Abstract 3595: In vivo acquired resistance to the mutant EGFR inhibitor Rociletinib (CO-1686) is associated with activation of the c-MET pathway

Abstract

Abstract Rociletinib is a novel, oral, targeted irreversible inhibitor of the cancer-causing mutant forms of EGFR currently being studied for the treatment of NSCLC. Rociletinib was designed to spare wild-type EGFR signaling. Heavily-pretreated T790M+ patients treated with rociletinib at 500 or 625mg BID demonstrated a 67% objective response rate (n = 56, Soria et al., ENA 2014). Despite these promising data, acquired resistance to rociletinib monotherapy is anticipated. To assess the in vivo mechanisms of acquired resistance to rociletinib, mice bearing PC-9 (EGFR del19) human NSCLC tumors were chronically dosed with erlotinib (50 mg/kg QD) or rociletinib (150 mg/kg BID). Rociletinib treated mice had an increased time to tumor progression as compared to erlotinib treated mice. Resistance, as defined by tumors reaching >300mm3, was observed in all (n = 10) erlotinib treated mice between days 42-61. Alternatively, resistance to rociletinib was only observed in 3/10 mice after 126 days of dosing. Emergence of the EGFR T790M resistance mutation was detected in all tumors resistant to erlotinib. Erlotinib resistant tumors (n = 7) were crossed over to rociletinib monotherapy on day 60 of the study at a mean tumor volume of 500mm3. Rociletinib treatment generated durable tumor regressions in both crossover and monotherapy treated mice, however continued dosing of rociletinib ultimately allowed for the collection of four resistant tumors. Rociletinib resistant tumors were analyzed using the SuraSeq 500 NGS panel, and all harbored copy number gains (n = 12-15) in MET and corresponding MET pathway activation as shown by RTK arrays and Western blotting. Combining rociletinib with the MET inhibitor crizotinib caused regression of the MET amplified rociletinib-resistant tumors. In separate experiments, the addition of 50 ng/ml exogenous HGF was sufficient to render several mutant EGFR cell lines immediately resistant to rociletinib, and this effect could be overcome with the combination of rociletinib and crizotinib. Finally, the combination of rociletinib and crizotinib also demonstrated potent activity in a patient derived L858R EGFR xenograft model with MET amplification (14 copies). Taken together, these data show that (1) in a PC-9 “front-line” model of mutant EGFR lung cancer, rociletinib has a longer time-to-resistance than erlotinib; and (2) MET/HGF pathway activation is a likely driver of acquired resistance to rociletinib in patients with mutant EGFR lung cancer, and can potentially be successfully prevented and/or treated with a combination of rociletinib plus a MET tyrosine kinase inhibitor. Citation Format: Henry J. Haringsma, Andrew Allen, Thomas C. Harding, Andrew D. Simmons. In vivo acquired resistance to the mutant EGFR inhibitor Rociletinib (CO-1686) is associated with activation of the c-MET pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3595. doi:10.1158/1538-7445.AM2015-3595