VS-7375 Yields Responses in KRAS G12D–Mutated Solid Tumors

VS-7375, an investigational oral KRAS G12D ON/OFF inhibitor, demonstrated robust antitumor activity across metastatic pancreatic ductal adenocarcinoma (PDAC), metastatic colorectal cancer (CRC), and advanced non–small cell lung cancer (NSCLC) in the ongoing phase 1/2 TARGET-D 101 trial (NCT07020221), according to a news release from Verastem Oncology.¹ The company also announced that it has reached alignment with the FDA on a phase 3 trial of the agent in first-line metastatic PDAC.

What were the efficacy results in pancreatic cancer?

Among 22 patients with metastatic PDAC who received VS-7375 at 900 mg once daily, with a median follow-up of 6.4 months, the confirmed objective response rate (ORR) was 50% (n = 4/8) in the second-line setting; in the second-line and later setting, it was 41% (n = 9/22), with 2 complete responses (CRs), one of which was confirmed and one was unconfirmed. In the third- and fourth-line setting, the confirmed ORR was 36% (n = 5/14). Patients had received a median of 2 prior lines of therapy (range, 1-3). The disease control rate was 86% in the second-line and later setting, and the 6-month landmark progression-free survival (PFS) and overall survival rates were 67% and 80%, respectively. At data cutoff, 16 of 22 patients remained on treatment.

In the 600-mg cohort (n = 27), 8 patients had objective responses, 4 of which were confirmed; 11 of 27 patients remained on treatment.

“The PDAC data provide the strongest evidence to date supporting 900 mg monotherapy as our go-forward dose,” stated Michael Kauffman, MD, PhD, president of development at Verastem Oncology.¹ “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. Our single-agent confirmed response rates in PDAC in [second line] as well as [third and fourth line] are among the highest reported to date with any RAS inhibitor, further strengthening our confidence as we advance VS-7375 into a first-line phase 3 trial in metastatic PDAC that we plan to open by the end of 2026.”

Among 17 patients with elevated baseline CA19-9 treated at 900 mg once daily, 15 had a reduction of more than 50%. In 12 evaluable patients with disease in the second-line and later setting, all had at least a 50% reduction in KRAS G12D variant allele frequency by cycle 3 day 1 of treatment; 11 of 12 (92%) had at least a 90% reduction, and 7 (58%) had 100% clearance of KRAS G12D circulating tumor DNA (ctDNA).

What were the results in colorectal and lung cancers?

In third-line and later metastatic CRC, VS-7375 at 900 mg plus an anti-EGFR antibody produced an ORR of 33% (n = 2/6), with 1 response confirmed. At 600 mg plus an anti-EGFR antibody (n = 24), 4 patients had objective responses, 3 of which were confirmed. According to the investigators, the 900 mg combination with anti-EGFR yielded deeper tumor reductions.

In second-line and later NSCLC, VS-7375 monotherapy at 600 mg once daily yielded a confirmed ORR of 43% (n = 10/23) and a 6-month PFS rate of 72% at a median follow-up of 4.4 months. The 900 mg dose level is currently under evaluation in the phase 2 TARGET-D 202 trial (NCT07659782). In an early first-line cohort of 8 patients with KRAS G12D adenocarcinoma of the lung receiving VS-7375 in combination with carboplatin plus pemetrexed and pembrolizumab (Keytruda) or with pembrolizumab, the ORR was 75% (n = 6/8). Six patients currently remain on therapy, and following the 600-mg dose level being cleared with standard of care (SOC) and no dose-limiting toxicities in September 2026, evaluation of the 900-mg dose plus SOC remains ongoing.

A total of 5 patients with KRAS G12D-mutant advanced NSCLC received VS-7375 monotherapy at 600 mg in the second or later line setting and had detectable KRAS G12D ctDNA at baseline, and all achieved complete clearance of detectable ctDNA.

What was the safety profile of VS-7375?

As of the September 29, 2026, data cutoff, among 48 patients with various KRAS G12D-driven tumor types treated with 900 mg of monotherapy, 2% discontinued treatment because of adverse events (AEs), and relative dose intensity was 97%. Treatment-related AEs (TRAEs) were mostly low-grade nausea, vomiting, and diarrhea that decreased over time with supportive care. Grade 3 TRAEs occurred in 10%, and grade 3 or higher gastrointestinal AEs occurred in 2% of patients. There were 2 cases of rash, none above grade 2, and no mucositis or stomatitis. No clinically meaningful cytopenias, liver function abnormalities, or cumulative toxicity were observed to date.

When combined with cetuximab (Erbitux), VS-7375 at both dose levels demonstrated no overlapping AEs with anti-EGFR therapy; rash was consistent with the known cetuximab safety profile. When combined with gemcitabine and nab-paclitaxel, hematologic AEs and neuropathy were deemed “most likely” attributable to gemcitabine and nab-paclitaxel.¹

How is TARGET-D 101 designed, and what comes next?

TARGET-D 101 is a multicenter, open-label dose-escalation and expansion trial that has enrolled more than 200 patients with advanced KRAS G12D–mutated solid tumors since June 2025. Efficacy analyses included patients who received at least 1 dose and began treatment by July 22, 2026. Eligible patients for the trial were at least 18 years of age with histologic or cytologic evidence of a locally advanced unresectable or metastatic solid tumor harboring a KRAS G12D mutation, as well as measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function.²

The planned phase 3 TARGET-D 301 trial in first-line metastatic PDAC will evaluate VS-7375. The company plans to open it by the end of 2026 and to meet with the FDA to discuss phase 3 designs in first-line CRC and NSCLC. CancerNetwork® previously reported preliminary TARGET-D 101 data in June 2026,³ and the FDA granted fast track designation for PDAC in July 2025.⁴

“We designed our development strategy for VS-7375 around the hypothesis that deep and sustained inhibition of KRAS G12D could translate into meaningful clinical activity while maintaining the tolerability needed for long-term use and combination therapy,” added Daniel Paterson, president and chief executive officer at Verastem Oncology.¹ “The [pharmacokinetic] and biomarker data support the target coverage and antitumor activity observed to date, which bolster our belief of the role VS-7375 will have in pancreatic cancer and other KRAS G12D-driven cancers and its potential to improve upon existing standard-of-care and RAS therapies.”

References

1. 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). News release. Verastem Oncology. October 14, 2026. Accessed October 14, 2026. https://tinyurl.com/ywsrawf7
2. A phase 1/2 study of VS-7375 in patients with KRAS G12D-mutated solid tumors. ClinicalTrials.gov. Updated April 22, 2026. Accessed October 14, 2026. https://tinyurl.com/346ecmhd
3. 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 October 14, 2026. https://tinyurl.com/37ehmybw
4. Verastem Oncology granted fast track designation for VS-7375. News release. Verastem Oncology. July 24, 2025. Accessed October 14, 2026. https://tinyurl.com/yawm2nmb