JIN-A02, a Mutant-Selective Fourth-Generation EGFR Inhibitor, Overcomes C797S-Mediated Resistance and Demonstrates Intracranial Activity in NSCLC

PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) have revolutionized the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations. However, acquired resistance-particularly the EGFR C797S mutation-remains a major clinical challenge. As no approved targeted therapies are available following disease progression on the third-generation EGFR-TKI osimertinib, this study aimed to evaluate JIN-A02, a novel fourth-generation EGFR-TKI, as a therapeutic strategy to overcome C797S-mediated resistance. EXPERIMENTAL DESIGN: JIN-A02, a fourth-generation EGFR TKI, was evaluated for its antitumor efficacy and blood-brain barrier penetration in in vitro and in vivo models of NSCLC harboring EGFR C797S and T790M mutations. RESULTS: JIN-A02 demonstrated potent antiproliferative activity in preclinical NSCLC models harboring EGFR C797S and T790M mutations, with superior inhibition of EGFR signaling compared with osimertinib. In both subcutaneous and orthotopic intracranial xenograft models, JIN-A02 elicited substantial tumor regression, indicating robust in vivo efficacy. The agent was well tolerated throughout the treatment period without notable toxicity. In line with preclinical data, early clinical trial data showed signs of efficacy, including three patients showing partial response. CONCLUSIONS: These findings highlight JIN-A02 as a promising therapeutic strategy to overcome C797S- and T790M-mediated resistance in EGFR-mutant NSCLC, including intracranial disease, and support its further clinical development.