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

Abstract

Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.

Conflict of interest statement

The authors declare no competing interests that could directly undermine, or be perceived to undermine the objectivity, integrity, and value of the publication, through a potential influence on the judgements and actions of authors regarding objective data presentation, analysis, and interpretation.

© 2021. The Author(s).

Figures

Fig. 1

Consort flow diagram.

Fig. 2. Progression Free Survival.

A PFS according to treatment arm (n 70); B PFS according to treatment arm and BRAF mutation in cfDNA (n 34). G1: Continuous arm and basal BRAF Positive in cfDNA, G2: Intermittent arm and basal BRAF Positive in cfDNA, G3: Continuous arm and basal BRAF Negative in cfDNA, G4: Intermittent arm and basal BRAF Negative in cfDNA.

Fig. 3. Summary of BRAF cfDNA results.

Arm A: Continuous arm; Arm B: Intermittent arm; CB: objective response or stable disease; m: months; NE resp: no response evaluation; No PD: patients without progression at data cut-off analysis; NR: no reached; PD: progression disease; *including two patients without basal samples.