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

Document Type

Conference Proceeding

Publication Date

3-5-2026

Publication Title

Cancer Res

Keywords

Oncology

Abstract

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.

Volume

86

Issue

5

First Page

2

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