Abstract CT060: First in human phase 1 study of D3S-002, a purposely designed ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations

Abstract Background: D3S-002 is a potent, selective oral ERK1/2 inhibitor, purposefully designed as a combination partner for KRAS G12X inhibitors to overcome feedback MAPK activation induced by these agents. In KRAS G12Ci resistant models, D3S-002 combined with D3S-001, a next-generation KRAS G12Ci, demonstrated significantly improved efficacy compared with either D3S-001 or D3S-002 alone, supporting clinical evaluation of this combination. Methods: This ongoing phase 1/2, open-label, dose-escalation and dose expansion study (NCT05886920) was designed to evaluate safety, tolerability, pharmacokinetics (PK) and recommended phase 2 dose of D3S-002 monotherapy or combination therapy in adult patients with advanced solid tumors harboring MAPK pathway mutations. The dose escalation part of D3S-002 monotherapy has been completed. The PK and safety profiles were evaluated with D3S-002 QD at 8 dose levels from 10mg to 240mg under BOIN design. Results: Thirty-two patients were enrolled in the dose escalation part of D3S-002 monotherapy across 10 sites in the US (n=2), Australia (n=15), and China (n=15). The No. of patients receiving 10mg, 20mg, 40mg, 60mg, 90mg, 135mg, 180mg or 240mg D3S-002 QD were 3, 3, 3, 3, 5, 3, 6, 6 respectively. The median duration of exposure was 1.3m (0.2-5.6). D3S-002 exhibits a dose-proportional PK profile with dose-dependent exposure increases from 10 mg to 240 mg QD and minimal accumulation after repeated dosing. Tmax was 1-3 hours, and terminal half-life of ∼3-5 hours was consistent across dose levels. This PK behavior aligns with D3S-002’s intentionally designed preclinical pharmacology, supporting pulsatile ERK inhibition that allows drug-free intervals in normal tissues while maintaining effective MAPK pathway suppression in tumors with elevated ERK activity. D3S-002 was well tolerated, with ≥Grade 3 TRAEs observed in 18.8% (6/32) of patients. No Grade 5 TRAEs were reported. TRAEs occurred in ≥10% of patients including AST/ALT increase and nausea. No significant correlation was observed between PK and changes in liver enzymes. Unlike other ERKi(s), skin toxicities (dermatitis acneiform: 6.5%, rash: 3.1%) and ocular toxicities (6.5%) are uncommon. The maximum tolerated dose was reached at 240 mg QD. Among 27 efficacy evaluable patients, the DCR was 25.9%. Tumor shrinkage was observed in 3 patients, including 1 unconfirmed partial response (PR). Guided by PK/safety profile, D3S-002 combination with D3S-001 will be initiated at 40 mg QD. Conclusions: D3S-002 demonstrates predictable, dose-proportional PK consistent with its preclinically designed pulsatile exposure profile, supporting its development as an optimal ERKi partner for synergistic combination with other MAPK pathway-targeted therapies. A clinical study evaluating D3S-002 in combination with D3S-001 for the treatment of patients with KRAS G12C-mutant NSCLC is currently underway. Citation Format: Yi-Long Wu, Michael Millward, Yanqiao Zhang, Matteo S. Carlino, Xian Wang, Amitesh Roy, Jun Zhang, Jun Zhao, Zhen Wang, Amy Weise, Debora Doroshow, Shaonan Wang, Zifei Fan, Rong Su, Jing Zhang, Jia Wang, Wenqian Wang, Cheng Chen, Qian Chen, Hui Wang, Zhijian Chen. First in human phase 1 study of D3S-002, a purposely designed ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations [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 CT060.