Elisrasib (D3S-001) GDP-bound KRAS G12C inhibitor drives 78%–81% ORR in 1L KRAS G12C NSCLC (±pembrolizumab)

Elisrasib (D3S-001) is an oral next-generation KRAS G12C inhibitor designed to bind the GDP-bound state to improve target engagement and resist growth factor–driven nucleotide exchange, evaluated in a Phase 1/2 study (NCT05410145) as first-line therapy for advanced KRAS G12C–mutant NSCLC at 600mg QD either as monotherapy (n=43; 41 evaluable) or with pembrolizumab 200mg q3w (n=52; 48 evaluable). ORR was 78.0% (32/41) with monotherapy (TPS <1%: 76.2%; ≥1%: 80.0%) and 81.2% (39/48) with the combo (TPS <1%: 70.6%; 1–49%: 72.7%; ≥50%: 95.0%); 6-month PFS rates were 68.9% (mono) and 74.6% (combo), with median PFS/DOR immature—response depth signals look well above typical 1L pembrolizumab+chemo benchmarks (e.g., ORR ~48% in KEYNOTE-189) and also above reported 1L adagrasib+pembrolizumab activity (KRYSTAL-7 ORR 44.3%), albeit with far shorter follow-up here. Safety: any-grade TRAEs were 95.3% (mono) and 92.3% (combo); grade ≥3 TRAEs were 7.0% vs 32.7%, with grade ≥3 ALT/AST increases 0%/0% (mono) vs 7.7%/5.8% (combo), echoing the known liver-toxicity watchout when KRAS G12C inhibitors are paired with PD-1 blockade; ctDNA dynamics were supportive (molecular response ≥90% MAF reduction in 83% mono and 100% combo among those tested).