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/m2 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. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Bayer, Genentech, Wyeth AstraZeneca AstraZeneca, Bayer, Genentech, Wyeth AstraZeneca