Verastem Oncology announced initial multi-tumor efficacy data and updated safety results from the ongoing TARGET-D 101 Phase 1/2 trial evaluating VS-7375, an investigational oral KRAS G12D (ON/OFF) inhibitor, in patients with advanced KRAS G12D-mutated solid tumors. The data, presented at an investor event on October 14, 2026, cover three tumor types: metastatic pancreatic ductal adenocarcinoma (mPDAC), metastatic colorectal cancer (mCRC), and advanced non-small cell lung cancer (NSCLC).
In the headline result, VS-7375 900 mg once daily monotherapy achieved a 50% confirmed objective response rate (ORR) in patients with second-line (2L) mPDAC, with a 41% confirmed ORR across the broader second-line and beyond (2L+) population. These findings are from an early-stage trial with a small evaluable population, and longer follow-up and larger, controlled studies will be required to establish the clinical significance of these results.
Key finding
In a Phase 1/2 trial of 22 evaluable patients, VS-7375 900 mg once daily monotherapy achieved a 50% confirmed ORR in 2L mPDAC and a 41% confirmed ORR across the 2L+ population, with a 67% six-month landmark progression-free survival rate; the small sample size and absence of a comparator arm are key limitations at this stage.
Study Design
| Trial | TARGET-D 101, Phase 1/2, multi-center, open-label, dose-escalation and dose-expansion study |
|---|---|
| Population | Adults with advanced KRAS G12D-mutated solid tumors, including mPDAC, mCRC, and advanced NSCLC; more than 200 patients enrolled to date |
| Treatment | VS-7375 as monotherapy (600 mg or 900 mg once daily) or in combination with anti-EGFR therapy, gemcitabine/nab-paclitaxel, or chemotherapy plus immunotherapy; evaluation of 1200 mg once daily ongoing |
| Primary endpoint | Not formally specified in the source; safety and efficacy (including ORR) are co-primary objectives of the Phase 1/2 design |
| Key secondary endpoints | Progression-free survival, overall survival, disease control rate, duration of response, pharmacokinetics, and biomarker assessments including ctDNA and CA19-9 |
The mITT population for each tumor type was defined as patients who received at least one dose of VS-7375 and started therapy on or before July 22, 2026. The data cutoff for efficacy was October 7, 2026; the safety data cutoff was September 29, 2026. Patient follow-up continues to mature across all cohorts, and Verastem noted that enrollment at the 900 mg dose level is actively expanding across tumor types.
Results and Safety
In mPDAC, the 22-patient mITT cohort treated with VS-7375 900 mg once daily had a median follow-up of 6.4 months. The confirmed ORR was 50% (4/8) in 2L, 41% (9/22) in 2L+, and 36% (5/14) in the 3L/4L setting. Two complete responses were observed in the 2L+ population — one confirmed and one unconfirmed with treatment ongoing. The disease control rate was 86%, the six-month landmark PFS rate was 67%, and the six-month landmark overall survival rate was 80%. Sixteen of 22 patients remained on treatment at the data cutoff. Biomarker data were notable: 15 of 17 patients with elevated baseline CA19-9 achieved greater than 50% reduction in the marker, and among 12 evaluable patients with detectable baseline KRAS G12D ctDNA, all 12 achieved at least a 50% reduction in variant allele frequency by cycle 3 day 1, with 58% achieving complete ctDNA clearance. Verastem also reported data for the 600 mg monotherapy cohort in mPDAC (n=27 mITT), in which four confirmed responses were observed; the company described a clear dose-response relationship favoring 900 mg.
In mCRC, the 900 mg plus anti-EGFR combination cohort included six mITT-evaluable patients in the 3L+ setting with a median follow-up of 6.1 months. The ORR was 33% (2/6), with one confirmed and one unconfirmed response; five patients remained on treatment. Data in this cohort are early, given the small patient number. At 600 mg plus anti-EGFR (n=24), three confirmed and one unconfirmed responses were reported. In NSCLC, 600 mg once daily monotherapy in 23 mITT-evaluable patients in the 2L+ setting produced a confirmed ORR of 43% (10/23) at a median follow-up of 4.4 months, with a six-month landmark PFS rate of 72% and 17 of 23 patients remaining on treatment. A small first-line combination cohort (n=8 mITT) treated with 600 mg plus carboplatin, pemetrexed, and pembrolizumab or pembrolizumab alone achieved a 75% ORR (6/8); these data are very preliminary given the cohort size and short follow-up.
Safety data from 48 patients receiving 900 mg once daily monotherapy showed a 2% discontinuation rate due to adverse events and a relative dose intensity of 97%. Treatment-related adverse events were predominantly low-grade gastrointestinal events — nausea, vomiting, and diarrhea — with Grade 3 treatment-related adverse events occurring in 10% of patients and Grade 3 gastrointestinal events in 2%. Only two cases of rash, both no greater than Grade 2, were observed; no mucositis, stomatitis, clinically meaningful cytopenias, or liver function abnormalities were reported. In combination cohorts, VS-7375 showed no overlapping adverse events with cetuximab, and hematologic toxicities in the gemcitabine/nab-paclitaxel combination were attributed primarily to the chemotherapy backbone. Verastem reported no evidence of cumulative toxicity with longer follow-up.
Clinical Context
KRAS G12D is among the most common oncogenic mutations in pancreatic cancer, colorectal cancer, and NSCLC, yet until recently no approved targeted therapies have directly addressed this variant. The response rates reported here for VS-7375 in previously treated mPDAC, a disease with historically poor prognosis and limited second-line options, represent a potentially meaningful signal, though the data derive from a small, non-randomized Phase 1/2 cohort and should be interpreted accordingly. The company noted that these single-agent confirmed ORRs in 2L and 3-4L PDAC are among the highest reported to date with any RAS inhibitor; however, cross-trial comparisons carry inherent limitations.
Verastem has reported FDA alignment on a three-arm Phase 3 trial design in first-line mPDAC, comparing VS-7375 plus anti-EGFR, VS-7375 plus gemcitabine/nab-paclitaxel, and investigator-choice standard-of-care chemotherapy, with dual-primary endpoints of PFS and ORR and overall survival as a secondary endpoint. The company plans to open the trial by year-end 2026. Phase 3 pivotal trial meetings with the FDA for first-line CRC and NSCLC are planned before year-end as well. Whether the early efficacy signals observed in Phase 1/2 will be replicated in adequately powered, randomized settings remains to be established.
Sources
- Verastem Oncology. “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).” Press release. October 14, 2026. View source.
