Abstract CT020: Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in advanced non-small cell lung cancer (NSCLC) previously treated with or without a KRAS G12C inhibitor: Results from a phase 1/2 study

Abstract Background: Elisrasib 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 first-generation G12Ci and has led to robust anti-tumor activity in G12Ci-naïve/-resistant PDX models. Ph1 results demonstrated favorable safety and promising efficacy across NSCLC, CRC and PDAC. Here, we present updated findings in previously treated locally advanced or metastatic NSCLC patients (pts) (naïve and refractory to G12Ci) from the ongoing Ph1/2 trial (NCT05410145). Methods: Pts with locally advanced or metastatic KRAS G12C-mutated NSCLC were eligible. All pts must had received at least one prior line of systemic treatment, including IO and/or platinum doublet chemotherapy. For G12Ci-refractory pts, they were required to have radiologically or clinically documented PD following a KRAS G12Ci. Elisrasib was administered orally QD in 21-day cycles at 6 planned dose levels (50-900mg) in the dose escalation and 600mg was selected as the treatment dose for expansion cohorts. The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy (Guardant360® CDx or OncoCompass® Target). Results: As of 06 Jan 2026, total 165 NSCLC pts across 9 countries received elisrasib monotherapy (2 in 50mg, 5 in 100mg, 4 in 200mg, 6 in 400mg, 144 in 600mg and 4 in 900mg). Median study follow up time for 2L+ G12Ci-naive and G12Ci-refractory NSCLC were 11. 3m and 10. 6m, respectively. TRAEs of any grade occurred in 143/165 (87. 9%) pts, ≥G3 TRAEs occurred in 19/165 (11. 5%) pts. The safety profile in NSCLC pts is comparable with overall population. In 2L+ G12Ci-naïve NSCLC (50-900mg QD), 84 pts were evaluable for efficacy. ORR was 57. 1% (48/84) with 1 CR and DCR of 98. 8%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8. 8m, 12. 5m, and 67%, respectively. At 600mg QD (68 evaluable pts), ORR was 55. 9% (38/68) with 1 CR and DCR of 98. 5%. mPFS, mDOR and 12m OS rate (OS was not matured) were 11. 8m, 14. 9m, and 71%, respectively. In 2L+ G12Ci-refractory NSCLC (600mg QD), 31 pts were evaluable for efifcacy. ORR was 32. 3% (10/31) and DCR of 83. 9%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8. 1m, 8. 2m, and 69%, respectively. PK at 600mg QD achieved Ctrough exposure (5. 6 nM) which was 5x greater than required exposure (1 nM) for complete TE. Baseline ctDNA G12C+ was detected in 68% (54/80, 4 pts were excluded due to incomplete data) of G12Ci-naïve and 68% (21/31) G12Ci-refractory pts, with 93% (50/54) and 76% (16/21) achieved molecular response (≥90% G12C MAF reduction), respectively. Notably, 4/5 G12Ci-refractory pts with G12C amplification, a known resistant MoA, showed tumor shrinkage, including three achieved cPR. Conclusions: Elisrasib monotherapy demonstrates robust and durable efficacy and favorable tolerability in 2L+ NSCLC pts, naïve and refractory to G12Ci. Citation Format: Byoung Chul Cho, Shun Lu, Ziming Li, John Park, Jun Zhao, Herbert Ho Fung Loong, Antoine Hollebecque, Bin Yang, Binchao Wang, Cheng Chen, Jia Wang, Shaonan Wang, Yandong Shen, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, George Zhi Jian Chen, Melissa Johnson, Tony Shu Kam Mok. Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in advanced non-small cell lung cancer (NSCLC) previously treated with or without a KRAS G12C inhibitor: Results from a phase 1/2 study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT020.