Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Combination therapy with BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) offers survival benefits for advanced melanoma patients with BRAF mutations.
• Preclinical research suggested intermittent dosing might delay drug resistance.

Purpose of the Study:

• To compare the antitumor activity of an intermittent versus a standard continuous dosing schedule of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF-mutant melanoma.
• To evaluate if an intermittent dosing schedule could offer superior progression-free survival (PFS).

Main Methods:

• Phase II, randomized, open-label clinical trial (NCT02583516).
• Patients with advanced BRAF-mutant melanoma received either continuous or intermittent dosing of vemurafenib plus cobimetinib.
• Progression-free survival (PFS) was the primary endpoint.
• Analysis of cell-free tumor DNA for BRAF mutations and next-generation sequencing (NGS) for resistance mutations.

Main Results:

• The trial did not meet its primary endpoint; intermittent dosing did not improve PFS compared to continuous dosing.
• The antitumor activity of the intermittent schedule was not superior to the standard continuous schedule.
• BRAF mutation detection in cell-free tumor DNA showed prognostic value for survival and correlated with clinical response, but not progression.
• NGS analysis identified de novo mutations in resistant cases.

Conclusions:

• An intermittent dosing schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule for advanced BRAF-mutant melanoma.
• BRAF mutation dynamics in cell-free tumor DNA can serve as a prognostic marker for survival and clinical response.
• Further research into resistance mechanisms, including de novo mutations identified by NGS, is warranted.