Abstract B185: TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent front mutation G2032R and gatekeeper mutation L2026M

The fusion kinases of ROS1and ALK have been identified as oncogene drivers in small portions of many malignancies, especially in non-small cell lung cancer (NSCLC). ALK/ ROS1/MET inhibitor crizotinibhas been approved by the US Food and Drug Administration for the treatment of ALK or ROS1-positive non-small cell lung cancer in 2011 and 2016, respectively. The emergence of drug resistance presents a major issue for targeted therapy. Although ceritinib, alectinib, and brigatinibhave been approved for crizotinib-refractory ALK + patients with NSCLC, treatment options for patients with ROS1+ NSCLC are limited, especially for crizotinib-refractory patients. Ceritiniband entectinib demonstrated clinical efficacy only in crizotinib-naive ROS1+ patients. The most common resistance mechanisms to crizotinibtreatment in ROS1+ NSCLC is the solvent front mutation ROS1G2032R and gatekeepermutation ROS1L2026M. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ROS1inhibitors in the clinic, was designed to overcome clinical resistance mutationssystematically. TPX-0005 potently inhibited both wild type and mutant ROS1sincluding solvent front mutations and gatekeepermutations. TPX-0005 showed pico-molar activity against ROS1kinase (IC 50 0.076 nM) in Reaction Biology kinase assay. The comparison of TPX-0005 with other ROS1inhibitors in Ba/F3 cell proliferation assays is presented in the table. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated ROS1 fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme ROS1inhibitor against WT and various mutated ROS1s. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116). ND: not determined. Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John Lim, Yishan Li. TPX-0005, a supreme ROS1inhibitor, overcomes crizotinib-resistant ROS1mutations including solvent front mutation G2032R and gatekeepermutation L2026M [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B185.