FDA Grants Fast Track Designation to VS-7375 for KRAS G12D-Mutated Advanced NSCLC

The FDA has granted a fast track designation (FTD) to VS-7375, an investigational oral KRAS G12D dual ON/OFF inhibitor being developed by Verastem Oncology for the treatment of adults with KRAS G12D-mutated unresectable locally advanced or metastatic non–small cell lung cancer (NSCLC) who have previously received platinum-based chemotherapy and an anti–PD-(L)1 therapy.¹ The designation highlights the significant unmet need among patients with KRAS G12D-driven tumors, a population for whom no FDA-approved targeted therapies currently exist.^1,2

According to Verastem Oncology, approximately 5% of NSCLC cases harbor a KRAS G12D mutation, translating to more than 8000 newly diagnosed patients in the United States annually. Patients with KRAS G12D-mutated disease are often associated with poorer outcomes and reduced responses to standard treatment approaches, underscoring the need for novel therapeutic options.¹

Targeting a Challenging KRAS Mutation

KRAS mutations are among the most common oncogenic drivers across solid tumors, with KRAS G12D representing approximately 26% of all KRAS alterations, making it the most prevalent KRAS mutation in human cancers.^1,2 Although the development of KRAS G12C inhibitors has transformed treatment for some patients with lung cancer, KRAS G12D has remained a particularly challenging target due to its molecular structure and signaling characteristics.²

VS-7375 is designed to inhibit both the active guanosine triphosphate-bound “ON” state and inactive guanosine diphosphate-bound “OFF” state of KRAS G12D.^1,2 This dual ON/OFF mechanism differentiates the agent from several investigational KRAS inhibitors that primarily target only 1 conformational state of the protein.²

Preclinical findings presented at the American Association for Cancer Research demonstrated that VS-7375 showed superior inhibition of KRAS G12D signaling compared with other investigational KRAS G12D-targeted therapies in multiple tumor models. In colorectal cancer xenograft models, VS-7375 induced tumor regression, whereas comparator ON-only inhibitors produced tumor growth inhibition without regression. Investigators also reported sustained tumor regression in pancreatic cancer models and enhanced activity when combined with cetuximab (Erbitux; Eli Lilly) in colorectal, pancreatic, and lung cancer models.²

Clinical Development Program Continues to Expand

The FDA’s FTD comes as Verastem continues to advance a broad clinical development program evaluating VS-7375 across multiple KRAS G12D-mutated malignancies.¹

The ongoing phase 1/2 TARGET-D 101 trial (NCT07020221) is evaluating VS-7375 as monotherapy and in combination regimens in patients with advanced KRAS G12D-mutated solid tumors, including pancreatic, colorectal, and lung cancers.^1,3 According to the company, dose escalation has progressed from 400 mg to 900 mg once daily without dose-limiting toxicities or major safety concerns observed to date.¹

Early data reported from 23 patients treated across the first 3 dose levels demonstrated that VS-7375 was generally well tolerated, with no drug-related liver function abnormalities or neutropenia greater than grade 2 observed at the January 2026 data cutoff.¹

Additionally, preliminary data from an ongoing Chinese phase 1/2 study (NCT06500676) showed encouraging antitumor activity, with overall response rates of 52% in pancreatic cancer and 42% in lung cancer among evaluable patients, alongside a manageable safety profile.^2,4

Registration-Directed Studies Underway

Verastem has also launched TARGET-D 202, a phase 2 registration-directed study evaluating a 900-mg once-daily dose of VS-7375 in patients with second- or third-line advanced NSCLC. The trial includes an assessment of patients with asymptomatic untreated brain metastases based on favorable preclinical intracranial tumor model data.¹

“Receiving FTD for VS-7375 reinforces both the significant unmet need and the potential of VS-7375 to improve outcomes for patients with KRAS G12D-mutated lung cancer,” Michael Kauffman, MD, PhD, president of development at Verastem Oncology, said in a company press release.¹

Conclusion

For oncology pharmacists, the emergence of KRAS-G12D-targeted therapies may further expand the role of biomarker testing and precision medicine in clinical practice. As molecular profiling becomes increasingly important for treatment selection, pharmacists are likely to play a key role in identifying eligible patients, interpreting genomic testing results, managing adverse effects, and supporting adherence to oral targeted therapies.

As clinical development progresses, VS-7375 may represent a promising targeted treatment strategy for patients with KRAS G12D-mutated NSCLC, a population that currently lacks approved mutation-specific therapeutic options.^1,2

REFERENCES

1. Verastem Oncology Announces U.S. FDA Fast Track Designation for VS-7375, an Oral and Potential Best-in-Class Investigational KRAS G12D (ON/OFF) Inhibitor for the Treatment of KRAS G12D-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer. Verastem Oncology. News release. June 3, 2026. Accessed June 24, 2026. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-us-fda-fast-track-designation-vs

2. Coma S, Malvezzi CC, Yan F, et al. Abstract A076: VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with superior anti-tumor efficacy relative to ON-only KRAS inhibitors. Molecular Cancer Therapeutics. 2025;24(10_Supplement):A076-A076. doi:10.1158/1535-7163.targ-25-a076

3. A Phase 1/​2 Study of VS-7375 in Patients With KRAS G12D-Mutated Solid Tumors. ClinicalTrials.gov identifier: NCT07020221. Updated April 22, 2026. Accessed June 24, 2026. https://clinicaltrials.gov/study/NCT07020221

4. A Study of GFH375 in Patients With Advanced Solid Tumors With KRAS G12D Mutation. ClinicalTrials.gov identifier: NCT06500676. Updated November 20, 2026. Accessed June 24, 2026. https://clinicaltrials.gov/study/NCT06500676