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

The US FDA has granted fast track designation to VS-7375, an investigational oral selective KRAS G12D inhibitor, for the treatment of adult patients with KRAS G12D-mutated unresectable locally advanced or metastatic non–small cell lung cancer (NSCLC) who have received prior platinum-based chemotherapy and an anti–PD-(L)1 antibody, either concurrently or sequentially.¹

This marks the second fast track designation for VS-7375. The FDA previously granted the designation in July 2025 for 2 KRAS G12D-mutated pancreatic indications: first-line treatment of locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), and treatment of PDAC in patients who have received at least 1 prior line of standard systemic therapy.²

"The [f]ast [t]rack [d]esignation for VS-7375 underscores the importance of our potential best-in-class KRAS G12D inhibitor," said Dan Paterson, president and chief executive officer of Verastem Oncology, in a news release. "Our goal is to accelerate the program's development given the lack of FDA-approved, KRAS G12D-targeted treatments for people living with KRAS G12D[-mutant] cancers."

Unmet Need in KRAS G12D–Mutated NSCLC

KRAS G12D represents the most prevalent KRAS mutation in human cancers, accounting for 26% of all KRAS mutations.³ In NSCLC specifically, the KRAS G12D variant occurs in approximately 5% of cases—an estimated 8000 patients in the United States annually. Despite the availability of FDA-approved agents targeting the KRAS G12C mutation, no therapies have been approved specifically for KRAS G12D-mutated cancers in any tumor type. Patients with this mutation who progress after platinum-based chemotherapy and immune checkpoint inhibition have limited therapeutic options.

Fast track designation is an FDA program designed to expedite the development and review of drugs intended to treat serious conditions and fill an unmet medical need. The designation facilitates more frequent communication with the FDA and may make agents eligible for accelerated approval, priority review, and rolling review, depending on subsequent data.¹

Mechanism of Action

VS-7375 is an oral, small-molecule inhibitor that targets both the active (ON) and inactive (OFF) conformational states of the KRAS G12D protein, a dual-state mechanism that distinguishes it from earlier KRAS-directed agents, which primarily bind the inactive GDP-bound state.¹ By inhibiting both states, VS-7375 is designed to more comprehensively suppress oncogenic KRAS G12D signaling through the RAS/MAPK pathway.

Clinical Development Program

In June 2025, Verastem Oncology initiated TARGET-D 101 (NCT07020221), a phase 1/2, open-label, multicenter, dose-escalation, dose-expansion, and combination study evaluating VS-7375 as monotherapy and in combination with cetuximab (Erbitux) in patients with advanced KRAS G12D-mutated solid tumors, including PDAC, NSCLC, and colorectal cancer. Enrollment is ongoing across 5 US sites, with plans for global expansion.⁴

Dose escalation has progressed from 400 mg once daily (QD) through 900 mg QD without dose-limiting toxicities or major safety concerns. The study is currently evaluating a 1200-mg QD monotherapy dose and a 900-mg QD cetuximab combination cohort. In data reported in March 2026 from 23 patients treated at 400-mg, 600-mg, and 900-mg QD dose levels (mean treatment duration, 1.6 months; range, 0.7-5.6 months), VS-7375 was generally well tolerated as of the January 30, 2026, data cutoff. No drug-related liver function test abnormalities or grade >2 neutropenia were observed, and rates of nausea, vomiting, and diarrhea were lower than those reported in a parallel study conducted in China by Verastem's partner, GenFleet Therapeutics. Additional efficacy and safety updates from TARGET-D 101 are expected in the first half and second half of 2026.

Following FDA feedback, Verastem has initiated three additional registration-directed phase 2 trials:

• TARGET-D 201 in metastatic PDAC
• TARGET-D 202 in advanced NSCLC (second or third line)
• TARGET-D 203 in metastatic colorectal cancer

TARGET-D 202 is a phase 2, open-label, multicenter study evaluating VS-7375 at 900 mg QD in patients with advanced NSCLC who have received 1 to 2 prior lines of therapy. Notably, based on preclinical activity in intracranial tumor models, the study also includes a cohort of NSCLC patients with asymptomatic, untreated brain metastases—a population historically excluded from targeted therapy trials.

Context in the KRAS Inhibitor Landscape

The approval of sotorasib (Lumakras)⁵ in 2021 and adagrasib (Krazati)⁶ in 2022 established KRAS G12C as a tractable oncology target; however, G12D has remained without an approved therapy. Structural differences between G12C and G12D have complicated drug design, as G12D lacks the cysteine residue that enabled covalent inhibitor strategies used in earlier KRAS-directed programs. VS-7375 represents one of several noncovalent approaches now in clinical development against this target.

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. News release. Verastem Oncology. June 3, 2026. Accessed June 4, 2026. https://tinyurl.com/5bnmebdv

2. 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 June 4, 2026. https://tinyurl.com/5e7ftfd9

3. Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol. 2022 Dec 9;6(1):91. doi: 10.1038/s41698-022-00334-z. PMID: 36494601; PMCID: PMC9734185.

4. Verastem Oncology Announces First Patient Dosed with VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor, in a U.S. Phase 1/2a Trial in KRAS G12D Advanced Solid Tumors. News release. Verastem Oncology. June 24, 2025. Accessed June 4, 2026. https://tinyurl.com/4ebe2njr

5. Lumakras FDA Approval History. Drugs.com. Updated January 18, 2025. Accessed Junr 4, 2026. https://tinyurl.com/264w5bet

6. Dhillon S. Adagrasib: First Approval. Drugs. 2023 Feb;83(3):275-285. doi: 10.1007/s40265-023-01839-y. PMID: 36763320.