Abstract 5462: BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC)

Abstract EGFR-activating mutations (Del19 or L858R) are major drivers in NSCLC (~40% in Asian and 10-20% in non-Asian). EGFR-TKIs have brought benefit to NSCLC patients with EGFR mutations, prolonging PFS and increasing quantity of life. Nevertheless, resistance inevitably emerges and leads to disease progression. Acquired EGFR C797S mutation is the most common event underlying resistance to the 3rd generation EGFR-TKIs, and there are no therapies. Herein, we report the discovery of BPI-361175, a 4th generation EGFR-TKI that overcomes EGFR resistant mutations. In vitro, BPI-361175 potently inhibited the activity of a variety of EGFR kinases, including triple (EGFRdel19 or L858R/T790M/C797S), double (EGFRdel19 or L858R/T790M, EGFRdel19 or L858R/C797S) and single (EGFRdel19 or L858R) mutations. Accordingly, BPI-361175 dose-dependently inhibited the phosphorylation of EGFR and the proliferation of cell lines harboring the above-mentioned mutations. Meanwhile, BPI-361175 were not active towards EGFRWT and IGF1R, therefore displayed good selectivity, both in kinase assays and in cell-based assays. In vivo, oral administration of BPI-361175 led to tumor suppression and regression in multiple EGFR mutant models, such as BaF3 EGFRDel19 or L858R/T790M/C797S, BaF3 EGFRDel19/C797S allograft models, and PC9 EGFRDel19/T790M/C797S, NCI-H1975 EGFRDel19/T790M/C797S, NCI-H1975 (EGFRL858R/T790M), HCC827 (EGFRDel19) CDX models, as well as a LDI-0025-200717 (EGFRDel19/T790M/C797S) PDX model. Remarkably, BPI-361175 significantly prolonged the life span of brain orthotropic BaF3 EGFRDel19/T790M/C797S allograft mice, demonstrating activity towards brain metastasis. In conclusion, BPI-361175 is a potent, selective, and orally bioavailable 4th generation EGFR-TKI which can potentially be used to treat NSCLC resistant mutations as well as at front line. Phase I clinical trial of BPI-361175 is enrolling patients in China, and US Phase I trial is expected to initiate in Q1 2022. Citation Format: Lijia Liu, Changyong Qiu, Xiangyong Liu, Yuanyan Lian, Haibo Chen, Xiaodong Song, Qichao Shen, Guolong Du, Jing Guo, Dan Yan, Hong Lan, Lieming Ding, Jiabing Wang. BPI-361175, a 4th generation EGFR-TKI for the treatment of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5462.