Abstract 3691: Met target inhibition-guided efficacy in preclinical models

Abstract

Abstract Background: A direct comparison of drug efficacy for the multiple agents currently in clinical development targeting MET-driven cancers would be useful for the selection of optimal treatment options. Previously, we utilized validated MET pharmacodynamic (PD) assays to compare the time course of phosphorylated-MET (pMET) suppression for five MET inhibitors (ASCO 2013). In the current study, we selected three candidates that demonstrated potent MET inhibition to compare anti-tumor efficacy. Methods: PD time course and tumor PK data were utilized to simulate a dosing schedule anticipated to produce >90% pMET suppression in a SNU5 gastric cancer xenograft model. From these data, dosing schedules of 44 mg/kg (Q12H) cabozantinib, 12.5 mg/kg (Q12H) EMD1214063, and 16.5 mg/kg (QD) foretinib were chosen to achieve necessary tumor exposure to suppress pMET. Once tumors reached a 150±50 mm3 size, drugs were administered continuously for 21 days and tumor volumes were measured intermittently for 62 days. To measure pMET suppression, tumor quadrants were collected at 4, 12, and 24 hrs from all treatment groups after dose 1 (day 1) and on day 8 (after dose 8 of foretinib or dose 14 of cabozantinib and EMD1214063). Results: Intact MET levels (pM/μg protein) were approximately 70% lower than vehicle controls at all day 8 collection points for all three drugs. The pY1234/35MET/MET ratios were 89%-99% (p<0.001) lower than vehicle controls on day 8 at 4 and 12 hrs post-dose for all three drugs. Compared to pretreatment levels, tumor volumes were reduced by 80-90% for all three drugs within 10-15 days post therapy and remained regressed until 13-20 days after treatment was stopped. Tumors then slowly regrew, but remained approximately 80% smaller than the vehicle group on day 62 (end of study). Conclusions: These studies demonstrate that PD response-guided regimens delivered drug doses that were lower than efficacious doses described previously (except cabozantinib), but effectively reduced tumor volume in SNU5 xenografts. The three MET inhibitors showed comparable anti-tumor efficacy when accompanied by equivalent pMET inhibition. Our data also affirms the utility of the MET PD assays to guide dose ranging studies. Funded by NCI Contract No HHSN261200800001E. Citation Format: Apurva K. Srivastava, Melinda G. Hollingshead, Jeevan P. Govindharajulu, Joseph M. Covey, Dane Liston, James Peggins, Donald P. Bottaro, John J. Wright, Robert J. Kinders, Joseph E. Tomaszewski, James H. Doroshow, Ralph E. Parchment. Met target inhibition-guided efficacy in preclinical models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3691. doi:10.1158/1538-7445.AM2014-3691