First in Human Phase 1 Study of D3S-002, a Purposely Designed ERK1/2 Inhibitor, in Advanced Solid Tumors with MAPK Pathway Mutations

Document Type

Conference Proceeding

Publication Date

4-17-2026

Publication Title

Cancer Res

Keywords

Oncology

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.

Volume

86

Issue

8

First Page

CT060

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