Title: Combined PD-1, BRAF and MEK inhibition in advanced BRAF -mutant melanoma: safety run-in and biomarker cohorts of COMBI-i
Author: Reinhard Dummer, Celeste Lebb, Victoria Atkinson, Mario Mandal, Paul D. Nathan, Ana Arance, Erika Richtig, Naoya Yamazaki, Caroline Robert, Dirk Schadendorf, Hussein A. Tawbi, Paolo A. Ascierto, Antoni Ribas, Keith T. Flaherty, Neha Pakhle, Catarina D. Campbell, Daniel Gusenleitner, Aisha Masood, Jan C. Brase, Eduard Gasal, Georgina V. Long
Abstract: Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients’ outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n=9) and biomarker (part 2; n=27) cohorts of the randomized, placebo-controlled, phase3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n=36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part1, the recommended phase3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400mg of spartalizumab every 4weeks plus 150mg of dabrafenib twice daily plus 2mg of trametinib once daily. Part2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3months). Spartalizumab plus dabrafenib and 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, and 17% permanently discontinued all three 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 associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.