Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

Abstract

BACKGROUND:

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.

METHODS:

We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.

RESULTS:

At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.

CONCLUSIONS:

Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

• Authors: Paul B Chapman, Axel Hauschild, Caroline Robert, John B Haanen, Paolo Ascierto, James Larkin, Reinhard Dummer, Claus Garbe, Alessandro Testori, Michele Maio, David Hogg, Paul Lorigan, Celeste Lebbe, Thomas Jouary, Dirk Schadendorf, Antoni Ribas, Steven J O'Day, Jeffrey A Sosman, John M Kirkwood, Alexander M M Eggermont, Brigitte Dreno, Keith Nolop, Jiang Li, Betty Nelson, Jeannie Hou, Richard J Lee, Keith T Flaherty, Grant A McArthur, BRIM-3 Study Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 364 Issue 26 Pg. 2507-16 (Jun 30 2011) ISSN: 1533-4406 [Electronic] United States
• PMID: 21639808 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Sulfonamides
• Vemurafenib
• Dacarbazine
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Dacarbazine (adverse effects, therapeutic use)
• Disease-Free Survival
• Female
• Humans
• Indoles (adverse effects, therapeutic use)
• Intention to Treat Analysis
• Male
• Melanoma (drug therapy, genetics, mortality)
• Middle Aged
• Mutation
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Sulfonamides (adverse effects, therapeutic use)
• Survival Analysis
• Vemurafenib
• Young Adult