Verastem Bets on Higher Cancer Drug Dose as It Maps Potential Approval Path

Key Points

• Verastem plans to prioritize a 900-milligram dose of experimental KRAS G12D inhibitor VS-7375 across cancer indications, citing greater drug exposure and dose response with tolerability comparable to the 600-milligram dose.
• The company is pursuing pancreatic cancer development through chemotherapy-based and chemotherapy-free regimens. It sees potential for accelerated approval in previously treated patients if response and durability data hold up, with phase 2 results possible as early as mid-2027.
• Verastem expects colorectal cancer updates in 2027 and is exploring lung cancer activity, including in patients with brain metastases. Its $250 million financing leaves it with more than $400 million in pro forma cash, which it says should fund operations into the first half of 2028.

Verastem NASDAQ: VSTM plans to advance a 900-milligram dose of its experimental KRAS G12D inhibitor VS-7375 across cancer indications, citing evidence of a dose response and a tolerability profile executives said was comparable to the 600-milligram dose.

At a fireside chat, company executives discussed development plans for pancreatic, colorectal and lung cancer, including possible paths to accelerated approval and upcoming clinical data. They also said a recent financing is expected to fund operations into the first half of 2028.

Why Verastem favors the higher dose

Ting Wu, Verastem’s vice president of clinical development, said disclosed clinical data showed a clear dose response between 600 and 900 milligrams. Drug exposure also rose proportionately with the dose, she said, while the tolerability profiles were identical.

Wu said partner GenFleet had dosed only three patients at 900 milligrams and chose to pursue 600 milligrams for speed rather than fully explore the higher dose. Chief Scientific Officer Jonathan Pachter said Verastem plans to use 900 milligrams across cancer indications and hopes to do so across combinations as well.

Pachter argued that VS-7375’s selectivity for the KRAS G12D variant and its activity against both the “on” and “off” states of the target distinguish it from other RAS inhibitors. He said the drug’s single-agent activity is important because patients may not be able to tolerate chemotherapy indefinitely.

For previously treated pancreatic cancer, Wu said the company is aiming for a single-agent response rate above 40% and progression-free survival above seven to nine months. Verastem plans to provide follow-up progression-free survival data from a disclosed 22-patient, 900-milligram dataset at future medical conferences, she said.

Combination and approval plans

Verastem is evaluating both chemotherapy-based and chemotherapy-free regimens in its planned TARGET-D 301 phase 3 pancreatic cancer study. Pachter said preclinical research supports combining VS-7375 with the EGFR inhibitor cetuximab, and Wu said early clinical responses with the combination have appeared faster and deeper than with monotherapy.

Pachter also cited a GenFleet update reporting a 71% response rate for the same G12D inhibitor combined with cetuximab in frontline pancreatic cancer. Wu confirmed that either regimen in TARGET-D 301 could produce a positive result for the trial; both would not need to succeed. The company has not disclosed details of the statistical plan.

In previously treated pancreatic cancer, Verastem believes it could pursue accelerated approval if its response and durability data hold up, Wu said. She pointed to an FDA review showing a 24% response rate in the G12D population for daraxonrasib, compared with 30% overall, as evidence of remaining need.

Pachter said the company expects its phase 2 pancreatic study to be fully enrolled by year-end and could have data as early as the middle of the following year for an accelerated approval submission. For the frontline phase 3 study, Wu said a potential accelerated approval would depend on the data reviewed by the FDA.

Colorectal, lung and financing updates

Wu said Verastem expects to disclose colorectal cancer data from approximately 10 phase 1 patients around the first quarter of 2027. Its phase 2 TARGET-D 203 study had dosed more than 50 patients, she said, with cohort data expected around the third or fourth quarter of 2027.

In lung cancer, Wu said physicians consulted by the company viewed a roughly 15-percentage-point difference in objective response rate, accompanied by longer progression-free survival, as clinically meaningful. Verastem is also studying activity in patients with central nervous system metastases and hopes to generate data in 2027.

Addressing differences between safety data from China and the U.S., Wu said Verastem had managed gastrointestinal adverse events proactively, including through preventive anti-nausea medication. She said the company had not seen meaningful hematologic adverse events in its ex-China population or a trend toward liver-function abnormalities in the data it reviewed. Possible explanations for regional differences remained uncertain, she said.

Wu said Verastem raised $250 million and has more than $400 million in pro forma cash. The funding is expected to support completion of the phase 2 studies and initiation of three phase 3 studies, she said. Pachter added that the pace of starting the frontline phase 3 trials is not dictated by the status of the phase 2 studies.

About Verastem (NASDAQ:VSTM)

Verastem, Inc. is a biopharmaceutical company focused on developing and commercializing medicines for cancer. Its research has centered on signaling pathways involved in tumor growth, including the RAS/MAPK pathway. The company's product, AVMAPKI FAKZYNJA CO-PACK, combines avutometinib and defactinib. The U.S. Food and Drug Administration approved the combination for certain adults with KRAS-mutated recurrent low-grade serous ovarian cancer who have received prior systemic therapy. Verastem is based in Needham, Massachusetts, and also develops investigational cancer therapies, including potential uses of avutometinib in combination with other medicines.

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