Phase 1 D3S-003 dual-state KRAS G12D inhibitor (targets GDP- and GTP-bound KRAS)

This first-in-human, open-label Phase 1 study evaluates D3S-003 monotherapy in adults with advanced/metastatic solid tumors harboring a KRAS p.G12D mutation, focusing on safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary anti-tumor activity. The trial uses sequential dose escalation with once-daily dosing (Part 1a) and twice-daily dosing (Part 1b) to identify dose-limiting toxicities and define a recommended dose for later development. D3S-003 (D3 Bio (Wuxi) Co., Ltd) is an oral, allele-specific KRAS G12D small-molecule inhibitor reported to bind both KRAS “OFF” (GDP-bound) and “ON” (GTP-bound) states—an angle meant to broaden pathway suppression beyond OFF-state-only approaches. The eligible population is molecularly defined rather than tumor-type-specific; clinically, KRAS G12D is especially common in pancreatic ductal adenocarcinoma (35–45%) and occurs in a minority of colorectal cancers (10–15%), making this a commercially significant target if efficacy translates. Today’s care for progressed KRAS G12D solid tumors is largely tumor-specific chemotherapy/targeted therapy where available (and immunotherapy in biomarker-selected settings), with clinical trials often the main option after standard regimens fail.