Abstract 6503: D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities

Abstract

Abstract First-generation KRAS G12C inhibitors [G12Ci(s)], such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its GDP- and GTP-bound states, raising controversy whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a second-generation GDP-bound G12Ci with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at sub-nanomolar concentrations, overcomes nucleotide cycling, and demonstrates durable anti-tumor activities preclinically and in a phase 1 clinical trial (NCT05410145). Covalent efficiency and TE kinetics were measured by SPR, LC-MS and ELISA. Anti-tumor efficacy was assessed in cell line-derived xenograft (CDX) and patient-derived xenograft or organoid (PDX or PDO) models. Activity in brain metastatic tumors and tumors with acquired resistance to sotorasib was investigated. Preclinically, D3S-001 exhibited exceptionally high covalent efficiency with a kinact/KI of 1.43 × 106 M−1s−1, the highest among all reported G12Ci(s) to date and a 20- to 70-fold improvement over adagrasib and sotorasib, respectively. In whole cells, D3S-001 depleted GTP-bound active KRAS G12C with an inactivation t1/2 of 5.8 minutes, allowing >95% TE (5x t1/2) in 30 minutes which is within the time required for epithelial growth factor (EGF) to induce KRAS GDP to GTP transition. By contrast, sotorasib and adagrasib required 3.7 and 2.8 hours, respectively, to reach 95% TE. In the presence of EGF, the ability of sotorasib and adagrasib to block KRAS was compromised by over 55%, whereas TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from earlier GDP-bound G12Ci(s). The covalent efficiency of D3S-001 correlated with robust anti-tumor activity at sub-nanomolar concentrations and durable tumor regressions in CDX and PDX/PDO models of different cancer types. In a sotorasib-resistant PDX model, D3S-001 exhibited robust efficacy of tumor regression, while sotorasib and adagrasib showed no effect. Treatment with D3S-001 also resulted in sustained intracranial tumor remission in brain metastasis models. In the first-in-human trial of D3S-001, durable RECIST responses in patients were observed across all dose cohorts from 50 mg to 900 mg QD. Durable intracranial activity was also observed. Response rate and duration are reported in a companion clinical trial abstract submitted to this AACR meeting. In conclusion, D3S-001 is a second-generation GDP-bound KRAS G12Ci that overcomes GDP-to-GTP cycling. Its high covalent efficiency and rapid TE kinetics correlated with robust anti-tumor activity preclinically and translated into promising clinical activity with a high response rate and durable responses in a phase 1 trial. Citation Format: Jing Zhang, Sun Min Lim, Mi Ra Yu, Cheng Chen, Jia Wang, Wenqian Wang, Haopeng Rui, Jingtao Lu, Shun Lu, Tony Mok, Zhi Jian Chen, Byoung Chul Cho. D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6503.