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-TKIs) 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.

[METHODS] 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 to 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 3 patients showing partial response.

[CONCLUSION] 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.