Novel Oral KRAS G12D Inhibitor Receives FDA Fast Track Designation in Advanced PDAC

Results from a phase 1/2a trial supported the designation for VS-7375 in those with PDAC harboring a KRAS G12D mutation.

The FDA has granted fast track designation (FTD) to an oral KRAS G12D inhibitor, VS-7375 (GFH375 in China), for the treatment of patients with KRAS G12D-mutated locally advanced or metastatic adenocarcinoma of the pancreas (PDAC) and in either the first-line of treatment or who received 1 prior line of standard systemic therapy, according to a press release from the developer, Verastem Oncology.¹

In April 2025, the FDA approved an investigational new drug application for VS-7375 in the treatment of patients with advanced solid tumors.²

Data supporting the FDA’s decision came from the multicenter, open-label phase 1/2a VS-7375-101 trial (NCT06500676) that evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the agent in those with advanced solid tumors harboring a KRAS G12D mutation. Initial safety and efficacy findings were shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.³

At the data cut-off of May 16, 2025, in 23 patients with PDAC treated at the target dose range, the overall response rate (ORR) was 52% (90% CI, 34%-70%) and the disease control rate (DCR) was 100% (90% CI, 88%-100%). Of these patients, 11 had stable disease and 12 experienced a partial response, of which 6 were confirmed; 5 patients were not on treatment at the time of analysis.

In all patients, the median time on treatment was 11.8 weeks (range, 0.1-42.1), the median time to response was 6.2 weeks (range, 6.0-24.7), and 36 of 62 patients remained on treatment.

“The Fast Track Designation for VS-7375 underscores the importance of our potential best-in-class KRAS G12D (ON/OFF) inhibitor. As we continue enrollment in our US phase 1/2a clinical trial, our goal is to accelerate the program’s development given the lack of FDA-approved, KRAS G12D-targeted treatments for [patients] living with KRAS G12D cancers,” said Dan Paterson, president and chief executive officer of Verastem Oncology, in the press release.¹ “Given the encouraging initial safety and efficacy results in China reported by our partner, GenFleet Therapeutics, at ASCO this year, we are excited to be advancing VS-7375 in the US to evaluate it in advanced pancreatic cancer and non–small cell lung cancer [NSCLC] and in combination with cetuximab [Erbitux] in advanced solid tumors, including colorectal cancer.”

A total of 62 patients were enrolled on the trial, 33 had PDAC. In the dose escalation and expansion portion of the trial, patients received doses ranging from 100 mg once a day to 900 mg once a day, as well as 300 mg twice a day; escalation occurred with accelerated titration and Bayesian optimal interval design plus backfilling. When the recommended phase 2 dose (RP2D) was identified, the indication was expanded to open 4 cohorts: an NSCLC cohort, a PDAC cohort, a colorectal cancer cohort, and another solid tumors cohort.

Eligible patients had advanced solid tumors with a KRAS G12D mutation, had been previously treated with standard therapies, and had an ECOG performance status of 0 or 1.

Of the 27 patients with PDAC who received either 400 mg or 600 mg daily or 300 mg twice a day, the median age of patients was 61 years (range, 46-74), 52% were male, and 93% had an ECOG performance status of 1. The number of prior anti-cancer therapies was 2 in 44%, more than 3 in 33%, and 1 in 22%. All patients had metastasis at baseline; 91% had liver metastasis, and 5% had bone metastasis.

The trial’s end points, in phase 1, were safety and tolerability, maximum tolerated dose and RP2D; anti-tumor activity such as ORR, DCR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, and biomarkers. In phase 2, they were ORR, DCR, PFS, OS, safety, and biomarkers.

Regarding safety, all patients experienced any grade treatment-related adverse effects (TRAEs), and 31% experienced a TRAE of grade 3 or higher; treatment-related serious AEs occurred in 10%. The most common TRAEs were diarrhea (69%), nausea (68%), vomiting (61%), and anemia (52%). The most common grade 3 or 4 TRAEs were neutrophil count decreased (8%) and diarrhea (5%). TRAEs led to dose reduction, dose interruption, and treatment discontinuation in 11%, 21%, and 3%, respectively.

In patients who received either 400 mg or 600 mg daily or 300 mg twice a day, TRAEs led to dose reduction, dose interruption, and treatment discontinuation in 10%, 18%, and 4%, respectively.

There were no dose-limiting toxicities or treatment-related deaths observed in the trial.

References

1. Verastem Oncology granted fast track designation for VS-7375 for the treatment of KRAS G12D-mutated locally advanced or metastatic pancreatic cancer. News release. Verastem Oncology. July 24, 2025. Accessed July 25, 2025. https://tinyurl.com/jpsuvksf
2. Verastem Oncology announces U.S. IND clearance of VS-7375, oral KRAS G12D (ON/OFF) inhibitor, enabling phase 1/2a trial in advanced solid tumors. News release. Verastem Oncology. April 23, 2025. Accessed July 25, 2025. https://tinyurl.com/ytyszczx
3. Ai X, Zhou A, Wu L, et al. A first-in-human phase I/II study of GFH375, a highly selective and potent oral KRAS G12D inhibitor in patients with KRAS G12D mutant advanced solid tumors. J Clin Oncol. 2025;43(suppl 16):3013. doi:10.1200/JCO.2025.43.16_suppl.3013