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.
Highlights
Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations
Our results fail to support an advantage of an intermittent schedule of BRAFi plus MEKi
The current findings suggest that the superiority of continuous dosing may be a class effect of BRAF/MEK inhibitors and reject the previous hypothesis from Algazi et al posing that the long half-life of trametinib may have blunted the drug withdrawal effect6
Summary
Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. 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). Three different combinations of B-Raf proto-oncogene, serine/threonine kinase inhibitors (BRAFi) with mitogenactivated protein kinase inhibitors (MEKi) have been approved for the treatment of BRAFV600 mutation-positive advanced melanoma1–3 This therapy has demonstrated high anti-tumor activity with fast responses in most patients. Callahan and colleagues described the case of a melanoma patient in which an intermittent schedule of vemurafenib achieved a long tumor response5 These findings led to the hypothesis that modulation of drug pressure through an intermittent dosing could delay the emergence of resistance and clinical studies were subsequently initiated. An exploratory translational sub-study in cell-free DNA (cfDNA) from serial plasma samples was pre-planned as a secondary endpoint
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