Abstract A005: D3S-002: A Purposefully Designed ERK1/2 Inhibitor Achieving Low-Dose, Pulsatile Target Inhibition for Combination with D3S-001, a New-Generation KRAS G12C Inhibitor

Recent genome-wide screens have identified ERK as a central signaling hub in KRAS-mutant tumors and a key driver of resistance to KRAS-targeted therapies. However, prior clinical development of ERK1/2 inhibitors has been hindered by narrow therapeutic windows and on-target toxicity. Consequently, achieving clinical success in targeting this critical kinase has long been a major challenge in oncology. With the modest durability of first-generation KRAS G12C inhibitors (G12Ci), combining ERK1/2 inhibitors with G12Ci represents a strong mechanistic approach. Notably, analyses of post-progression tumor tissue and ctDNA from G12Ci-refractory patients revealed diverse resistance mechanisms converging on ERK1/2, further supporting this combination strategy. We hypothesize that effective combination therapy requires a potent, selective G12Ci as the foundation, with the ERK1/2 inhibitor primarily suppressing non–KRAS G12C–mediated feedback rather than compensating for incomplete inhibition by suboptimal G12Ci. D3S-001, a next-generation G12Ci achieving complete target coverage at its clinical dose, has demonstrated robust activity in NSCLC patients who are G12Ci-naïve (ORR 67%, DCR 100%) or previously treated with other G12C inhibitors (ORR 30%, DCR 80%). These findings support evaluating whether ERK1/2 inhibition can further improve outcomes in G12Ci-refractory disease. D3S-002 is an ERK1/2 inhibitor purposefully optimized as a combination partner for D3S-001. It shows potent enzymatic inhibition, high selectivity, a target-residence t1/2 of ∼30 minutes and a plasma PK t1/2 of 1–4 hours across species. This profile enables pulsatile ERK blockade, allowing drug-free intervals in normal tissues while maintaining effective MAPK pathway suppression in G12Ci–pretreated tumors with elevated ERK signaling. In preclinical xenograft models resistant to first-generation G12Ci, D3S-001 monotherapy achieved tumor stasis, whereas the addition of D3S-002 induced marked tumor regression with minimal body-weight loss. In resistance models driven by KRAS amplification, low-dose D3S-002 (25 mg/kg QD) combined with D3S-001 significantly extended disease control compared with D3S-001 alone, supporting clinical evaluation of this combination strategy. The safety and PK of D3S-002 were evaluated in a global Phase 1 trial (NCT05886920) enrolling 32 patients in the United States (n=2), Australia (n=15), and China (n=15). D3S-002 was well tolerated, with Grade ≥3 treatment-related adverse events in 18.8% (6/32), and a MTD of 240 mg QD. PK analyses showed transient Cmax pulses (Tmax 1–3 hours), near-zero Ctrough, and a plasma t1/2 of 2–4 hours, consistent with the intended pulsatile profile. These results demonstrate that D3S-002’s preclinical design has translated into favorable tolerability and the desired PK characteristics, supporting its development as a clinical combination partner for D3S-001. A Phase I/II proof-of-concept study evaluating the D3S-002/D3S-001 combination in KRAS G12C–mutant NSCLC patients who progressed on prior G12Ci therapy is now in preparation. Citation Format: Jing Zhang, Wenqian Wang, Zhiqiang Zheng, Xin Xiong, Shaonan Wang, Jia Wang, Zifei Fan, Hui Wang, Qian Chen, Cheng Chen, Michael Millward, Zhen Wang, Jun Zhao, Jun Zhang, Amy Weise, Rong Su, Zhi Jian Chen, Yi-Long Wu. D3S-002: A Purposefully Designed ERK1/2 Inhibitor Achieving Low-Dose, Pulsatile Target Inhibition for Combination with D3S-001, a New-Generation KRAS G12C Inhibitor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A005.