VS-7375 Shows Antitumor Activity in PDAC, Other KRAS G12D–Mutant Tumors

The oral KRAS G12D inhibitor VS-7375 (Verastem) generated durable responses in previously treated metastatic pancreatic ductal adenocarcinoma (PDAC), along with encouraging early activity in colorectal cancer (CRC) and non–small cell lung cancer (NSCLC), according to the first multi-tumor update from the phase 1/2 TARGET-D 101 trial.¹

Among 22 patients with PDAC treated with VS-7375 at 900 mg once daily after a median of 2 prior lines (range, 1-3), the confirmed objective response rate (ORR) was 41% (9/22) at a median follow-up of 6.4 months (range, 0.8-10.9).¹ The confirmed ORR reached 50% (4/8) in the second line and 36% (5/14) in the third or fourth line. Two patients had complete responses, 1 of which awaits confirmation.

The disease control rate was 86%, the 6-month landmark progression-free survival (PFS) rate was 67%, and the 6-month overall survival (OS) rate was 80%. At the time of the analysis, 16 patients remained on therapy. Two nonevaluable patients died of causes unrelated to treatment. Of noted, at the lower dose of 600 mg (n = 27), 8 patients responded (4 confirmed), with shallower tumor reductions.

Biomarker findings tracked with these responses. At 900 mg, 15 of 17 patients with elevated baseline CA19-9 had declines greater than 50%. Of 12 patients with detectable circulating tumor DNA (ctDNA), all had at least a 50% reduction in KRAS G12D variant allele frequency by cycle 3 day 1, 92% had at least a 90% reduction, and 58% cleared ctDNA completely.

VS-7375 Activity in CRC and NSCLC

In third-line or later CRC, 900 mg plus anti-EGFR therapy yielded an ORR of 33% (2/6; 1 confirmed) with no target lesion growth after a median 6.1 months; at 600 mg (n = 24), 4 patients responded (3 confirmed).

In patients with previously treated NSCLC, 600 mg monotherapy produced a confirmed ORR of 43% (10/23), including in taxane-pretreated patients, with responses as early as week 6 and a 6-month PFS rate of 72%. All 5 evaluable patients with baseline ctDNA achieved clearance. In the frontline setting, 600 mg with carboplatin, pemetrexed (Alimta), and pembrolizumab (Keytruda), or with pembrolizumab alone, produced an ORR of 75% (6/8).

"Patients with KRAS G12D–driven cancers deserve an effective, highly targeted therapy suitable for long-term treatment. 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," Michael Kauffman, MD, PhD, president of development at Verastem Oncology, stated in a press release.

"The PDAC 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. Our single-agent confirmed response rates in PDAC in 2L as well as 3-4L 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. We believe the emerging antitumor activity in non–small cell lung and colorectal cancers, together with the favorable tolerability profile that allows for multiple combinations, also supports the broader development opportunity, both as monotherapy and in combination in the frontline setting, for VS-7375," added Kauffman.

VS-7375 Safety Profile at the 900-mg Dose

Among 48 patients receiving 900 mg monotherapy, 2% discontinued because of adverse events (AEs), and median relative dose intensity was 97%.¹ Treatment-related AEs (TRAEs) were mostly low-grade nausea, vomiting, and diarrhea; grade 3 TRAEs occurred in 10%, including grade 3 gastrointestinal events in 2%. Two cases of rash (grade 2 or lower) occurred, with no mucositis, stomatitis, clinically meaningful cytopenias, liver abnormalities, or cumulative toxicity. Cetuximab (Erbitux) combinations showed no overlapping AEs, and hematologic AEs and neuropathy with gemcitabine plus nab-paclitaxel (Abraxane; GnP) were attributed to the chemotherapy.

TARGET-D 301 Phase 3 Trial in First-Line Metastatic PDAC

Following FDA alignment, the 3-arm TARGET-D 301 trial will compare VS-7375 900 mg plus anti-EGFR therapy, VS-7375 900 mg plus GnP, and investigator's choice of GnP or modified FOLFIRINOX, with PFS and ORR as dual primary end points and OS as a secondary end point.¹ Verastem plans to open the trial by year-end 2026. The 900-mg dose is also being studied in the phase 2 TARGET-D 202 (NSCLC) and TARGET-D 203 (CRC) trials.

"The clinical activity observed with VS-7375 is complemented by striking molecular responses in patients with pancreatic cancer, including deep reductions in KRAS G12D variant allele frequency and ctDNA clearance in more than half of the evaluable patients," Manuel Hidalgo, MD, PhD, director of the Gastrointestinal Cancer Center at New York University Langone Health, and a professor of medicine at NYU Grossman School of Medicine, stated in the news release.

"These molecular data provide additional evidence of the meaningful biological activity of VS-7375. Equally important, its tolerability profile provides a promising foundation for evaluation of VS-7375 in combination regimens and earlier treatment settings," added Hidalgo, who is is an investigator in the ongoing phase 1 and Phase 2 trials evaluating VS-7375.

Reference

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). News release. Business Wire. October 14, 2026. Accessed October 15, 2026. https://tinyurl.com/23pbhk67