Acquired and Lost BRAF/MEK Resistance in Melanoma: A Prospective Study

Rechallenge with dabrafenib and trametinib among patients who progressed with BRAF inhibition with or without MEK inhibition may be effective in patients with BRAF^V600-mutant melanoma, according to a study published in The Lancet Oncology.¹

BRAF and MEK inhibitors are effective strategies for treating BRAF^V600-mutant melanoma, but tumors usually acquire treatment resistance within 1 to 3 years of treatment initiation, leading to disease progression.

For this prospective, phase 2 trial (ClinicalTrials.gov Identifier: NCT02296996), researchers enrolled 25 patients whose disease progressed with BRAF inhibition with or without MEK inhibition to receive further BRAF and MEK inhibition with dabrafenib plus trametinib. All patients discontinued prior BRAF/MEK inhibitors within 12 weeks of rechallenge initiation.

There were 8 partial responses and 10 cases of stable disease. The treatment combination was well-tolerated, though there were 2 grade 3 adverse events.

Elevated lactate dehydrogenase at baseline and detectable BRAF^V600mut ctDNA after 2 weeks of rechallenge treatment were each associated with inferior progression-free survival.

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The authors concluded that treatment with dabrafenib plus trametinib after progression on initial BRAF/MEK inhibition should be examined in a larger trial. The optimal timing for re-initiating dabrafenib plus trametinib treatment is not, however, explicitly noted.

Reference

1. Schreuer M, Jansen Y, Planken S. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF^V600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017 Mar 3. doi: 10.1016/S1470-2045(17)30171-7 [Epub ahead of print]