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. Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.
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.[33,34]
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[35,36,37] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[2,38,39,40] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a CR.[38,40] A randomized trial compared IV DTIC with temozolomide (TMZ), an oral agent that hydrolyzes to the same active moiety as DTIC; OS was 6.4 months versus 7.7 months, respectively (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ and therefore, demonstration of similarity did not result in approval from the FDA.[Level of evidence: 1iiA] An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients (NCT00091572). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard dose, single-agent DTIC.[Level of evidence: 1iiA]