VS-7375 Shows Early Promise Against KRAS G12D–Mutant Solid Tumors

The investigational oral KRAS G12D inhibitor VS-7375 (GFH375) has shown a promising early safety profile and preliminary antitumor activity in pretreated patients with advanced solid tumors harboring a KRAS G12D mutation, according to a recent update of the phase 1/2a VS-7375-101 trial (NCT07020221).¹

In the monotherapy dose-escalation portion of the study, VS-7375 cleared both dose levels of 400 mg and 600 mg daily, with no dose-limiting toxicities or new safety signals observed. Specifically, there were no reports of nausea, vomiting, or diarrhea greater than grade 1, setting the stage for a favorable tolerability profile and continued evaluation of the regimen in subsequent cohorts.

“We’re encouraged by the early safety experience in this study, including the [gastrointestinal] tolerability we’ve seen to date and absence of cutaneous toxicities,” said John Hayslip, MD, chief medical officer of Verastem Oncology, in a news release.¹

Furthermore, 4 out of 5 efficacy-evaluable patients (80%) who have reached response assessment have experienced a tumor reduction and remain on treatment.

“Preliminary safety and tolerability data from our ongoing [p]hase 1/2a trial indicate that VS-7375…can be administered at efficacious doses while effectively managing gastrointestinal [adverse] effects,” added Dan Paterson, president and CEO of Verastem Oncology, in the news release.¹ “While still early, we are pleased to see antitumor activity among pretreated patients with advanced pancreatic cancer and other solid tumors.”

Despite the widespread prevalence of the KRAS G12D mutation, the most prevalent KRAS mutation appearing across multiple solid tumors, there are no FDA-approved therapies targeting this mutation.¹ VS-7375 approaches this treatment gap with a unique dual targeting mechanism of both the ON and OFF states of the KRAS G12D protein.

Earlier this year, the FDA cleared the investigational new drug application of VS-7375 following the agent’s approval in China in 2024, enabling the initiation of this phase 1/2a trial. In July 2025, the FDA also granted the agent fast track designation in KRAS G12D-mutated pancreatic adenocarcinoma (PDAC), highlighting the critical unmet need in patients harboring this mutation.

In August 2025, data on the agent’s clinical profile in patients with advanced non–small cell lung cancer (NSCLC) in China were revealed in a late-breaking abstract at the IASLC 2025 World Conference on Lung Cancer, which reported an objective response rate of 57.7% (n = 15/26) and disease control rate of 88.5% (n = 23/26) in the NSCLC cohort.²

About the VS-7375-101 Trial

VS-7375-101 is a multicenter, nonrandomized phase 1/2a dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of VS-7375 as monotherapy and in combination with cetuximab (Erbitux) in adult patients with previously treated advanced KRAS G12D mutant solid tumors, including PDAC, NSCLC, and colorectal cancer.³ With an estimated enrollment of 330 patients, the study is currently recruiting in 5 sites across the United States and plans to expand globally.

Next Steps in Development

Following these positive data, monotherapy dose escalation will continue to a dose of 900 mg, at which point investigators will establish the recommended phase 2 dose and launch the dose expansion portion in patients with PDAC and NSCLC.¹ Additionally, a cohort evaluating the combination of VS-7375 plus cetuximab is now open and enrolling patients; depending on outcomes in this cohort, the sponsor will initiate dose expansion in patients with colorectal cancer.

“As we continue monotherapy dose escalation, we are excited to open the combination cohort evaluating VS-7375 with cetuximab just months after trial initiation. By starting this combination cohort at a dose of VS-7375 that has previously demonstrated monotherapy efficacy, we expect to accelerate our clinical development program with other standard-of-care combination cohorts,” added Paterson on next steps.¹

An interim safety and efficacy update from the trial is expected from the sponsor in the first half of 2026.

REFERENCES

1. Verastem Oncology announces encouraging preliminary data from ongoing phase 1/2a dose escalation trial of VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, in patients with KRAS G12D mutant solid tumors. News release. Verastem Oncology. October 23, 2025. Accessed October 29, 2025. https://tinyurl.com/bdfbk3at

2. Verastem Oncology Announces Late-Breaking Abstract from Partner GenFleet Therapeutics’ Study in China of GFH375 (VS-7375) in Advanced Non-Small Cell Lung Cancer at IASLC 2025 World Conference on Lung Cancer. News release. August 13, 2025. Accessed November 3, 2025. https://tinyurl.com/mr24mmuk

3. A Phase 1/​2a study of VS-7375 in patients with KRAS G12D-mutated solid tumors. ClinicalTrials.gov. Updated October 1, 2025. Accessed October 29, 2025. https://clinicaltrials.gov/study/NCT07020221