Telisotuzumab Vedotin (c-Met ADC) shows 100% ORR in KRAS G12C patients and doubled survival in 2L+ MET-high EGFRwt NSCLC

Telisotuzumab vedotin (Teliso-V), a c-Met-targeted ADC bearing the MMAE payload, was given at 1.9 mg/kg Q2W to 83 2nd line+, EGFR-wild-type, c-Met-overexpressing non-squamous NSCLC patients in LUMINOSITY Stage 2 (NCT03539536). 20-25% of NSCLC cases overexpress c-MET. Baseline ctDNA median VAF (2.05%) stratified prognosis: high vs low ctDNA showed identical ORR (28.6%) yet low ctDNA enjoyed longer mPFS (8.1 vs 5.4 mo) and mOS (16.3 vs 8.5 mo). Notably, all five patients with KRAS G12C (13% of all NSCLC cases) achieved responses (100% ORR), while non-actionable KRAS variants responded in 23% (3/13). Week-6 molecular response (≥50% ctDNA fall) predicted higher ORR 35%, mPFS 8.5 mo, and mOS 15.5 mo. Docetaxel ± ramucirumab (a VEGFR2 antagonist)—current SOC after IO/TKI failure—delivers ORR 10–23% and mPFS ~4.5 mo in metastatic NSCLC, indicating Teliso-V’s competitive efficacy with a biomarker-guided edge.