Efficacy and safety of AZD6244 (ARRY-142886) as second/third-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC).

8029 Background: The Raf/MEK/ERK signaling pathway is necessary for oncogenic function, and in NSCLC pts constitutive activation of this pathway has been correlated with BRAF/KRAS gene mutations. MEK1/2 inhibition block the Raf/MEK/ERK pathway since these kinases lie downstream of Ras, and ERK1/2 are the only known substrates of MEK1/2. Here we evaluate the efficacy and safety of oral AZD6244 - a potent, selective, ATP uncompetitive inhibitor of MEK1/2 - vs pemetrexed (PEM), which is currently approved and widely used for second/third-line treatment, in pts with advanced NSCLC.,Pts who have previously received one or two chemotherapy regimens (prior surgery and/or localized radiation allowed) were randomized 1:1 to oral AZD6244 (100 mg BID) or iv infusion of PEM (500 mg/m over 10 min q3w). Pts in the PEM arm also received corticosteroid premedication and vitamin supplementation. The primary objective of this Phase II exploratory study was to evaluate the efficacy of AZD6244 vs PEM as second- or third-line treatment of advanced NSCLC by assessment of disease progression.,Of 84 pts aged 21-80 years, 40 were randomized to AZD6244 and 44 to PEM. The majority (79%) were second-line. Baseline characteristics of the two groups were comparable. There were 28 (70%) and 26 (59%) pts with a progression event in the AZD6244 and PEM groups, respectively (HR 1.35; 80% CI 0.93, 1.94; p=0.30). A secondary analysis of PFS (AZD6244: median 67 days; PEM median 90 days; HR 1.08, 80% CI 0.75, 1.54; p=0.79) supported the primary endpoint. Two objective responses were seen in each arm. Most pts in both arms experienced adverse events (AEs): 73% with AZD6244, 80% with PEM. Dermatitis acneiform (43%), diarrhea (33%), nausea (20%) and vomiting (20%) were the most common with AZD6244. Fatigue (37%), anemia (29%), nausea (24%) and anorexia (22%) were the most common with PEM. Of 11 pts with serious AEs (4 AZD6244) only neutropenia occurred in 2 pts (PEM).,Although there was evidence of anti-tumor activity with AZD6244, there was no significant difference observed between AZD6244 and PEM for the primary disease progression endpoint. AZD6244 was well tolerated in this patient population. [Table: see text].