YH42946, a novel and selective tyrosine kinase inhibitor, demonstrates potent antitumor activity against EGFR exon 20 insertion mutations and HER2 alterations in NSCLC

EGFR exon 20 insertion mutations and HER2 alterations are oncogenic drivers in non–small cell lung cancer (NSCLC) with limited therapeutic options. YH42946 is an orally available tyrosine kinase inhibitor designed to selectively target these alterations while sparing EGFR wild-type. Here, we evaluated the in vitro and in vivo antitumor efficacy of YH42946. YH42946 potently inhibited cell viability in Ba/F3 models expressing EGFR exon 20 variants (ASV, SVD, GY; IC 50 < 10 nM, HH; IC 50 < 15 nM) and in patient-derived cells (IC50 < 20 nM), with minimal activity in EGFR wild-type cells (IC 50 > 1000 nM), and showed favorable or comparable activity to reference TKIs. It also exhibited potent activity in HER2 -altered models (YVMA, GSP, VC; IC 50 < 10 nM). Mechanistically, YH42946 demonstrated potent antitumor activity in CDX/PDX models, inducing significant tumor regression and effectively inhibiting phospho-EGFR/HER2 signaling. High-dose (50 mg/kg and 60 mg/kg) groups achieved near-complete tumor eradication, and strong, dose-dependent efficacy was also observed in an intracranial HER2 model, confirming CNS penetration. These results support YH42946 as a promising best-in-class candidate for EGFR exon 20 insertion mutations and HER2 alteration NSCLC, currently under phase I clinical evaluation (NCT06616766).