Pediatric preclinical testing program (PPTP) evaluation of the MEK1/2 inhibitor AZD6244 (ARRY-142886)

2998 Background : AZD6244 is a potent, selective, and uncompetitive inhibitor of MEK1/2 kinases that is currently in phase 2 clinical development. The activity of AZD6244 was evaluated against the PPTP’s in vitro and in vivo panels. Methods : The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). AZD6244 was tested in vitro at concentrations from 1.0 nM to 10 μM and was tested against the PPTP in vivo panel using a BID schedule (excepting weekends for which a QD schedule was used), with oral administration for 6 weeks at a dose of 100 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Results : AZD6244 demonstrated a clear cytotoxic effect against Kasumi-1, an AML cell line with an activating KIT mutation. The IC50 for Kasumi-1 was 200 nM, similar to IC50 values for AZD6244 in adult cancer cell lines with activating BRAF or RAS family mutations. Several other cell lines showed a limited response to AZD6244 that was consistent with a primarily cytostatic effect, while 18 cell lines had IC50 values > 10 μM. AZD6244 was well tolerated in vivo with toxicity in 2.6% of treated animals compared to 0% of control animals. AZD6244 significantly increased EFS in 10 of 37 (27%) evaluable solid tumor xenografts. Significant differences in EFS distribution occurred in the majority of xenografts in the glioblastoma panel (3 of 4) and in one-half of the xenografts from the osteosarcoma panel (3 of 6). None of the 6 evaluable ALL xenografts demonstrated significant increases in EFS. The EFS T/C values were below the criteria for intermediate activity for the time to event measure of activity (EFS T/C > 2) in all but three evaluable lines: the GBM xenograft BT-39 and two osteosarcoma xenografts (OS-1 and OS-33). The best objective response was PD2 (progressive disease with growth delay), with PD2 activity concentrated in the glioblastoma panel (2 of 4) and the osteosarcoma panel (3 of 6). Conclusions : AZD6244 was highly active against a PPTP cell line with an activating KIT mutation, but was not active against the majority of the cell lines of the PPTP in vitro panel and did not significantly inhibit growth for most of the xenografts in the PPTP in vivo panel. These observations are consistent with the relative paucity of BRAF and RAS family mutations in the pediatric cancers included in this evaluation. Combinations of AZD6244 with agents targeting other signaling pathways involved in survival/proliferation are of interest for future PPTP evaluations of AZD6244. (Supported by NCI NO1CM42216)