Abstract 793: Insulin-like growth factor 1 (IGF1R)/insulin receptor (INSR) inhibitory activity of rociletinib (CO-1686) and its metabolites in nonclinical models
Authors: Simmons Andrew D. , Jaw-Tsai Sarah , Haringsma Henry J. , Allen Andrew , Harding Thomas C. 
Published: August 2015

Abstract
Rociletinib (CO-1686) 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). Adverse events (AEs) typical of wild-type EGFR inhibition, such as cutaneous toxicities, have not been observed. The most frequent AE in patients dosed with rociletinib is hyperglycemia (32% all grades/14% grade 3), which is typically managed with oral hypoglycemic therapy. Rociletinib does not directly play a role in hyperglycemia based on kinase and cellular profiling, toxicology studies performed in Sprague-Dawley rats and beagle dogs, and an oral glucose tolerance test (OGTT) in Sprague-Dawley rats. We examined the hypothesis that hyperglycemia may result from a metabolite of rociletinib. Metabolite profiling from in vitro hepatocyte incubations, as well as the analysis of plasma samples from healthy subjects and NSCLC patients, revealed three metabolites of interest referenced according to their protonated molecular ion: M460, M502, and M544. Metabolites M460 and M502 are present in higher levels in humans than in rats and dogs, whereas M544 levels are comparable between human and rat. In patients the levels of M502 are at least 5-fold greater than that of M460. All 3 metabolites demonstrated limited potency against EGFR, T790M EGFR, and HER2. Expanded cellular profiling revealed that M460 and M502 have 2-3 fold and 3-7 fold greater potency against INSR and IGF1R, respectively, as compared to rociletinib, whereas metabolite M544 demonstrated similar or reduced potency. Metabolite profiling in rats suggests that M502 is rapidly converted to M544 by acetylation, thus a rat OGTT was performed with a single dose of M502 at 1000 mg/kg to reach exposure levels comparable to those observed in rociletinib treated NSCLC patient samples. Metabolite M502 caused significant elevations in post-prandial glucose and insulin excursion. Taken together, the increased potency of M502 towards IGF1R and INSR, its absolute exposure in humans and the rat OGTT results suggest that M502 is likely to play a causative role in the hyperglycemia observed in patients. Additional data on the clinical implications of these findings, as well as the role of IGF1R pathway activation in resistance to EGFR inhibitors, will be presented.
Citation Format: Andrew D. Simmons, Sarah Jaw-Tsai, Henry J. Haringsma, Andrew Allen, Thomas C. Harding. Insulin-like growth factor 1 (IGF1R)/insulin receptor (INSR) inhibitory activity of rociletinib (CO-1686) and its metabolites in nonclinical models. [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 793. doi:10.1158/1538-7445.AM2015-793