Abstract 4006: TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC

Targeting mutated EGFR is a clinically validated approach for tackling non-small cell lung cancer (NSCLC). Approximately 20% of patients with advanced NSCLC harbor an EGFR mutation. Osimertinib is a 3rd-generation oral EGFR-TKI targeting the EGFR sensitizing mutations Del19 and L858R, as well as an acquired mutation, T790M. Despite osimertinib's efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. Development of another mutation, C797S is the most common mechanism of acquired resistance following osimertinib treatment. This mutation occurs with about 12% frequency after a 1L therapy of osimertinib, and with approximately 17% frequency after a 2L therapy. Here, we report TRX-221 as a novel 4th-generation EGFR-TKI that can overcome C797S-mediated acquired resistance in NSCLC models in vitro and in vivo. TRX-221 exhibited potent inhibitory activity against multiple EGFR mutant kinases, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, L858R/C797S, Del19/T790M, L858R/T790M, Del19, and L858R. Likewise, TRX-221 potently inhibited the proliferation of Ba/F3 cells stably overexpressing these eight EGFR mutants. TRX-221 however showed sparing activity against EGFR wild-type kinase and cell lines. TRX-221 also demonstrated marked anti-proliferative activity against osimertinib-resistant patient-derived cancer cell lines (PDCs). With favorable DMPK profiles, once-daily oral dosing of TRX-221 induced strong anti-tumor effects in a dose-dependent manner in a variety of osimertinib-resistant CDX and PDX models. As a reversible, selective, and broad-spectrum 4th-generation EGFR-TKI, TRX-221 is currently undergoing IND-enabling studies and shows strong potential as a therapeutic solution to treat advanced NSCLC patients harboring EGFR mutations. Citation Format: Sumin Lim, Seulgi Choi, Ju-Kyung Lee, Eunhyun Choi, Sungwon Lee, Kwangwoo Chun, Myoungki Baek, Jiyeon Park, Jihyun Kim, Areum Kang, Younghoon Kim, Namkyoung Kim, Byoungchul Cho, Taebo Sim, Koo Lee. TRX-221, a novel 4th-generation EGFR inhibitor for overcoming C797S mutation-mediated acquired resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4006.