Sevabertinib (HER2 TKI) sustains 67–75% ORR in HER2-mutant NSCLC with no ILD signal

Sevabertinib is a potent, reversible, oral HER2 (ERBB2) tyrosine kinase inhibitor evaluated at 20mg BID in the open-label Phase I/II SOHO-01 trial (NCT05099172) in advanced HER2–tyrosine kinase domain–mutant NSCLC that was either previously treated but HER2-therapy–naïve (Cohort D; n=81) or treatment-naïve (Cohort F; n=73). As of Nov 17, 2025 (median follow-up 19.5 mo D; 15.0 mo F), BICR ORR was 66.7% (D) and 75.3% (F) with mDoR 9.5 mo (D) and 12.2 mo (F) and mPFS 8.3 mo (D) and 13.5 mo (F)—numerically above the typical 2L+ benchmark for trastuzumab deruxtecan in HER2-mutant NSCLC (ORR ~58%, mPFS ~9.9 mo), while the 1L mPFS compares favorably to broad 1L chemo-IO regimens in unselected metastatic nonsquamous NSCLC (mPFS ~8.8 mo) but needs randomized confirmation in the HER2-mutant subset. Grade ≥3 TRAEs occurred in 39.5% (D) and 24.7% (F); diarrhea was common (86–88%) with grade 3 diarrhea 23.5% (D) and 5.5% (F), and there were no ILD cases, no grade 4 diarrhea, and no discontinuations due to diarrhea (a notable differentiator vs ADC-class pneumonitis risk).