Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM).

Abstract

2511 Background: D, T, and Ipi are each indicated for treatment of patients (pts) with MM (D+T in BRAF V600 mutation–positive MM). D and T can be safely combined and prolong progression-free survival compared with monotherapy. Combining D+T with the CTLA-4 antibody Ipi has the potential to improve treatment outcomes, but the safety profile is unknown. A recent report suggested caution in combining the BRAF inhibitor vemurafenib (V) with Ipi; V+Ipi resulted in G3 elevations of ALT in 6/10 pts leading to study discontinuation (NEJM2013 368; 14). The present study will characterize the safety of D±T+Ipi, select recommended phase 2 doses (RP2Ds), and report efficacy. Methods: Pts with stage IIIc/IV BRAF V600E /K mutation–positive MM and ≤1 prior treatments are eligible. Dose escalation occurs in cohorts of 3-6 pts followed by expansion (≤30 pts) at the RP2D. At data cutoff (Nov 8, 2013), 10 pts were enrolled: 4 received D+Ipi (doublet), 2 received D only (withdrawn before Ipi treatment), and 4 received D+T+Ipi (triplet). Results: Median age of the10 pts was 59.5 y (range, 32-75 y). Doublet: D 150 mg bid + Ipi 3 mg/kg q3w × 4 doses was well tolerated and selected as RP2D. No G3/4 ALT elevations or dose-limiting toxicities (DLTs) were observed. The most frequent adverse events (AEs; ≥2) were chills, fatigue, hand-foot syndrome, pyrexia, and maculopapular rash. Of 4 pts, 2 are ongoing and 2 stopped treatment (disease progression). Pts are currently being enrolled at this dose level in the expansion. Triplet: At current doses (D 100 mg bid/T 1 mg qd+Ipi 3 mg/kg q3w × 4), no G3/4 ALT elevations and 1 DLT (G3 colitis; associated with Ipi) occurred. The most frequent AEs (≥2) were pyrexia, chills, arthralgia, insomnia, and maculopapular rash. One pt had G4 renal insufficiency that reversed rapidly. Of 4 pts treated, 1 stopped treatment (DLT), and 3 are ongoing. Updated safety data and preliminary efficacy data will be presented for both cohorts. Conclusions: To date the combinations of D+Ipi and D+T+Ipi appear to be tolerable and have not been associated with significant hepatotoxicity in MM, suggesting differences between BRAF inhibitors when combined with Ipi. Clinical trial information: NCT01767454.