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Clinical Trial
. 2011 Jun 30;364(26):2507-16.
doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.

Improved survival with vemurafenib in melanoma with BRAF V600E mutation

Paul B Chapman  1 , 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
Collaborators, Affiliations
Clinical Trial

Improved survival with vemurafenib in melanoma with BRAF V600E mutation

Paul B Chapman et al. N Engl J Med. .

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.).

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Figures

Figure 1
Figure 1. Overall Survival
Panel A shows Kaplan–Meier estimates of survival in patients in the intention-to-treat population. Patients could be evaluated for overall survival if they had undergone randomization at least 2 weeks before the clinical cutoff date. An inadequate number of patients were evaluated after 7 months of follow-up in either study group to provide reliable Kaplan–Meier estimates of the survival curves. The vertical lines indicate that patients’ data were censored. Panel B shows hazard ratios and 95% confidence intervals (CI) for rates of overall survival in prespecified subgroups of patients, according to various baseline characteristics. In both panels, data are shown for patients who received no study treatment (48 patients in the dacarbazine group and 2 patients in the vemurafenib group) and for 1 patient who was assigned to the dacarbazine group but who received vemurafenib. NR denotes not reached.
Figure 2
Figure 2. Progression-free Survival
Panel A shows Kaplan–Meier estimates of progression-free survival in patients in the intention-to-treat population. Patients could be evaluated for progression-free survival if they had undergone randomization at least 9 weeks before clinical cutoff date. The median progression-free survival was 5.3 months for vemurafenib and 1.6 months for dacarbazine. The vertical lines indicate that patients’ data were censored. Panel B shows hazard ratios and 95% confidence intervals (CI) for progression-free survival in prespecified subgroups of patients, according to baseline characteristics. In both panels, data are shown for patients who received no study treatment (48 patients in the dacarbazine group and 2 patients in the vemurafenib group) and for 1 patient who was assigned to the dacarbazine group and who received vemurafenib. NR denotes not reached.
Figure 3
Figure 3. Best Tumor Response for Each Patient
Data regarding the best tumor response are shown for 209 patients in the vemurafenib group (Panel A) and 158 patients in the dacarbazine group (Panel B) who were registered at least 14 weeks before the clinical cutoff date on December 30, 2010, and who had undergone at least one tumor assessment after treatment. Each bar represents data for an individual patient. Colors indicate the tumor substage for each patient. The percent change from baseline in the sum of the diameters of the target lesions is shown on the y axis. Negative values indicate tumor shrinkage.
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