Abstract
Single-agent MEK inhibition is most effective in BRAF inhibitor–naïve melanoma patients.
Major finding: Single-agent MEK inhibition is most effective in BRAF inhibitor–naïve melanoma patients.
Approach: Patients with BRAF-mutant melanoma were stratified based on previous BRAF inhibitor therapy.
Impact: BRAF inhibitor resistance mechanisms may confer resistance to subsequent MEK inhibitor therapy.
Activating BRAF mutations are found in approximately half of cutaneous melanomas and constitutively activate downstream MEK signaling. BRAF inhibitors extend progression-free and overall survival in many patients with metastatic BRAF-mutant melanoma, but resistance rapidly develops. First-line MEK inhibitor monotherapy is also effective in patients with metastatic BRAF-mutant melanoma, but the effect of sequential use of BRAF and MEK inhibitors is unknown. In an openlabel, multicenter, phase II study, Kim and colleagues evaluated the activity of single-agent MEK inhibition with trametinib in patients with metastatic BRAF-mutant melanoma enrolled into one of two cohorts: those who had previously been treated with a BRAF inhibitor (either vemurafenib or dabrafenib) and those who had previously received only chemotherapy or immunotherapy. The primary endpoint for both cohorts was to determine the response rate, and a 2-stage design was used such that, if the response rate was lower than 10% at the interim analysis, enrollment would be stopped. Although 20% of patients in the group previously treated with BRAF inhibitors had stable disease, no confirmed responses were observed and enrollment in that cohort was terminated. The median progression-free survival in the BRAF inhibitor-treated group was 1.8 months, and the median overall survival was 5.8 months. However, in the BRAF inhibitor–naïve group, the overall response rate was 25%, with 1 complete response and 13 partial responses, and counting patients with stable disease, the disease control rate was 75%. The median progression-free survival in this group was 4.0 months, and the median overall survival was 14.2 months. These findings indicate that trametinib has minimal activity in patients whose disease has progressed on BRAF inhibitor therapy and suggest that mechanisms of acquired resistance to BRAF inhibitors confer resistance to MEK inhibitors.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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