Verastem’s VS-7375 Shows 50% Response Rate in Pancreatic Cancer

Verastem Oncology reported a confirmed objective response rate (ORR) of 50% (4 of 8 patients) with investigational VS-7375 at 900 mg once daily in patients with second-line metastatic pancreatic ductal adenocarcinoma (mPDAC). In the broader second-line-or-later population of 22 patients receiving the same dose, the confirmed ORR was 41% (9/22).

Updated findings from the Phase 1/2 TARGET-D 101 trial (NCT07020221), announced on October 14, 2026, also showed molecular responses and preliminary activity across additional tumour types, alongside a tolerability profile that supports further investigation. The company also reported alignment with the U.S. Food and Drug Administration (FDA) on the design of a proposed Phase 3 trial in first-line pancreatic cancer.

Pancreatic Cancer Responses Support 900 mg Dose Selection

At the October 7, 2026, data cutoff, 22 patients receiving 900 mg once-daily monotherapy had a median follow-up of 6.4 months and had received a median of two prior treatment lines. The confirmed ORR was 41% (9/22) in second-line or later disease and 36% (5/14) in third- or fourth-line disease. Two complete responses were reported, one confirmed and one unconfirmed.

The disease control rate in the second-line-or-later population was 86%. Landmark six-month progression-free survival (PFS) and overall survival (OS) rates were 67% and 80%, respectively, while 16 of 22 patients remained on treatment.

At 600 mg, eight of 27 patients achieved responses, including four confirmed responses. The company reported deeper tumor reductions and a higher confirmed response rate at 900 mg, supporting its selection of this dose for further development. However, these separate dose cohorts do not establish comparative efficacy through randomized evidence.

 Biomarker Findings Support Biological Activity

Among 12 evaluable patients with detectable baseline KRAS G12D circulating tumor DNA (ctDNA), all achieved at least a 50% reduction in variant allele frequency by cycle 3, day 1. Eleven had reductions of at least 90%, and seven achieved complete clearance of detectable ctDNA.

CA19-9, a tumor-associated biomarker used in pancreatic cancer, declined by more than 50% in 15 of 17 patients with elevated baseline levels. These findings complement the observed tumor responses, although biomarker reductions alone do not establish a survival benefit.

VS-7375 is an investigational oral inhibitor designed to target both the active (ON) and inactive (OFF) states of KRAS G12D. The mutation is common in pancreatic cancer, and no FDA-approved therapy specifically targets KRAS G12D.

Early Activity Extends to Lung and Colorectal Cancer

In second-line-or-later non-small cell lung cancer (NSCLC), 600 mg monotherapy produced a confirmed ORR of 43% (10/23), with a six-month landmark PFS rate of 72% at a median follow-up of 4.4 months. All five evaluable patients with detectable baseline KRAS G12D ctDNA achieved complete clearance of detectable ctDNA. A separate first-line NSCLC combination cohort reported an ORR of 75% (6/8) with 600 mg plus standard-of-care treatment, including chemotherapy and immunotherapy regimens. These preliminary findings require confirmation in larger studies.

In third-line-or-later colorectal cancer, 900 mg combined with anti-EGFR therapy produced an ORR of 33% (2/6), comprising one confirmed and one unconfirmed response. Five patients remained on treatment. Enrollment at 900 mg continues in the registration-directed TARGET-D 203 study (NCT07659795).

Tolerability and Phase 3 Development

Among 48 patients receiving 900 mg monotherapy across tumor types, 2% discontinued treatment because of adverse events, and median relative dose intensity was 97%. Treatment-related events were primarily low-grade nausea, vomiting and diarrhea. Grade 3 treatment-related adverse events occurred in 10% of patients, while 2% experienced Grade 3 gastrointestinal events. Two cases of rash were reported, neither above Grade 2; no mucositis or stomatitis was observed. These findings are encouraging, although longer follow-up is needed to characterise safety during sustained treatment and combination therapy.

The planned first-line mPDAC Phase 3 trial, TARGET-D 301, will compare three regimens: VS-7375 900 mg plus anti-EGFR therapy without chemotherapy; VS-7375 plus gemcitabine/nab-paclitaxel; and investigator-selected gemcitabine/nab-paclitaxel or modified FOLFIRINOX. PFS and ORR are the dual primary endpoints, with OS secondary. Verastem plans to open the trial by year-end 2026.

VS-7375 also holds FDA Fast Track Designation in pancreatic cancer and previously treated NSCLC.

Clinical Interpretation

The update supports further investigation of VS-7375, particularly the 900 mg regimen in previously treated pancreatic cancer. The confirmed responses, ctDNA reductions and sustained treatment in most patients provide complementary early signals of activity. However, the second-line estimate is based on only eight patients, follow-up remains limited, and the study is uncontrolled. The proposed chemotherapy-free first-line regimen is a development hypothesis, not a demonstrated advantage. Randomized Phase 3 evidence will be needed to determine whether VS-7375 improves clinical outcomes over established chemotherapy.

Reference

VS-7375 Demonstrates Robust Anti-Tumor Activity Across Advanced KRAS G12D-Mutant Cancers, highlighted by 50% Confirmed ORR in 2L Pancreatic Ductal Adenocarcinoma and Two Complete Responses in 2L+ Disease (One Confirmed), Verastem Oncology, 14 October 2026

A Phase 1/​2 Study of VS-7375 in Patients with KRAS G12D-Mutated Solid Tumors, ClinicalTrials.gov ID NCT07020221