Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
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BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).
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BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type.
“For instance, BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type (45–49).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [49]
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- Authors
- Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., Kudchadkar, R., Burris, H. A., Falchook, G., Algazi, A., Lewis, K., Long, G. V., Puzanov, I., Lebowitz, P., Singh, A., Little, S., Sun, P., Allred, A., Ouellet, D., Kim, K. B., Patel, K., & Weber, J.
- Affiliations
- Massachusetts General Hospital (US)
- Sarah Cannon Research Institute (GB)
- University of California, San Francisco (US)
- University of Colorado Cancer Center (US)
- The University of Sydney (AU)
- Vanderbilt University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Austin Hospital (AU)
- Dana-Farber Cancer Institute (US)
- GlaxoSmithKline (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-11
- Volume
- 367
- Issue
- 18
- Pages
- 1694-1703
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3549295
- OpenAlex
- W2156078931
- Cited by
- 2,810
- References
- 27
- Citations by year
- 2026: 66 · 2025: 78 · 2024: 104 · 2023: 135 · 2022: 185 · 2021: 161 · 2020: 169 · 2019: 200 · 2018: 168 · 2017: 233 · 2016: 255 · 2015: 345 · 2014: 401 · 2013: 286 · 2012: 18
- FWCI
- 135.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (K24CA097588, P30CA016672)
- National Center for Research Resources (UL1RR024148)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, BRAF V600 mutation, dabrafenib, trametinib, combination therapy, BRAF inhibitors, MEK inhibitors, MAPK pathway reactivation, cutaneous squamous cell carcinoma, fever, progression-free survival, drug safety, pharmacokinetics, metastatic melanoma, targeted therapy resistance, overall survival
- MeSH terms
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Drug Therapy, Combination, Female, Fever, Humans, Imidazoles, Male, Melanoma, Middle Aged, Mutation, Oximes, Pyridones, Pyrimidinones, Disease-Free Survival, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Proto-Oncogene Proteins B-raf
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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