Microscopic image of non-small cell lung cancer – Generated with Google Gemini AI
Updated clinical data from a phase 1/2 study (NCT07020221) in China of the investigational oral KRAS G12D inhibitor, VS-7375 (GFH375), have demonstrated compelling efficacy in patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12D mutation.1 The findings, which represent a significant increase in response rates from previously reported data, are scheduled for presentation at the IASLC 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain. The data highlight the potential of this agent in a patient population with high unmet clinical need.
The study, a collaboration between Verastem Oncology and GenFleet Therapeutics, provides the latest insights into the clinical profile of VS-7375, a dual “ON/OFF” KRAS G12D inhibitor. According to the late-breaking abstract, the objective response rate (ORR) at the recommended phase 2 dose of 600 mg once daily was 68.8% (n = 11/16).
“These data at WCLC build on the encouraging data presented at [the American Society of Clinical Oncology (ASCO) Annual Meeting] earlier this year, where GenFleet initially reported an ORR of 42% in 12 patients with advanced non-small cell lung cancer harboring a KRAS G12D mutation,” said Dan Paterson, president and chief executive officer of Verastem Oncology, in a press release.
Across all dose levels in the NSCLC cohort, the ORR was 57.7% (n = 15/26), with a disease control rate (DCR) of 88.5% (n = 23/26). All patients in the NSCLC cohort had metastatic disease at baseline, with the vast majority (64.3%) having received at least 2 prior lines of systemic therapy and nearly all (96.4%) having been previously treated with an anti–PD-1/PD-L1 agent. These patient characteristics underscore the advanced and heavily pretreated nature of the study population, making the observed response rates particularly encouraging.
The phase 1/2 trial, initiated in July 2024, included a total of 142 patients across multiple tumor types,2 with a median follow-up time of 4.5 months as of the July 15, 2025, data cutoff.1 The study population was composed of patients with advanced NSCLC, pancreatic ductal adenocarcinoma (PDAC), and other solid tumors, with 28, 85, and 29 patients, respectively. While efficacy data were specified for the NSCLC cohort, the safety profile was reported cumulatively across all 142 patients. The safety analysis revealed that treatment-related adverse events (TRAEs) were predominantly grade 1 or 2 in severity. The most common TRAEs, occurring in at least 20% of patients, included diarrhea, vomiting, nausea, and decreased appetite. The incidence of grade 3 or higher TRAEs and severe AEs was 27.5% and 7.7%, respectively. Of the 142 patients in the safety population, 11 required dose reduction and 6 discontinued treatment due to TRAEs, with no TRAE-related deaths reported. These data suggest a manageable safety profile for VS-7375 at the doses studied.
The KRAS G12D mutation is the most prevalent KRAS mutation, accounting for 26% of all KRAS-mutated cancers. It is particularly common in pancreatic cancer (37%) and colorectal cancer (12.5%), as well as NSCLC (5%). Despite its prevalence, there are currently no FDA-approved therapies specifically targeting this mutation. The dual “ON/OFF” mechanism of VS-7375 represents a novel approach to inhibiting both the active and inactive states of the KRAS G12D protein, distinguishing it from other agents that may only target 1 state.
In April 2025, the FDA cleared the investigational new drug application of VS-7375.3 Last month, the FDA granted fast track designation to VS-7375 in KRAS G12D-mutated PDAC.4