Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for <i>BRAF</i>-mutant advanced melanoma: Phase 1 KEYNOTE-022 study.

Abstract

3014 Background: The anti–PD-1 antibody pembro has demonstrated durable responses in ~30%-40% of patients (pts) with advanced melanoma. The combination of BRAF inhibitor D and MEK inhibitor T, the standard treatment for BRAF-mutant melanoma, leads to rapid responses and improved survival, but 50% of pts eventually experience disease progression around 12 mo. KEYNOTE-022 (NCT02130466) is a phase 1/2 study designed to assess safety and efficacy of the recommended doses of pembro in combination with D and T. Here, we report on the safety and efficacy of this triplet combination in BRAF-mutant melanoma in phase 1 testing. Methods: Key eligibility criteria included BRAFV600E/K-mutant stage III/IV advanced melanoma, ≥ 1 measurable lesion per RECIST v1.1, ECOG PS 0-1, and no prior treatment with BRAF/MEK inhibitors. A 3 + 3 design was used for dose escalation, with dose confirmation in an expansion cohort guided by the toxicity probability interval method. Pts received pembro 2 mg/kg Q3W + D 150 mg twice daily (BID) + T 2 mg daily (QD). AEs (NCI CTCAE v4.0) were collected throughout the study + 30 days; DLT observation window was the first 6 wk after dosing. Primary efficacy end point was ORR (RECIST v1.1, investigator). Results: As of the Jan 2016 data cutoff, 15 pts were enrolled across the dose determination and dose confirmation arms. The predefined criteria for progression to phase 2 were met, with DLTs reported in 3 pts: pt 1 had gr 4 neutropenia (treatment interrupted); pt 2 had gr 4 ALT increased (discontinued); pt 3 had gr 3 ALT, AST, and gamma-glutamyltransferase increased (discontinued). All events resolved. Overall, 10 (67%) pts experienced gr 3-4 treatment-related AEs, with 5 (33%) discontinuations; there were no treatment-related deaths. ORR (unconfirmed) in 15 pts was 60% (n = 9 PR, n = 2 SD, n = 3 PD). Based on these results, the recommended phase 2 regimen is pembro 2 mg/kg Q3W + D 150 mg BID + T 2 mg QD. Conclusions: The approved doses of pembro in combination with D + T administered concurrently provided a manageable toxicity profile in pts with BRAF-mutant melanoma. A phase 2 study will further evaluate safety and efficacy of this triplet combination as first-line therapy for BRAF-mutant melanoma. Clinical trial information: NCT02130466.