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Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib
Open accessAbstract
BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
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“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 [45]
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Metadata
- Authors
- Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., Hersey, P., Kefford, R., Lawrence, D., Puzanov, I., Lewis, K. D., Amaravadi, R. K., Chmielowski, B., Lawrence, H. J., Shyr, Y., Ye, F., Li, J., Nolop, K. B., Lee, R. J., Joe, A. K., & Ribas, A.
- Affiliations
- Vanderbilt University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Abramson Cancer Center (US)
- University of Colorado Denver (US)
- New York University (US)
- Moffitt Cancer Center (US)
- Peter MacCallum Cancer Centre (AU)
- University of Pittsburgh (US)
- Massachusetts General Hospital (US)
- University of Newcastle Australia (AU)
- Melanoma Institute Australia (AU)
- Vanderbilt-Ingram Cancer Center (US)
- University of California, Los Angeles (US)
- Vanderbilt University Medical Center (US)
- Plexxikon (United States) (US)
- ORCID
- Sosman, Jeffrey A.
- Kim, Kevin B.
- Schuchter, Lynn
- Gonzalez, Rene
- Pavlick, Anna C.
- Weber, Jeffrey S.
- McArthur, Grant A.
- Hutson, Thomas E.
- Moschos, Stergios J.
- Flaherty, Keith T.
- Hersey, Peter
- Kefford, Richard
- Lawrence, Donald
- Puzanov, Igor
- Lewis, Karl D.
- Amaravadi, Ravi K.
- Chmielowski, Bartosz
- Shyr, Yu
- Ye, Fei
- Li, Jiang
- Lee, Richard J.
- Ribas, Antoni
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-02-23
- Volume
- 366
- Issue
- 8
- Pages
- 707-714
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3724515
- OpenAlex
- W2168143310
- Cited by
- 2,156
- References
- 36
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 56 · 2023: 85 · 2022: 113 · 2021: 88 · 2020: 110 · 2019: 109 · 2018: 132 · 2017: 171 · 2016: 198 · 2015: 258 · 2014: 318 · 2013: 306 · 2012: 160
- FWCI
- 133.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- National Cancer Institute (K24CA097588, P30CA076292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- vemurafenib, BRAF V600 mutation, metastatic melanoma, BRAF inhibitors, overall survival, overall response rate, duration of response, progression-free survival, cutaneous squamous cell carcinoma, keratoacanthoma, adverse events
- MeSH terms
- Vemurafenib, Adult, Aged, Female, Humans, Indoles, Male, Melanoma, Middle Aged, Mutation, Neoplasm Metastasis, Sulfonamides, Treatment Outcome, Disease Progression, Proto-Oncogene Proteins B-raf, Kaplan-Meier Estimate
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