Abstract CT303: Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy or combination therapy with cetuximab in previously treated metastatic CRC and PDAC: 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. Elisrasib exhibits robust anti-tumor activity in PDX models including CRC and PDAC. In CRC, combination with cetuximab further enhanced the depth of response by mitigating MAPK pathway reactivation driven by EGFR. Here, we report findings of elisrasib in previously treated metastatic G12Ci-naïve CRC and PDAC as monotherapy or in G12Ci-naïve CRC as combination therapy (with cetuximab) from the ongoing Ph1/2 trial (NCT05410145). Methods: Patients (pts) with locally advanced or metastatic KRAS G12C-mutated CRC and PDAC were eligible. Elisrasib is administered orally QD in 21-day cycles at 50-900mg as monotherapy (mono) and at 600mg as combination therapy (combo) with cetuximab (400 mg/m2 loading dose then 250 mg/m2 weekly). The key objectives included safety, efficacy, and ctDNA by liquid biopsy (Guardant360® CDx or OncoCompass® Target). Results: As of 06 Jan 2026, total 70 pts (47 CRC and 23 PDAC) across 9 countries received elisrasib mono (CRC: 2 in 100mg, 1 in 200mg, 2 in 400mg, 38 in 600mg, 4 in 900mg; PDAC: 1 in 50mg, 1 in 400mg, 20 in 600mg, 1 in 900mg) and 31 pts CRC had received elisrasib combo. Median study follow-up was 17m for mono CRC, 7.6m for mono PDAC, 12.4m for combo CRC, respectively. In mono CRC arm, 41/47 (87.2%) pts had any grade TRAEs, 8/47 (17.0%) pts had G3 TRAEs. In mono PDAC arm,14/23 (60.9%) pts had any grade TRAEs, 2/23 (8.7%) pts had G3 TRAEs. In combo CRC arm, 31/31 (100%) pts had any grade TRAEs, 15/31 (48.4%, including 19.4% related to elisrasib) pts had G3 TRAEs. Most Grade 3 TRAEs were Cetuximab induced skin toxicities. Of total 101 pts, no G4/5 TRAEs. In mono CRC (100-900mg), 36 pts were evaluable for efficacy. ORR was 47.2% (17/36) with 1 CR and DCR of 86.1%. mPFS, mDOR and 12m OS rate (OS not matured) were 8.5m, 13.1m, and 83%, respectively. At 600 mg (31 evaluable pts), ORR was 45.2% (14/31) with 1 CR and DCR of 87.1%. mPFS, mDOR and 12m OS rate (OS not matured) were 9.5m, 13.1m, and 83%, respectively. In mono PDAC (50-900mg), 22 pts were evaluable for efficacy. ORR was 68.2% (15/22) and DCR of 95.5%. mPFS, mDOR and 12m OS rate (OS not matured) were 11.1m, 8.4m, and 78%, respectively. At 600 mg (19 evaluable pts), ORR was 63.2% (12/19) and DCR of 94.7%. mPFS, mDOR and 12m OS rate (OS not matured) were 13.5m, 10.8m, and 93%, respectively. In combo CRC (600mg), 29 pts were evaluable for efficacy. ORR was 62.1% (18/29) with 1CR and DCR of 96.6%. mPFS, mDOR and 12m OS rate (OS not matured) were 8.2m, 6.9m, and 92.6%, respectively. PK at 600mg QD achieved Ctrough exposure (3.1 nM) which was 3x greater than required exposure (1 nM) for complete TE, and remains similar between mono and combo. Baseline ctDNA G12C+ was detected in 86% (31/36) of CRC mono, 93.1% (27/29) of CRC combo and 78% (16/20) of PDAC mono pts, with 77% (24/31), 96% (26/27) and 75% (9/12) achieved molecular response (≥90% G12C MAF reduction), respectively. Conclusions: Elisrasib with or without cetuximab has demonstrated promising efficacy and favorable tolerability in pts of 2L+ CRC and PDAC naïve to G12Ci. Citation Format: Kanwal Pratap Raghav, Jun Zhang, Myung-Ah Lee, Jingdong Zhang, John Park, Yanqiao Zhang, Susana Rosello Keranen, Byoung Chul Cho, Herbert Ho Fung Loong, Cheng Chen, Huan Li, Shaonan Wang, Yandong Shen, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, George Zhi Jian Chen, Jayesh Desai, Antoine Hollebecque. Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy or combination therapy with cetuximab in previously treated metastatic CRC and PDAC: 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(8_Suppl):Abstract nr CT303.