Abstract
Resistance to BRAF plus MEK inhibitors may be reversible in patients with BRAFV600-mutant melanoma.
Major finding: Resistance to BRAF plus MEK inhibitors may be reversible in patients with BRAFV600-mutant melanoma.
Approach: Rechallenge with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib was evaluated.
Impact: Patients who have progressed on BRAF inhibitors may respond to rechallenge with dabrafenib plus trametinib.
Activating BRAFV600 mutations drive tumor progression by constitutively activating MAPK signaling in approximately half of patients with melanoma. Patients with BRAFV600-mutant tumors initially respond well to combination therapies targeting BRAF and MEK, but in most patients acquired resistance leads to disease progression. Resistance to BRAF inhibitors occurs via BRAF-independent reactivation of the MAPK pathway, not by mutations that preclude BRAF inhibitor binding. This suggests the possibility for effective rechallenge with BRAF inhibitors after disease progression, and preclinical and early clinical data support this notion. Thus, Schreuer and colleagues performed a prospective, open-label, single-arm, phase II trial to evaluate the antitumor activity of rechallenge with BRAF and MEK inhibitors in patients with advanced BRAFV600-mutant melanoma who had previously progressed on BRAF-inhibitor regimens. A total of 25 patients were treated with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib after at least 12 weeks off BRAF inhibitor treatment. The primary endpoint was overall response, and secondary endpoints included safety and progression-free survival. Partial responses were achieved in 8 of 25 patients (32%), 6 of whom had previously progressed on dabrafenib plus trametinib and two of whom had progressed on BRAF inhibitor monotherapy. Stable disease was observed in 10 of 25 patients (40%). The median progression-free survival was 4.9 months. Rechallenge with dabrafenib plus trametinib was well tolerated; there were no unexpected adverse events and the majority of adverse events were grades 1–2. Treatment-related grade 3 adverse events occurred in 2 patients. Taken together, these findings demonstrate that resistance to BRAF and MEK inhibitors may be reversible, and rechallenge with dabrafenib plus trametinib warrants further investigation in patients with BRAFV600-mutant melanoma who have previously progressed on BRAF inhibitors.
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