The prognosis for patients with metastatic melanoma is poor, ranging from 8 to 18 months, with only 1 drug currently approved in the United States for this patient population. Results of a phase 3 trial comparing that drug with the investigational agent vemurafenib show promise for patients with BRAF V600E mutation (Chapman PB, et al. N Engl JMed. 2011; 364:2507-2516).
Approximately 40% to 60% of cutaneous melanomas involve mutations in the BRAF gene that can activate tumor growth through the mitogenactivated protein kinase pathway. Previous studies have suggested that melanomas with the BRAF V600E mutation are more aggressive and less sensitive to chemotherapy than those with the BRAF wild-type mutation.
In early-phase clinical trials, vemurafenib, a BRAF kinase inhibitor that targets the BRAF V600E mutation, was associatedwith response rates >50%in patients with BRAF V600E mutation melanoma. Now, in the phase 3 BRAF Inhibitor in Melanoma (BRIM)-3 clinical study, the benefits of vemurafenib and dacarbazine (DTIC-Dome)—the only US and Food and Drug Admin - istration–approved chemotherapeutic agent for the treatment of metastatic melanoma—were compared in patients with metastatic cancer. A total of 675 patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation were randomly assigned to oral vemurafenib 960 mg twice daily (N = 337) or to dacarbazine 1000 mg/m2 infused every 3 weeks (N = 338). At 6 months, the OS was 84% among patients receiving vemurafenib versus 64% among those receiving dacarbazine, and the estimated median progression- free survival (PFS) was 5.3 months and 1.6 months, respectively.
Compared with dacarbazine, vemurafenib was associated with a 63% relative risk reduction for death and a 74% risk reduction of either death or disease progression. The response rate with vemurafenib was 48% versus 5% with dacarbazine. The results show improved OS and PFS with vemurafenib monotherapy in this patient population. Further - more, a survival benefit was observed in all subgroups of patients receiving vemurafenib, including those with stage M1c disease or an elevated lactate dehydrogenase level, conditions associated with an especially poor prognosis.
The most common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, secondary neoplasia (keratoacanthoma or squamous-cell carcinoma), photosensitivity, nausea, and diarrhea. In all cases of secondary neoplasia (18%) associated with vemurafenib, the lesions were removed by simple excision and no modifications in drug dose were necessary.
