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 <1% and 20 ≥1%) out of 43 pts were efficacy evaluable. Overall ORR was 78.0% (32/41). Subgroup ORRs in TPS <1% and ≥1% were 76.2% and 80.0%, respectively. Median PFS and DOR were immature. 6m PFS rate was 68.9% and 6m DOR rate was 77.2%. Above results provide first time evidence of G12Ci monotherapy in 1L NSCLC. In combo, 48 (PD-L1 TPS 22C3: 17 <1%, 11 1-49%, and 20 ≥50%) out of 52 pts were efficacy evaluable. Overall ORR was 81.2% (39/48). Subgroup ORRs in TPS <1%, 1-49%, and ≥50% were 70.6%, 72.7% and 95.0%, respectively. Median PFS and DOR in the overall combo population were immature. 6m PFS rate was 74.6% and 6m DOR rate was 80.5%. Toxicity profile is summarized in Table. Baseline ctDNA G12C+ was detected in 90% (37/41) of mono and 80% (37/46) of combo. 35 mono and 25 combo pts completed on-treatment ctDNA analysis, with 83% and 100% achieved molecular response (≥90% G12C MAF reduction), respectively. PK at 600mg QD achieved C trough exposure of ~5nM and ~3nM with mono and combo, respectively, with overlapping variabilities at steady state, both well above the required exposure (1nM) for complete TE. Conclusions: Both elisrasib monotherapy and in combination with pembrolizumab show strong efficacy and good tolerability as 1L treatments for G12C-mutant NSCLC, warrant for randomized study to evaluate elisrasib as a potential new standard of care. Clinical trial information: NCT05410145 . TRAEs* 1L NSCLC Mono (N=43) 1L NSCLC Combo (N=52) Any Grade 41 (95.3%) 48 (92.3%) ≥G3 3 (7.0%) 17 (32.7%) LFT TRAEs* by PT (≥G3) ALT increased 0 4 (7.7%) AST increased 0 3 (5.8%) *TRAEs for combo cohort is related to elisrasib and/or pembrolizumab.