Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that has been compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]). A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.
With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months versus 2.7 months for dabrafenib and DTIC, respectively. OS data are limited by the median duration of follow up and crossover. Partial response was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.[Level of Evidence: 1iiDiii]
The most frequent AEs in patients treated with dabrafenib were cutaneous (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in twelve patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.
Trametinib is an orally available, small molecule, selective inhibitor of MEK1 and MEK2. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAP kinases.
A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with V600E, 40 with V600K and 1 with both mutations). Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover was allowed, and the primary endpoint was PFS. The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). Median OS has not yet been reached.