VS-7375

Overview

VS-7375 (GFH375) is an oral, small-molecule KRAS G12D inhibitor designed to bind both the active (GTP-bound, “ON”) and inactive (GDP-bound, “OFF”) states. It is being co-developed by Verastem Oncology (ex‑Greater China rights) and GenFleet Therapeutics (China). A first‑in‑human Phase 1/2 study is ongoing in China (NCT06500676), and a U.S. Phase 1/2a trial was initiated in June 2025 after IND clearance in April 2025. (trial.medpath.com)

Mechanism of action

GFH375/VS‑7375 selectively targets KRAS G12D and inhibits signaling by binding KRAS in both ON and OFF conformations, aiming for more complete pathway suppression than state‑selective agents. Preclinical data show potent, selective anti‑tumor activity across KRAS G12D models, phospho‑ERK inhibition, oral bioavailability, intracranial activity in mouse models, and enhanced efficacy in combination with a RAF/MEK clamp (avutometinib) or with cetuximab. (aacrjournals.org)

Clinical development

• China Phase 1/2 (NCT06500676): Multicenter, open‑label; dose escalation/expansion in advanced solid tumors with KRAS G12D mutations; target enrollment ~390; recruiting across ~20 sites. (trial.medpath.com)
• U.S. program: IND cleared April 23, 2025; Phase 1/2a in advanced KRAS G12D–mutant solid tumors initiated June 2025. (investor.verastem.com)

Efficacy

Early, investigator‑reported results from the China Phase 1 dose‑escalation (data cut May 16, 2025; efficacy‑evaluable cohorts at 400–600 mg QD):
- Pancreatic ductal adenocarcinoma (PDAC): ORR 52% (23 evaluable); DCR 100%.
- Non‑small cell lung cancer (NSCLC): ORR 42% (12 evaluable); DCR 83%. (investor.verastem.com)

Subsequent late‑breaking abstract (WCLC 2025; data cut July 15, 2025) in NSCLC reported higher response rates with more follow‑up: ORR 68.8% at the recommended Phase 2 dose and 57.7% across all dose levels (n=28 NSCLC; median follow‑up 4.5 months). These findings are preliminary and conference‑abstract–level. (investor.verastem.com)

Note: No peer‑reviewed, full clinical manuscripts were identified as of October 7, 2025.

Safety

In the China Phase 1 population (data cut March 31, 2025; 100–900 mg QD), no dose‑limiting toxicities were observed; treatment‑related adverse events were mostly Grade 1–2. Most common TRAEs (≥20%): diarrhea, nausea, vomiting, anemia. Grade ≥3 TRAEs included decreased neutrophil count (8%) and diarrhea (5%). (investor.verastem.com)

Further reading

• AACR 2025 abstract: preclinical mechanism and combination data for GFH375 (VS‑7375). (aacrjournals.org)
• AACR 2024 news release summarizing preclinical results. (prnewswire.com)
• China Phase 1/2 trial record (NCT06500676) with study design and status. (ichgcp.net)
• Verastem press release summarizing ASCO 2025 rapid oral data (ORR in PDAC/NSCLC) and U.S. IND clearance. (investor.verastem.com)
• WCLC 2025 late‑breaking abstract notice for NSCLC efficacy update. (investor.verastem.com)

Cautious interpretation is warranted: efficacy and safety data are from early‑phase, conference‑level disclosures and may evolve with ongoing dose expansion, longer follow‑up, and peer‑reviewed publication.

Last updated: Oct 2025