Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma.

Abstract

9004 Background: BRAF mutations play an oncogenic role in melanomas. Selumetinib (AZD6244, ARRY-142886) inhibits MEK1/2 downstream of B-Raf and may have an additive effect to chemotherapy. We prospectively evaluated SEL + DTIC vs PBO + DTIC in patients with stage III-IV BRAF mutation-positive advanced cutaneous or unknown primary melanoma (NCT00936221). Methods: Eligible patients (pts) received iv DTIC 1000 mg/m2, and po SEL 75 mg or matched PBO bd as first-line treatment. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability. Results: A total of 385 pts were screened across 44 centers; 91 patients were randomized (SEL + DTIC, 45; PBO + DTIC, 46). One pt from each group did not receive the randomized treatment. Baseline characteristics were balanced between the two groups, with the exception of histology, gender and previous medications. At data cut-off, 66 deaths had occurred (73% maturity) and median follow-up was 12.3 mo. OS was longer for SEL + DTIC vs PBO + DTIC (median 13.9 vs 10.5 mo), but this did not meet statistical significance (HR 0.93; 80% CI 0.67, 1.28; 1-sided p=0.3873). PFS was significantly improved for SEL + DTIC vs PBO + DTIC, median 5.6 vs 3.0 mo (HR 0.63; 80% CI 0.47, 0.84; 1-sided p=0.021). ORR was 40% with SEL + DTIC vs 26% with PBO + DTIC. Most frequent adverse events (AEs) observed with SEL + DTIC were: nausea (64%), dermatitis acneiform (52%), diarrhea (48%), vomiting (48%), and peripheral edema (43%). AEs that led to hospitalization were higher for SEL + DTIC vs PBO + DTIC (36 vs 13%), and were mostly infections and gastrointestinal disorders. The incidence of grade ≥3 AEs (68 vs 42%), serious AEs (50 vs 18%) and discontinuation of the randomized treatment due to AEs were higher for SEL + DTIC vs PBO + DTIC (16 vs 4%). Conclusions: Clinical activity was observed in patients with BRAF mutation-positive melanoma treated with SEL + DTIC, reflected by a nonsignificant improvement in OS and a significant benefit in PFS. Tolerability of this combination was generally consistent with the monotherapy safety profiles. Clinical trial information: NCT00936221.