Elisrasib (D3S-001), a next-generation GDP-bound KRAS G12C inhibitor, as first-line therapy for KRAS G12C mutation–positive non–small cell lung cancer (NSCLC).

8511 Background: Elisrasib (D3S-001) is a next-generation KRAS G12C inhibitor (G12Ci) designed to improve target engagement (TE) efficiency and overcome growth factor-induced nucleotide exchange. This unique MoA distinguishes elisrasib from prior G12Ci and has demonstrated robust and durable anti-tumor activity in PDX models, and in combination with immunotherapy (IO) in immunocompetent models. Current ongoing phase 1/2 trial (NCT05410145) evaluates elisrasib as monotherapy (mono) or combination (combo) with pembrolizumab as first line (1L) therapy for advanced NSCLC harboring G12C mutation. Methods: Treatment naïve patients (pts) with G12C mutant advanced stage NSCLC were eligible. Elisrasib is administered 600mg QD orally in a 21-day cycle as mono or combo with pembrolizumab i.v. 200mg Q3W. The key objectives included safety and efficacy. ctDNA dynamic was analyzed by Guardant360 CDx or OncoCompass Target panels. Results: As of 06 Jan 2026, 43 pts and 52 pts received mono and combo. Median study follow up was 8.5m and 5.7m in mono and combo, respectively. In mono, 41 (PD-L1 TPS [22C3]: 21