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Clinical Trial
. 2012 Feb 23;366(8):707-14.
doi: 10.1056/NEJMoa1112302.

Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib

Jeffrey A Sosman  1 , Kevin B Kim, Lynn Schuchter, Rene Gonzalez, Anna C Pavlick, Jeffrey S Weber, Grant A McArthur, Thomas E Hutson, Stergios J Moschos, Keith T Flaherty, Peter Hersey, Richard Kefford, Donald Lawrence, Igor Puzanov, Karl D Lewis, Ravi K Amaravadi, Bartosz Chmielowski, H Jeffrey Lawrence, Yu Shyr, Fei Ye, Jiang Li, Keith B Nolop, Richard J Lee, Andrew K Joe, Antoni Ribas
Affiliations
Clinical Trial

Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib

Jeffrey A Sosman et al. N Engl J Med. .

Abstract

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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Figures

Figure 1
Figure 1. Objective Tumor Responses with Vemurafenib, According to Metastatic Stage
Ten patients had 100% reduction in target lesions; two of these had nontarget lesions and were therefore considered to have a partial response, for a total of eight complete responses as defined on the basis of the Response Evaluation Criteria in Solid Tumors (version 1.1). Up to five measurable target lesions (no more than two per organ) were selected to assess response. A complete response was defined as the disappearance of all target lesions and nontarget lesions. A partial response was defined as a decrease of at least 30% in the sum of the diameters of target lesions, as compared with the baseline sum of the diameters.
Figure 2
Figure 2. Times to Response and Progression among the 69 Patients Who Had a Response
Of the 70 patients who had a response, 69 patients were evaluated for duration of response (1 patient was considered unable to be evaluated for duration of response owing to discrepant data at the time of database cutoff).
Figure 3
Figure 3. Kaplan–Meier Estimates of Progression-free and Overall Survival
Shown is the percentage of vemurafenib-treated patients with progression-free survival (Panel A) and overall survival (Panel B). The dashed lines indicate the medians. Tick marks along the curves represent the date of the last tumor assessment before the time of data cutoff among patients with censored data without disease progression or death.
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