Combination of RAS inhibition and immunotherapy provides breakthrough for pancreatic cancer

Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS kept pancreatic cancer at bay in preclinical models for significantly longer than the same targeted therapy by itself, according to researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine's Abramson Cancer Center. The results, published in Cancer Discovery, prime the combination strategy for future clinical trials.

Combatting the "undruggable" RAS genes

Patients with pancreatic cancer have an overall poor prognosis: in most patients, the disease has already spread at the time of diagnosis, resulting in limited treatment options. Nearly 90 percent of pancreatic cancers are driven by KRAS mutations, the most common cancer-causing gene mutation across cancer types, which researchers long considered "undruggable." In 2021, the first KRAS inhibitor was approved to treat non-small cell lung cancer with KRAS G12C mutations, but with longer follow-up, it has become clear that KRAS-mutant cancers can quickly evolve to resist therapies targeted at one specific form of the gene mutation.

We've been excited by the prospect of RAS inhibition for pancreatic cancer, which remains one of the deadliest and most difficult forms of cancer to treat. While the first wave of KRAS inhibitors have had limited impact in cancer care, this research shows that newer RAS inhibition tools may have an immune stimulatory effect, making them ideal to pair with immunotherapy for longer and better treatment response."

Ben Stanger, MD, PhD, co-corresponding senior author, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center

Previous research led by Stanger and Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center, who is also co-corresponding author on this study, showed that a small molecule inhibitor specifically targeting KRAS G12D, the form of the mutation more commonly found in pancreatic cancer, stimulated the immune system while shrinking tumors or stopping cancer growth in preclinical mouse models of pancreatic cancer.

A new type of RAS inhibitor

In this study, the researchers used RAS(ON) multi-selective inhibitors, the investigational agent daraxonrasib (RMC-6236) and the preclinical tool compound RMC-7977 (both discovered by Revolution Medicines, whose scientists contributed to the study). These inhibitors use a different mechanism of action than most other KRAS inhibitors (including that in the previous study) to target the active or ON-state of multiple forms of RAS mutations.

"The benefit of this 'multi-selective' approach is that the inhibitors are designed to inhibit multiple RAS mutations, so if the cancer mutates, and another type of RAS mutation emerges, the treatment may not necessarily stop working," Vonderheide explained.

The research team found that not only was RAS(ON) multi-selective inhibition effective in preclinical pancreatic cancer models, but it was even more effective when combined with immunotherapy. Using the combination approach, all mouse models had tumor shrinkage and half had a complete response, meaning the tumor was eliminated.

The research team used a Penn-developed immunocompetent model considered the gold standard worldwide for assessing potential therapies for pancreatic ductal adenocarcinoma. This model allows the tumor to spontaneously evolve after implantation, making it possible to discern the drug's impact on the surrounding tumor microenvironment. The research team found that RAS(ON) multi-selective inhibition reshaped the tumor microenvironment by bringing in more T cells and other immune cells, making the tumor particularly receptive to immunotherapy.

Next steps and clinical trial information

Daraxonrasib (RMC-6236) is already being tested in clinical trials across the United States. A clinical trial testing RAS(ON) inhibitors with other anticancer agents in certain patients with gastrointestinal solid tumors is now open at several sites across the country, including at Penn Medicine. 

"We're hopeful that we're starting to crack the code on immunotherapy and RAS therapy for pancreatic cancer," Vonderheide said. "After decades of limited progress, it's encouraging to see new treatment approaches making their way into the clinic for patients."

The study was supported by Revolution Medicines, the National Institutes of Health (R01CA252225, R01CA276512, P30DK050306, P30CA016520) the Department of Defense (W81XWH2210730), the Molecular Pathology and Imaging Core, A Love for Life, the Basser Center for BRCA, and the Penn Pancreatic Cancer Research Center.