VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents
Presenter: Jonathan Pachter, PhD Session: Novel Antitumor Agents 3 Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Silvia Coma 1 , Ian Smith 2 , Cristina Caffarra Malvezzi 3 , Clint A. Stalnecker 4 , Emilia Berardelli 3 , Enrico Patrucco 3 , Fusheng Zhou 5 , Channing Der 4 , Chiara Ambrogio 3 , David G. DeNardo 2 , Jonathan A. Pachter 1 1 Verastem Oncology, Needham, MA, 2 Department of Medicine, Washington University School of Medicine, st louis, MO, 3 Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy, 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, 5 Genfleet Therapeutics, Shanghai, China
Abstract
KRAS G12D is the most prevalent KRAS mutation in human cancers, present in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. Currently, there are no FDA-approved RAS inhibitors for patients with KRAS G12D-mutated (mt) cancers. VS-7375 (GFH375) is an oral, selective KRAS G12D dual ON/OFF inhibitor exhibiting extremely high affinity (K D = 12-18 pM) and long residence time (18-24 hours) for the ON and OFF states of human KRAS G12D. VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing across multiple KRAS G12D mt xenograft models representing pancreatic, colorectal and lung cancers. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared efficacy in KRAS G12D mt in vivo models relative to the KRAS G12D ON-only inhibitor zoldonrasib (RMC-9805) and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236). In the KP4 KRAS G12D pancreatic cancer model, VS-7375 (50 mg/kg twice daily orally) showed similar initial tumor regression (through day 9) relative to zoldonrasib (100 mg/kg once daily orally) and daraxonrasib (25 mg/kg once daily orally). However, by approximately 20 days of dosing, zoldonrasib and daraxonrasib progressively lose their anti-tumor activity with associated tumor outgrowth (mean tumor volume >850 mm 3 by day 30) in contrast to those treated with VS-7375 which showed sustained tumor regression (mean tumor volume ~80 mm 3 by day 30). Accordingly, pharmacodynamic analysis with pathway-specific gene signatures showed that whereas all three KRAS inhibitors inhibited MAPK, MYC and PI3K signaling at day 6, only the G12D ON/OFF inhibitor VS-7375 maintained inhibition of these signaling pathways by day 20. VS-7375 also showed deeper tumor regression compared to these RAS ON-only inhibitors in KRAS G12D mt lung and colorectal xenograft models. Currently, we are assessing the anti-tumor efficacy of VS-7375 in combination with other anti-cancer agents including EGFR, PRMT5 and FAK inhibitors. Briefly, the combination of the anti-EGFR antibody cetuximab with VS-7375 induced strong tumor growth inhibition in KRAS G12D mt cancer models. Furthermore, addition of a PRMT5 inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt;MTAP-deleted pancreatic cancer models. Lastly, addition of a FAK inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt cancer models, altogether supporting the potential clinical evaluation of novel combination strategies with VS-7375 in patients with KRAS G12D mt cancers for maximal anti-tumor efficacy and durability. VS-7375 is currently in phase 1/2 clinical evaluation in the US (VS-7375-101; NCT07020221) and in advanced clinical evaluation in China (NCT06500676) as monotherapy and in combination with cetuximab or chemotherapy ± pembrolizumab for patients with KRAS G12D mt cancers.
Disclosure
S. Coma, Verastem Oncology Employment, Stock, Stock Option. I. Smith, None.. C. Caffarra Malvezzi, None.. C. A. Stalnecker, None.. E. Berardelli, None.. E. Patrucco, None. F. Zhou, GenFleet Employment. C. Der, None.. C. Ambrogio, None.. D. G. DeNardo, None. J. A. Pachter, Verastem Oncology Employment, Stock, Stock Option.
Cited in
Control: 7162 · Presentation Id: 8866 · Meeting 21436