Abstract 3063: Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC therapy

Abstract EGFR T790M mutation which renders resistance to the first-generation EGFR inhibitors,accounts for about 50% of all originally responsive non-small cell lung cancer patients. In order to overcome this type of resistance, we have developed a small molecular drug candidate with unique structural features that offer differentiated pharmacological and safety profiles pre-clinically when compared with other leading third-generation EGFR inhibitors. The compound selectively inhibits T790M as well as activating EGFR mutations, with much less inhibition to the wild type EGFR. Enzymatic inhibition IC50 against EGFR T790M,T790M/Del19 and T790M/L858R is less than 1nM. In addition, enzymatic inhibition IC50 against EGFR activating mutations Del19 and L858R is around 1nM, with much less inhibition to the wild type EGFR, a 10-time selection ratio. In cell based assays, the compound potently inhibits proliferation of EGFR T790M mutated NSCLC cell lines H1975(T790M/L858R)and PC9-GR(T790M/Del19)with an IC50 around 3nM. Similarly, it potently inhibits EGFR activating mutant NSCLC cell lines HCC827(Del19)and PC9(Del19). However, the compound displays about 200-fold less sensitivity to the EGFR wild type cancer cell line A431, with an IC50 around 600nM. When dosed to tumor-bearing animals, the compound dose-dependently induces profound regression of xenografts derived from both H1975 and primary human lung cancer LU1868, both of which carry an EGFR T790M mutation. It also induces regression of HCC827 xenografts potently, similarly to the first- and second-generation EGFR inhibitors; whereas it displays much less inhibition to the EGFR wild type A431 xenografts, demonstrating a higher specificity to the mutated EGFR forms when compared with the EGFR inhibitors on market. The drug candidate displays favorable PK and safety profiles. These properties warrant further development of this compound as first- as well as second-line therapy for NSCLC. Citation Format: Rudi Bao, Peng Gao, Fujun Zhang, Zhaolong Tong, Hongping Yu, Yaochang Xu. Discovery of a third-generation EGFR inhibitor, which is highly selective and potent against both resistant and activating EGFR mutations for NSCLC therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3063.