TSN1611 (KRAS G12D ON/OFF inhibitor) posts 50% ORR and early intracranial activity in metastatic NSCLC

TSN1611 is a highly selective oral small-molecule KRAS G12D inhibitor designed to bind both GTP-bound (ON) and GDP-bound (OFF) KRAS; in a multi-regional Phase 1/2 dose-escalation/optimization study (NCT06385925), metastatic KRAS G12D–mutant NSCLC patients heavily pretreated with chemotherapy and/or PD-(L)1 therapy were treated at 600–1200mg BID. In response-evaluable NSCLC (n=20/26 total NSCLC), ORR was 50% (10 PRs; 95% CI 27.2–72.8) with DCR 90%, median time to response 1.4 months, and a not-yet-mature PFS with a 9-month PFS rate of 54.5% (range 1.3+ to 12.9+ months); this looks meaningfully above typical post–platinum/ICI single-agent docetaxel or docetaxel+ramucirumab activity (historically ORR 10–25% and median PFS ~3–4.5 months, depending on regimen/eligibility). Across all treated solid tumors (n=117), Grade 3 TRAEs were 9.4% (mostly single events), dose interruptions occurred in 17.1% and reductions in 7.7%, with no TRAE-related discontinuations; common TRAEs included GI toxicity (diarrhea 53.0%, nausea 48.7%, vomiting 46.2%) and cytopenias (anemia 17.9%), plus transaminase increases (10–13%).