JIN-A02: A Promising Fourth-Generation EGFR-TKI for Overcoming EGFR C797S Triple Mutation Resistance in NSCLC

Researchers have been investigating the novel EGFR TKI, JIN-A02, for its potential in treating non-small cell lung cancer (NSCLC) with EGFR mutations. EGFR mutations are prevalent in about half of Asian NSCLC cases, and resistance to EGFR-targeted therapies usually emerges after a year or so of treatment. The EGFR C797S mutation has been identified as a possible resistance mechanism, and there are currently no targeted therapies for it. JIN-A02 has shown potent anti-tumor activity against double or triple EGFR mutations in preclinical models.

In their experiments, researchers utilized Ba/F3 cell lines and patient-derived cell lines with EGFR mutations to evaluate JIN-A02's inhibitory activity. They also implanted triple-mutant EGFR tumors in mice to test its in vivo efficacy. The results indicated that JIN-A02 significantly inhibited the cellular activity of engineered Ba/F3 cells with mutations ex19del/T790M/C797S and L858R/T790M/C797S. It also demonstrated comparable potency to osimertinib in various EGFR mutations and was effective against rare mutations like L718Q.

JIN-A02 was notably more effective than osimertinib in inhibiting EGFR ex19del/T790M/C797S in a PDC model, while sparing EGFR WT activity. In xenograft mouse models, JIN-A02 showed significant tumor growth inhibition at certain dosages, and in the PDC xenograft model, it led to substantial tumor regression. The antitumor efficacy was dose-dependent, and no significant toxicity was observed.

The study concludes that JIN-A02 could be a promising fourth-generation EGFR TKI with high potency and selectivity, effective against various EGFR mutations, including C797S, and could offer new therapeutic options for patients who have become resistant to previous EGFR TKIs. A first-in-human trial is planned to further evaluate its clinical efficacy and safety.