For decades, one gene has been at the center of some of cancer’s most aggressive and hard-to-treat tumors. The KRAS (Kirsten rat sarcoma virus) gene is mutated in roughly 30 percent of human cancers and acts as a master switch that tells cells when to grow and divide. When a mutation locks this switch into the “on” position, cancer can spread quickly and resist even intensive treatment like chemotherapy and radiation.
KRAS G12D is one of the most common mutations in the KRAS gene and is found across a range of cancers. Depending on the cancer type, it accounts for 20–50 percent of KRAS-mutated tumors, including roughly one-third of pancreatic cancers, half of ampullary carcinomas, 48 percent of appendiceal adenocarcinomas, 44 percent of cholangiocarcinomas, and smaller but notable proportions of small bowel and colorectal cancers.
KRAS G12D is the most common KRAS mutation in pancreatic ductal adenocarcinomas (PDAC), the most aggressive and lethal form of pancreatic cancer, with a five-year survival rate below five percent and few effective treatment options. Patients with KRAS G12D mutations typically have a worse prognosis than patients with other KRAS variants. And until recently, there were no drugs capable of directly targeting it.
Now, early clinical results suggest that such a strategy may finally be emerging. In October, Verastem Oncology reported preliminary findings from its Phase 1/2a trial of VS-7375, an oral KRAS G12D inhibitor designed to block the protein in both its active and inactive states.
A growing field of inhibitors
For decades, the K-Ras protein has been considered ‘undruggable’ because its surface lacks the deep pockets that small molecules need to bind. That perception began to shift in 2013, when researchers discovered a previously hidden pocket in a related mutated protein, KRAS G12C. This led to the development of G12C-targeted inhibitors, such as sotorasib and adagrasib, which are now approved for patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC).
G12D, however, is harder to target than G12C. Dan Paterson, President and CEO of Verastem, explained to DDN, “The KRAS G12D mutation has been challenging to target because it lacks an accessible binding pocket needed for drug interaction and inhibition. In addition to binding issues, drug absorption and bioavailability have also been challenging barriers for recent investigative candidates to overcome.” Despite these challenges, several drug candidates are now in preclinical or early clinical testing, each using a different strategy.
One of the earliest discoveries in the field was in 2021 with MRTX1133, a non-covalent inhibitor that can bind both the active and inactive forms of the K-Ras protein. By preventing downstream signaling, MRTX1133 provided the first proof of concept that the historically ‘undruggable’ G12D mutation could be targeted effectively with small molecules. Since then, preclinical studies have shown it has robust anti-tumor activity, and the compound has now moved into Phase 1 clinical trials.
In 2024, another KRAS G12D inhibitor, HRS-4642, was developed and tested. This high-affinity, selective inhibitor blocks the K-Ras protein from binding to key proteins, inhibiting the signaling pathway that drives tumor growth. Early Phase 1 data in NSCLC showed preliminary evidence of anti-tumor activity, with some patients achieving partial responses.
Other investigational approaches include AST2169, a liposomal KRAS G12D inhibitor that downregulates multiple signaling pathways and induces apoptosis in tumor cells, and RMC-9805, a covalent, mutation-selective inhibitor that binds to the active form of the K-Ras protein with the help of cyclophilin A, blocking the signaling pathways that promote tumor growth. Another strategy is ASP3082, a targeted protein degrader that recruits an E3 ubiquitin ligase to selectively degrade the K-Ras protein.
Verastem Oncology, in partnership with GenFleet Therapeutics, have developed VS-7375, a first-in-class oral therapy with a unique ON/OFF mechanism that disrupts multiple downstream signaling pathways. Jonathan Pachter, Chief Scientific Officer at Verastem, said, “We believe VS-7375, an oral G12D inhibitor, has best-in-class potential by targeting both the active (“ON”) and inactive (“OFF”) forms of KRAS G12D. This dual mechanism is designed to enable deep and durable inhibition of tumor growth, which can lead to greater and more sustained anti-tumor activity than inhibitors that target only one state of the protein.”
Early clinical data from Phase 1/2 trials in China and the US indicate robust tumor responses and a manageable safety profile, making it one of the leading candidates in the current pipeline.
A glimmer of hope
Verastem Oncology’s Phase 1/2a trial of VS-7375 recruited patients with advanced solid tumors, including pancreatic cancer. The early results showed that the first two monotherapy dose levels, 400mg and 600mg daily, were well tolerated with no dose-limiting toxicities and only mild gastrointestinal side effects.
In the first evaluable group of patients with advanced KRAS G12D-mutant cancers, four out of five patients experienced tumor shrinkage and now remain on the treatment. These early findings build on recent results from GenFleet Therapeutics, where preliminary data showed a 58 percent response rate in patients receiving second-line treatment for PDAC and a 68 percent response rate in previously treated NSCLC, according to Pachter.
The US study is now escalating to a higher dose and has opened a combination arm pairing VS-7375 with cetuximab, aimed initially at colorectal cancer but with implications across solid tumors.
If future results continue to show benefit — and confirm durability — VS-7375 could represent one of the first mutation-specific targeted therapies for pancreatic cancer. While the data is still early and the patient numbers are small, it’s hard not to be optimistic when the field has been waiting decades for a therapy that can directly hit KRAS G12D.
