Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study
Open accessAbstract
Background In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.Methods Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.Findings 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.Interpretation Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation.Funding F Hoffmann-La Roche-Genentech.
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Maturation of survival data increased the ESMO-MCBS score of vemurafenib in metastatic melanoma from 3 based on PFS to 4 based on OS.
“Maturation of survival data also increased the ESMO-MCBS score of vemurafenib in the treatment of metastatic melanoma [116, 117] from ESMO-MCBS 3 based on PFS to 4, based on OS.”
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- Authors
- McArthur, G. A., Chapman, P. B., Robert, C., Larkin, J., Haanen, J. B., Dummer, R., Ribas, A., Hogg, D., Hamid, O., Ascierto, P. A., Garbe, C., Testori, A., Maio, M., Lorigan, P., Lebbé, C., Jouary, T., Schadendorf, D., O'Day, S. J., Kirkwood, J. M., Eggermont, A. M., Dréno, B., Sosman, J. A., Flaherty, K. T., Yin, M., Caro, I., Cheng, S., Trunzer, K., & Hauschild, A.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Memorial Sloan Kettering Cancer Center (US)
- Institut Gustave Roussy (FR)
- Royal Marsden Hospital (GB)
- The Netherlands Cancer Institute (NL)
- University of Zurich (CH)
- University of California, Los Angeles (US)
- University Health Network (CA)
- Angeles Clinic and Research Institute (US)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- University of Tübingen (DE)
- European Institute of Oncology (IT)
- University of Siena (IT)
- University of Manchester (GB)
- Hôpital Saint-André (FR)
- Essen University Hospital (DE)
- Beverly Hills Cancer Center (US)
- University of Pittsburgh (US)
- Centre Hospitalier Universitaire de Nantes (FR)
- Vanderbilt University (US)
- Massachusetts General Hospital (US)
- Genentech (US)
- F. Hoffmann-La Roche AG (CH)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- McArthur, Grant A
- ORCID
- McArthur, Grant A
- Chapman, Paul B
- Robert, Caroline
- Larkin, James
- Haanen, John B
- Dummer, Reinhard
- Ribas, Antoni
- Hogg, David
- Hamid, Omid
- Ascierto, Paolo A
- Garbe, Claus
- Testori, Alessandro
- Maio, Michele
- Lorigan, Paul
- Jouary, Thomas
- Schadendorf, Dirk
- Kirkwood, John M.
- Eggermont, Alexander M
- Dréno, Brigitte
- Sosman, Jeffrey A
- Flaherty, Keith T
- Caro, Ivor
- Trunzer, Kerstin
- Hauschild, Axel
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 15
- Issue
- 3
- Pages
- 323-332
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC4382632
- OpenAlex
- W2111404068
- Cited by
- 977
- References
- 27
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 29 · 2023: 38 · 2022: 50 · 2021: 64 · 2020: 85 · 2019: 86 · 2018: 101 · 2017: 146 · 2016: 122 · 2015: 136 · 2014: 76 · 2013: 2 · 2012: 2
- FWCI
- 65.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- F. Hoffmann-La Roche
- 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 V600E mutation, BRAF V600K mutation, metastatic melanoma, dacarbazine, overall survival, progression-free survival, long-term follow-up, BRAF inhibitors, treatment-naive patients, sensitivity analysis, treatment efficacy and safety, targeted therapy
- MeSH terms
- Vemurafenib, Adult, Aged, Dacarbazine, Female, Follow-Up Studies, Humans, Indoles, Male, Melanoma, Middle Aged, Mutation, Sulfonamides, Disease-Free Survival, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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