Verastem's KRAS G12D Drug Posts Pancreatic Responses, Advances to Phase III

Key Points

• VS-7375 showed encouraging pancreatic cancer activity: Among 20 evaluable heavily pretreated patients receiving 900 mg, eight had confirmed responses, including one complete response, while median progression-free survival was 6.5 months and still increasing.
• The drug also demonstrated early activity in other cancers, including a 43% confirmed response rate in previously treated non-small cell lung cancer at 600 mg and tumor shrinkage in all evaluable colorectal cancer patients.
• Verastem is advancing VS-7375 into registrational trials: The FDA agreed to the design of the frontline pancreatic Phase III TARGET-D 301 study, expected to begin by year-end, while Phase II studies in pancreatic, colorectal and lung cancers continue.

Verastem NASDAQ: VSTM presented updated clinical data for VS-7375, an oral, highly selective KRAS G12D inhibitor, from its ongoing TARGET-D 101 study in patients with pancreatic ductal adenocarcinoma, colorectal cancer and non-small cell lung cancer. The company also outlined plans for registrational Phase II studies and frontline Phase III trials.

Dan Paterson, Verastem’s president and chief executive officer, said the company believes the drug’s oral bioavailability, dose-proportional exposure and selective mechanism differentiate it from other RAS-targeting therapies. He said the company’s planned go-forward dose is 900 mg once daily and that the safety profile has enabled a reported median relative dose intensity of 97% at that dose.

Pancreatic Cancer Data

Michael Kauffman, Verastem’s president of development, presented data from 22 heavily pretreated pancreatic cancer patients treated with 900 mg of VS-7375. Of the 20 patients evaluable for radiographic response, eight had confirmed responses, including one confirmed complete response. The company said another patient had a partial response with an initial reading consistent with a complete response pending confirmation.

Among eight patients treated in the second-line setting, four had confirmed responses. Five of 14 patients treated in the third- or fourth-line setting had confirmed responses. Kauffman said 16 of the 22 patients remained on treatment, including 15 without progression.

Verastem reported progression-free survival of 6.5 months and said the measure was still increasing. The company also reported that 12 of 12 evaluable patients with detectable circulating tumor DNA had at least a 50% reduction in KRAS G12D variant allele frequency, with 11 showing at least a 10-fold reduction.

Manuel Hidalgo, co-director of the Gastrointestinal Cancer Center at NYU Langone Health and an investigator in the program, discussed a 55-year-old pancreatic cancer patient who had progressed after modified FOLFIRINOX and gemcitabine/ABRAXANE. Hidalgo said the patient experienced rapid pain relief, discontinued morphine and achieved a confirmed partial response while remaining on study.

Colorectal and Lung Cancer Updates

In colorectal cancer, Verastem presented early data from six intention-to-treat patients at the 900 mg dose, with five patients represented in the disclosed tumor-response chart. One patient left the trial before the first scan, according to Kauffman. The company reported one confirmed response and one unconfirmed response, while stating that all patients with available scans experienced tumor shrinkage.

For previously treated non-small cell lung cancer, the company reported a 43% confirmed overall response rate at the 600 mg dose. Kauffman said all partial responses occurred at the first scan and were ongoing at the time of the update. The 900 mg dose is being evaluated in an accelerated-approval-oriented Phase II study, though the company did not provide updated 900 mg lung cancer efficacy data.

Verastem also reported preliminary frontline lung cancer combination data at 600 mg with chemotherapy and immunotherapy. In eight intention-to-treat patients, the company reported a 75% overall response rate to date, including confirmed and unconfirmed responses.

Safety and Combination Strategy

Ting Wu, Verastem’s vice president of clinical development, said gastrointestinal adverse events—including nausea, diarrhea and vomiting—were the most common treatment-related events. These events were predominantly Grade 1 or Grade 2, according to the company. Verastem reported no Grade 4 or Grade 5 treatment-related events in the monotherapy cohort, while 10% of patients experienced a Grade 3 treatment-related event.

Wu said the company has used prophylactic 5-HT3 antiemetic treatment during the first two cycles. She said gastrointestinal events did not appear to accumulate over time, and that the proportion of patients without gastrointestinal adverse events increased from about 25% in the first cycle to 40% after six months on therapy.

The company said it has not observed clinically significant hematologic toxicity or liver enzyme elevations, which it believes supports combinations with chemotherapy, EGFR inhibitors and immune checkpoint inhibitors. Verastem said it has cleared the 900 mg dose in combinations with anti-EGFR agents and gemcitabine/nab-paclitaxel, while frontline pancreatic combination data are expected in the first quarter of next year.

Regulatory and Development Plans

Verastem said the FDA has agreed to the design of its Phase III frontline pancreatic cancer study, TARGET-D 301, which the company expects to open by year-end. The three-arm study will compare VS-7375-based approaches with standard chemotherapy and will allow patients in the control arm to cross over to VS-7375 following independently confirmed radiographic progression.

Kauffman said the FDA agreed to make overall response rate a co-primary endpoint alongside progression-free survival, with overall survival designated as a secondary endpoint. Verastem said the study could potentially support a discussion with the FDA under its FrontRunner program after enrollment of approximately two-thirds of planned participants, though the agency has not agreed in advance to grant accelerated approval.

The company expects to complete enrollment in its pancreatic and colorectal Phase II studies by year-end and complete lung cancer Phase II enrollment during the first half of next year. Paterson also said Verastem’s financing announced alongside the presentation is expected to fund operations into 2028 and beyond Phase II readouts, while adding that the company may pursue a partnership to help broaden development across the three cancer types.

About Verastem (NASDAQ:VSTM)

Verastem Oncology NASDAQ: VSTM is a biopharmaceutical company focused on developing and commercializing targeted therapies for cancers driven by abnormalities in the RAS/MAPK signaling pathway. The company's research is aimed at addressing cancers with limited treatment options, including ovarian cancer and other solid tumors.

Verastem's lead product, avutometinib, is a treatment targeting the RAF/MEK signaling pathway and is marketed in the United States under the brand name Avmapki for certain patients with recurrent low-grade serous ovarian cancer.

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