Discovery of a novel potent EGFR inhibitor against EGFR activating mutations and on-target resistance in NSCLC

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard first-line therapy for EGFR-mutated non-small-cell lung Cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available post-progression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios.

Experimental design: The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/Organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model.

Results: We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood-brain barrier (BBB).

Conclusions: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high BBB penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.