Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i

Abstract

Checkpoint inhibitors and targeted therapies lead to long-term survival in metastatic melanoma, but many patients still experience progression, and novel treatment strategies are needed.1,2 We report efficacy, safety, and biomarker findings from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti–programmed death receptor 1 (PD-1) antibody spartalizumab in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. All patients (N = 36) had previously untreated BRAF V600–mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg spartalizumab every 4 weeks plus 150 mg dabrafenib twice daily plus 2 mg trametinib once daily. Part 2 characterized changes in programmed death ligand 1 (PD-L1) levels and CD8+ cells upon treatment (primary endpoint) and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints of both parts (median follow-up, 24.3 months). Spartalizumab plus dabrafenib plus trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥ 3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, but only 17% permanently discontinued all 3 study drugs, due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T-cell inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety, and on-treatment biomarker modulations with spartalizumab plus dabrafenib plus trametinib were promising, and biomarkers that may predict long-term benefit were identified.