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.
AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and 10% of those receiving chemotherapy. The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Central serous retinopathy and retinal-vein occlusion are uncommon, but serious, AEs associated with trametinib. On-study cutaneous SCCs were not observed.
Combinatorial therapy with signal transduction inhibitors
Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAP kinase pathway. Early phase II data with combinations of BRAF and MEK inhibitors have supported testing this combination in phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase. This agent had minimal activity as a single agent in melanoma and two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[32,33]