VS-7375 produced a responses previously treated metastatic pancreatic ductal adenocarcinoma.
VS-7375 generated promising responses in patients with KRAS G12D–mutated metastatic pancreatic ductal adenocarcinoma (mPDAC) treated in the second-line setting, according to initial data from the phase 1/2 TARGET-D 101 trial (NCT07020221).1
At a median follow-up of 6.4 months (range, 0.8-10.9), across all 22 patients in the modified intent-to-treat population who received VS-7375 at 900 mg daily in the second-line or later setting, the confirmed overall response rate (ORR) was 41%. This ORR included 2 complete responses (CRs): 1 confirmed and 1 unconfirmed in a patient still on treatment. The disease control rate was 86%, and the 6-month landmark progression-free survival (PFS) and overall survival (OS) rates were 67% and 80%, respectively.
Moreover, VS-7375 generated a confirmed objective response rate (ORR) of 50% (n = 8). In the third- or fourth-line setting, the confirmed ORR was 36% (n = 14).
“Today’s first multi-tumor clinical dataset for VS-7375 demonstrates compelling and robust responses across KRAS G12D-mutated cancers, marking an important development milestone and reinforcing our conviction that VS-7375 has the potential to become both a best-in-class therapy and the first therapy used for these patients,” said Michael Kauffman, MD, PhD, president of development at Verastem Oncology in a news release. “The mPDAC data provide the strongest evidence to date supporting 900 mg monotherapy as our go-forward dose. At this dose, among all 22 patients, no tumor target lesions grew, responses were deep, two patients achieved a complete response, and most of the patients remain on therapy”
Notably,
Verastem and the FDA have agreed on the design of the phase 3 TARGET-D 301 trial of VS-7375 in first-line mPDAC.1 The company expects to open the study by the end of 2026. The trial will include three arms:
The dual primary end points are PFS and ORR, and OS is a secondary end point.
TARGET-D 101 is an open-label, multicenter trial that is enrolling patients that have a locally advanced unresectable or metastatic solid tumor with a KRAS G12D mutation confirmed by histology or cytology.3 Patients also needed measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ and cardiac function. Adverse effects (AEs) from earlier treatment had to have resolved to grade 1 or lower or to baseline.
Additionally, patients were excluded if they had received prior treatment with a direct, specific KRAS G12D inhibitor, known central nervous system metastases that were symptomatic, untreated, or actively progressing, inability to swallow oral medication, received chemotherapy, targeted therapy, or nonpalliative radiotherapy within 4 weeks or 5 half-lives before cycle 1, day 1, or received immunotherapy within 4 weeks before cycle 1, day 1.
The trial is assessing VS-7375 alone or with other agents in patients with advanced KRAS G12D–mutated solid tumors like mPDAC, non–small cell lung cancer (NSCLC), and metastatic colorectal cancer (mCRC).
In the 600 mg monotherapy cohort (n = 27), 8 patients had objective responses, four of them confirmed, and 11 patients were still receiving treatment.1 The 900 mg dose led to higher responses than 600 mg, with broadly comparable AE profiles. The company has selected 900 mg as its go-forward dose across tumor types, and a 1200 mg once-daily dose is also under evaluation.
The median number of prior lines of therapy in the 900 mg mPDAC cohort was 2 (range, 1-3), including standard-of-care chemotherapy.
Six patients with mCRC in the third-line or later setting received VS-7375 900 mg with anti-EGFR therapy. The ORR for these patients was 33% at a median follow-up of 6.1 months (range, 0.4-7.0). With 600 mg plus anti-EGFR therapy (n = 24), 4 patients responded (three confirmed), and 14 remained on study treatment.
In advanced NSCLC treated in the second-line or later setting, 600 mg monotherapy (n = 23) yielded a confirmed ORR of 43% at a median follow-up of 4.4 months (range, 2.4-12.4). The 6-month landmark PFS rate was 72%, and 17 patients continued on therapy.
The first-line lung adenocarcinoma cohort (n = 8), patients received VS-7375 600 mg with carboplatin, pemetrexed, and pembrolizumab (Keytruda), or with pembrolizumab alone. The ORR was 75% at a median follow-up of 4.4 months (range, 0.9-5.8), and six patients remained on treatment.
As of a September 29, 2026, data cutoff, 2% of the 48 patients who received 900 mg VS-7375 monotherapy across tumor types had discontinued treatment because of AEs. Most treatment-related AEs (TRAEs) were low-grade nausea, vomiting, and diarrhea. Ten percent of patients had a grade 3 TRAE, and 2% had a grade 3 gastrointestinal TRAE. By month 6, approximately 40% of patients had no GI AEs.
Rash occurred in 2 patients at 900 mg and did not exceed grade 2. No patients developed mucositis or stomatitis, and no clinically relevant cytopenias or liver function changes were reported.
