Tackling KRAS G12D

The oncogene KRAS is taking center stage in pancreatic cancer research.

Drugs targeting RAS, and KRAS in particular, are poised to potentially change the treatment of metastatic disease. While the current focus has been on the KRAS inhibitor daraxonrasib, there are many other KRAS inhibitors in the pipeline. These drugs are not carbon copies of each other; different inhibitors target KRAS and its variants differently.

One such agent is VS-7375, from Verastem Oncology, which targets KRAS G12D in its so-called “on” and “off” state. Interim results from a phase I/II trial, which is currently recruiting, are very promising. The drug was granted a Fast Track designation by the FDA in 2025 for the first-line treatment of patients with KRAS G12D-mutated locally advanced or metastatic pancreatic cancer, whether they have had chemotherapy or not. (Fast Track is a process designed to facilitate the development and expedite the review of new drugs intended to treat or prevent serious conditions and address unmet medical needs.)

What Is VS-7375?

 KRAS mutations are among the most common genes that help drive normal cells to become cancerous across many solid tumors. Mutations in the KRAS gene are the primary driver for more than 90 percent of pancreatic cancers, explains gastrointestinal oncologist Leon Pappas, M.D., Ph.D., M.S.C., who is leading the phase I/II study of the drug at Massachusetts General Hospital in Boston.

There is a significant amount of variety in KRAS mutations and the efficacy of drugs for them. There are drugs effective against KRAS G12C, found in about 13 percent of lung cancers but very few pancreatic cancers. This KRAS mutation presents a “hook” that traditional, covalent drugs can “latch on” to KRAS G12D, the mutation that drives about 40 percent of pancreatic cancers, does not present that opportunity. The G12D mutation lacks a so-called binding pocket necessary for drug interaction.

But unlike KRAS G12C mutations, which have been comparatively more straightforward to target with conventional drug development methods, it’s been a “greater challenge to target KRAS G12D because it doesn’t offer the same chemical ‘hook’ as KRAS G12C and spends more time on the active, ‘on’ state of the molecule,” Pappas says. Indeed, the unique structure of KRAS G12D makes it a tough target.  

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Moreover, the G12C mutant version of the KRAS protein spends more time in the inactive “off” state of the molecule. This allows drugs to bind to and inhibit the protein using a specific pocket, to lock the protein into an “off” state. Targeting the G12D mutation is much more complex because it spends more time in the active “on” state. That’s where VS-7375 comes into play.

Older inhibitors generally bind to KRAS in its resting state, or in science speak its inactive guanosine diphosphate-bound (GDP-bound)  “off”state. But VS-7375 is designed to inhibit both the active guanosine triphosphate-bound (GTP-bound) “on” state as well as its “off” state. By targeting both the on and off states of KRAS, signaling can be shut down through the RAS/MAPK pathway, Pappas explains. “The pathway (RAS/MAPK) is responsible for messaging that controls cell behaviors like survival, growth, and division,” he notes. “When there’s a mutation, that signaling drives uncontrolled cell growth, which is the definition of cancer. By shutting down that signaling you are, in theory, shutting down the signals driving the cancer.”

Indeed, early interim results from the phase I/II study are promising. The study is evaluating the safety and efficacy of VS-7375 in patients with previously-treated advanced KRAS G12D mutant solid tumors, including advanced pancreatic cancer, both as monotherapy and in combination with other standard of care treatments.

In results reported in the fourth quarter of 2025, VS-7375 cleared both the 400 mg daily and 600 mg monotherapy doses with no dose-limiting toxicities observed, according to the company. In addition, no new safety signals have been observed relative to results, as indicated by earlier data presentations in both pancreatic cancer and non-small cell lung cancer by Verastem partner GenFleet Therapeutics, in its ongoing phase I/II clinical study in China evaluating VS-7375 (known as GFH375).

Specifically, at the two dose levels evaluated in the U.S. cohorts, no nausea, vomiting, or diarrhea greater than Grade 1 were reported. Monotherapy dose escalation in the VS-7375 study started at doses identified in GenFleet’s study, 400 mg and 600 mg. GenFleet chose 600 mg as their recommended Phase 2 dose in China.

In June of 2026, the company announced further dose escalation and expansion highlights. For example, promising clinical activity was observed at 900 mg monotherapy in previously-treated metastatic pancreatic cancer, with evidence of dose-dependent anti-tumor activity between 600 mg and 900 mg. The safety profile was favorable, with adverse events primarily consisting of low-grade nausea, vomiting, and diarrhea, which decreased over time.

Further Trials

Verastem also announced the initiation of a trial dubbed TARGET-D 201. This trial is a phase II, open-label, multicenter study to evaluate VS-7375 at 900 mg once daily both as monotherapy and in combination with full-dose cetuximab in patients with second-line metastatic pancreatic ductal carcinoma. The study is also evaluating VS-7375 900 mg and cetuximab in the first-line metastatic pancreatic cancer setting, representing a potential chemotherapy-free frontline regimen, according to the company.

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Although the drug is exciting and represents a novel approach to tackling a tough-to-target KRAS mutation, it’s important to note that larger, randomized phase III trials remain the gold standard for comprehensive evaluation of activity in a specific clinical setting, says Pappas. “This is a molecule with a sound biological rationale and promising early-phase results,” he adds. “We look forward to seeing how the drug performs in the expansion cohorts and in combination with cetuximab, and of course in the upcoming larger advanced trials.”

The excitement about options now available to patients is palpable, he notes. “In the span of only a few years, we have seen a flurry of drug development targeting RAS, and multiple patients achieving notable benefit from these drugs,” Pappas states. “These are significant advances for patients with pancreatic cancer, and I am excited for the future of RAS targeting in this disease.”