AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study.

9033 Background: AZD6244 is an orally available, potent, selective, ATP uncompetitive inhibitor of MEK1/2, with preclinical and phase I data suggesting it has the potential for anti-tumor activity in pts with melanoma. Here we evaluate the efficacy and safety of AZD6244 vs TMZ in an overall population of advanced melanoma pts and in mutated BRAF (BRAF+) or mutated NRAS (NRAS+) subgroups. METHODS: Eligibility included AJCC stage 3/4 malignant melanoma, RECIST measurable disease, and no prior chemotherapy for advanced melanoma. Pts were randomized 1:1 to AZD6244 (100mg BD continuously) or TMZ (200 mg/m(2) for 5 days, q28d). Pts randomized to TMZ could receive AZD6244 after disease progression. The primary outcome variable was progression-free survival (PFS), which was then adjusted for source of primary tumor (uveal vs non-uveal), mutation status, LDH (> or ≤2 x ULN), and WHO PS (0-2). Mutation status was assessed in archival or fresh tumor samples by DNA sequencing. RESULTS: A total of 104 and 96 pts were randomized to AZD6244 and TMZ, respectively. To date, 146 pts have their mutation status confirmed, 67 were BRAF+, and 24 NRAS+. Of the non-uveal pts, 50% were BRAF+ and 68% were either BRAF+ or NRAS+. For PFS, there was no difference between the two treatment arms in the overall population (151 events; HR 1.07; 80% CI 0.86, 1.34) or in the BRAF+ subgroup (HR 0.85; 80% CI 0.58, 1.24). Overall survival (OS) data are immature (67 deaths) but the interim analysis showed no difference between the two arms in the overall population (HR 1.23; 80% CI 0.88, 1.71). In BRAF+ pts (25 deaths) the HR estimate for OS favored AZD6244 (HR 0.68; 80% CI 0.38, 1.21). Six pts receiving AZD6244 had a confirmed PR, of which 5 were BRAF+ (12% of BRAF+ pts). Nine pts receiving TMZ had a confirmed PR, 3 of which were BRAF+ (12% of BRAF+ pts). Commonly reported adverse events with AZD6244 were acneiform dermatitis (60%), diarrhea (56%), nausea (50%), peripheral edema (38%), fatigue (27%), and vomiting (26%). Updated trial data will be presented. CONCLUSIONS: Anti-tumor activity with AZD6244 has been seen but there was no significant difference in PFS between the treatment arms. The trial is being followed for mature OS data. [Table: see text].