 19.7-41.5) for the 74 with mutant BRAF status. The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipilimumab therapy, or PD-L1 status of the tumor. The median duration of objective response was 14.8 months (95% CI, 11.1-24.0 months) for wild-type BRAF and 11.2 months (95% CI, 7.3-22.9 months) for mutant BRAF. Median time to objective response was 2.2 months in both patient groups. The incidence of treatment-related adverse events of any grade was 68.3% in the wild-type BRAF group and 58.5% in the mutant BRAF group, with grade 3 or 4 adverse events in 11.7% and 2.8% of patients, respectively. Treatment-related AEs of any grade that occurred in at least 5% of patients in either group were fatigue, pruritus, rash, and diarrhea. CONCLUSIONS AND RELEVANCE: The results of this retrospective analysis suggest that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAF inhibitor or ipilimumab treatment.
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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 [1]
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- Authors
- Larkin, J., Lao, C. D., Urba, W. J., McDermott, D. F., Horak, C., Jiang, J., & Wolchok, J. D.
- Affiliations
- Royal Marsden Hospital (GB)
- University of Michigan (US)
- Earle A. Chiles Research Institute at Providence Cancer Center, Portland, Oregon
- Beth Israel Deaconess Medical Center (US)
- Bristol-Myers Squibb (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Larkin, James
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-07-01
- Volume
- 1
- Issue
- 4
- Pages
- 433
- ISSN
- 2374-2437 (ISSN-L)
- OpenAlex
- W1534815147
- Cited by
- 223
- References
- 24
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 12 · 2022: 14 · 2021: 21 · 2020: 29 · 2019: 23 · 2018: 26 · 2017: 40 · 2016: 31 · 2015: 6
- FWCI
- 14.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- nivolumab, BRAF V600 mutation, BRAF wild-type melanoma, advanced melanoma, metastatic melanoma, anti-PD-1 therapy, objective response rate, treatment safety, BRAF inhibitor therapy, ipilimumab, PD-L1 expression, duration of response, subgroup analysis, immunotherapy efficacy, drug safety profile, adverse events
- MeSH terms
- Ipilimumab, Nivolumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Clinical Trials as Topic, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Melanoma, Middle Aged, Mutation, Neoplasm Staging, Phenotype, Retrospective Studies, Skin Neoplasms, Time Factors, Biomarkers, Tumor, Signal Transduction, Treatment Outcome, Disease Progression, Genetic Predisposition to Disease, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Kaplan-Meier Estimate, Young Adult, Programmed Cell Death 1 Receptor
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