Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone.,These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma.,COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.,Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram.,Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma.,The primary end point was investigator-assessed progression-free survival.,Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).,At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]).,The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively.,Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.,The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results.,Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
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.,Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear.,Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation