Plexxikon has announced efficacy and safety data from the BRIM3 trial, a large, randomized, multicenter phase 3 clinical study of Vemurafenib ( Zelboraf ) in patients with previously untreated metastatic melanoma with the BRAFV600 mutation. The BRIM3 study met the pre-specified criteria for co-primary endpoints of overall survival ( OS ) and progression-free survival ( PFS ).
For patients treated with Vemurafenib compared to those treated with chemotherapy, the risk of death was significantly reduced, by 63%, as reflected by the hazard ratio of 0.37, and a p value of less than 0.0001. In addition, Vemurafenib treatment significantly reduced the risk of disease progression, by 74% ( hazard ratio=0.26; p<0.0001 ).
Vemurafenib is an oral, novel drug that targets an oncogenic BRAF mutation, present in about half of all melanomas.

BRIM3 trial

Key data from the 675-patient BRIM3 trial, based on the analysis as of December 30, 2010, showed:

• six months after randomization to treatment, 84 percent of Vemurafenib-treated patients were alive, compared to 64% of patients randomized to chemotherapy;

• more patients treated with Vemurafenib experienced tumor shrinkage ( 48.4% ) than patients treated with chemotherapy ( 5.5% );

• median overall survival could not be reliably estimated at the time of this analysis since the median time for patients receiving treatment was only 3.75 months ( median follow up ). However, at that time, the estimated median OS in the Vemurafenib treatment arm was 9.23 months compared to 7.75 months in the chemotherapy arm. As of an updated analysis on March 1, 2011, the estimated median OS was 10.51 months for the Vemurafenib treatment arm, while the chemotherapy arm remained unchanged at 7.75 months;

• median progression-free survival was 5.3 months compared to 1.6 months in the chemotherapy arm;

• all subgroups of patients in the Vemurafenib arm showed consistent benefit in terms of overall survival, progression-free survival and tumor shrinkage, regardless of disease staging, age, gender or performance status.

In January 2011, the Data Safety Monitoring Board for BRIM3 recommended termination of the study due to compelling efficacy data, and further recommended that study patients receiving chemotherapy have the option to crossover to the Vemurafenib treatment arm.

BRIM2 trial

BRIM2 met its primary endpoint, and these data were consistent with earlier BRIM2 data reported at the Society for Melanoma Research in November 2010. This study enrolled 132 previously treated melanoma patients with the BRAFV600 mutation, and updated results showed: tumor shrinkage with a confirmed response rate of 53%; 29% of patients showed stable disease; median progression-free survival was 6.7 months; median duration of response also was 6.7 months; median overall survival had not been reached; however, at 12 months, 58% of patients treated with Vemurafenib were alive. Median follow up was 10 months.


The safety profile demonstrated in both BRIM3 and BRIM2 trials was consistent with previous Vemurafenib data. The most frequent grade 3 adverse event observed in these studies was cutaneous squamous cell carcinoma, a common skin cancer treated by local excision, with continuation of treatment. The most common adverse events were rash, increased sun sensitivity, joint pain, hair loss and fatigue. Adverse events also were generally reversible with dose modification or interruption. Possible serious side effects of Vemurafenib include liver problems, changes in heartbeat or very fast or abnormal heartbeats and allergic reactions.

Melanoma is the most serious type of skin cancer and is growing at a rate of about five to six percent annually. More than 68,000 people in the U.S. and 160,000 people worldwide are diagnosed with melanoma each year. It is one of the deadliest cancers, with a five-year survival rate of 15 to 20 percent for people with advanced ( stage IV ) melanoma, according to the American Cancer Society.
Risk factors for melanoma include a positive family history of melanoma, prior melanoma, multiple clinically atypical moles or dysplastic nevi, inherited genetic mutations, fair skin and sun exposure. However, melanoma can occur in any ethnic group and also in areas of the body without substantial exposure to the sun.

Source: Plexxikon, 2011

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