Abstract CT117: A phase 1 study of D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, as monotherapy in patients with KRAS G12C-mutated solid tumors

Abstract Background: D3S-001 is a second-generation (2G) GDP-bound KRAS G12C inhibitor (G12Ci). Its high covalent potency and rapid target engagement kinetics correlated with robust anti-tumor activity preclinically and translated into promising clinical activity in a phase 1 first-in-human trial (FIH). Here we report clinical data from D3S-001 FIH trial (NCT05410145). Methods: D3S-001 was administered as monotherapy to patients (pts) with KRAS G12C mutated advanced solid tumors at 6 planned dose levels (50-900mg QD) from 3 countries. The key objectives were safety, PK, antitumor activity, and ctDNA kinetics. Results: As of 6 Feb 2024, a total of 41 pts (25 non-small cell lung cancer [NSCLC], 12 colorectal cancer [CRC] and 4 pancreatic cancer [PDAC]) were dosed. Median follow-up was 5.1 months (m, range 0.2-15.4m) and 28 pts (68.3%) remain on-study treatment. No treatment-related DLT or deaths were observed. Treatment-related AEs (TRAE) of any grade occurred in 30 pts (73.2%). Of which, 6 (14.6%) were Grade 3 (no Grade 4 or higher). D3S-001 dose was modified in 11 pts (26.8%) due to TRAE, and no pts had dose discontinuation due to TRAE. PK analysis indicates dose/exposure linearity and terminal plasma T1/2 of ~11 hours. Of 37 pts with post-baseline tumor assessments, 33 were naïve to G12Ci and 4 were G12Ci pre-treated. In 33 G12Ci naïve pts, PRs were achieved in 25/33 overall population (75.8%, 95% CI 57.7, 88.9%), in 14/20 NSCLC pts (70.0%, 95% CI 45.7, 87.2%), in 7/9 CRC pts (77.8%, 95% CI 40.2, 96.1%), and in 4/4 PDAC pts (100.0%, 95%CI 39.6, 100.0%). CNS efficacy was observed in 2/6 NSCLC pts. Of all G12Ci naive pts (n=36), 6-month PFS rate is 69.1% (95% CI 46.3, 83.7%), but median PFS and DoR are not yet mature. Deeper tumor reductions were observed in 5 out of 9 G12Ci naïve pts after intra-subject dose escalation. All 4 G12Ci pre-treated pts (2 NSCLC, 2 CRC) showed stable disease at the first post-baseline assessment. Serial assessment of ctDNA showed significant declines in G12C VAF as early as on Day 8 of treatment. 600mg QD was selected as RP2D. Conclusions: D3S-001, a 2G G12Ci, is well tolerated and delivers promising anti-tumor activity in pts with NSCLC, CRC, and PDAC carrying KRAS G12C mutation across all dose levels in FIH trial. Citation Format: Byoung Chul Cho, Shun Lu, Myung Ah Lee, Zhengbo Song, John Park, Sun Min Lim, Ziming Li, Jun Zhao, Gary Richardson, Yanqiao Zhang, Jun Zhang, Anwen Liu, Cheng Chen, Jia Wang, Jingtao Lu, Haopeng Rui, Qian Chen, Hui Wang, Jing Zhang, Zhi Jian Chen, Tony Mok. A phase 1 study of D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, as monotherapy in patients with KRAS G12C-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT117.