VS-7375 Exhibits Activity in KRAS G12D–Mutated Solid Tumors

VS-7375, an investigational oral KRAS G12D (ON/OFF) inhibitor, demonstrated encouraging clinical activity and a favorable safety and tolerability profile across multiple dose levels and tumor types in the ongoing phase 1/2 TARGET-D 101 trial (NCT07020221), according to a news release from Verastem Oncology.¹

Activity was observed in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), metastatic colorectal cancer (CRC), and advanced non–small cell lung cancer (NSCLC), both as monotherapy and in combination with anti-EGFR therapy or standard-of-care chemotherapy. Developers also announced their intent to evaluate VS-7375 alongside the investigational pan-RAS molecular glue, ERAS-0015.

What were the early efficacy results from TARGET-D 101?

VS-7375 demonstrated antitumor activity at the 400-mg, 600-mg, and 900-mg once daily dose levels as monotherapy and in combination with anti-EGFR therapy. In previously treated metastatic PDAC, 93% (n = 13/14) of patients who were heavily pretreated in the second to fourth line receiving 900 mg of monotherapy achieved greater than 50% reduction in the tumor marker CA19-9; all 14 evaluable patients had elevated baseline CA19-9 of more than 37 U/mL and remained on treatment. Investigators observed evidence of dose-dependent activity between 600 mg and 900 mg. Preliminary data suggested that combining VS-7375 with the anti-EGFR antibody cetuximab (Erbitux) was associated with deeper, more rapid tumor reductions, even at a subtherapeutic 400-mg dose.

In metastatic CRC, preliminary efficacy was seen with VS-7375 plus full-dose cetuximab at both 600 mg and 900 mg. In advanced NSCLC, preliminary efficacy was observed at 600 mg of monotherapy.

What was the safety profile of VS-7375?

As of the June 12, 2026, data cutoff, VS-7375 monotherapy showed a favorable and manageable safety profile at the 600-mg (n = 57) and 900-mg (n = 25) dose levels. Treatment-related adverse events (TRAEs) were primarily low-grade nausea, vomiting, and diarrhea that diminished over time, with substantially reduced incidence after cycle 1. Most gastrointestinal effects were managed with standard supportive care; 1 grade 3 case of nausea at 900 mg resolved in 4 days after optimizing anti-emetic agents. A low frequency of rash was reported, with no events above grade 1. No clinically meaningful cytopenias or liver function abnormalities were observed at either dose level, and no unexpected AEs or cumulative toxicities were reported to date.

“VS-7375 has demonstrated anti-tumor activity across multiple dose levels and tumor types, encouraging signals from rational combination strategies, and a favorable safety profile that improves meaningfully beyond the first treatment cycle, underscoring its potential to be not only the best-in-class oral KRAS G12D inhibitor, but also the preferred treatment option for patients with KRAS G12D–mutated cancers,” said Michael Kauffman, MD, PhD, president of development at Verastem Oncology, in the press release.¹

What is VS-7375 and how does the TARGET-D program work?

VS-7375 is an investigational, potent, selective oral KRAS G12D dual ON/OFF inhibitor designed to bind to both the active and inactive states of KRAS G12D, potentially inhibiting signaling more completely than agents targeting a single state. KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancers. The press release highlighted that it occurs most commonly in pancreatic cancer (40%), CRC (15%), endometrial cancer (8%), biliary tract cancer (7% to 15%), and NSCLC (5%). No FDA-approved therapies currently target KRAS G12D specifically.

Dose escalation in TARGET-D 101 is ongoing at 1200 mg once daily, and the TARGET-D program has expanded to include 3 phase 2 registration-directed trials: TARGET-D 201 (NCT07644559) in second-line metastatic PDAC, TARGET-D 202 (NCT07659782) in NSCLC, and TARGET-D 203 (NCT07659795) in metastatic CRC.

What is VS-7375’s regulatory and development history?

Previously, the FDA granted fast track designation to VS-7375 for first-line and previously treated KRAS G12D–mutated PDAC in July 2025.² In June 2026, the FDA granted an additional fast track designation to the agent for KRAS G12D–mutated unresectable locally advanced or metastatic NSCLC in patients who were previously treated with platinum-based chemotherapy and an anti–PD-(L)1 antibody.³

References

1. Verastem Oncology announces positive preliminary data from the TARGET-D 101 phase 1/2 trial of VS-7375 in advanced KRAS G12D-mutated solid tumors. News release. Verastem Oncology. June 24, 2026. Accessed June 25, 2026. https://tinyurl.com/37ehmybw
2. Verastem Oncology granted fast track designation for VS-7375. News release. Verastem Oncology. July 24, 2025. Accessed June 25, 2026. https://tinyurl.com/yawm2nmb
3. 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 25, 2026.