Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation 

 at bay in preclinical models for significantly longer than the same targeted therapy by itself, according to researchers from the 

 at the University of Pennsylvania and Penn Medicine’s 

, 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 

 mutations, the most common cancer-causing gene mutation across cancer types, which researchers long considered “undruggable.” In 2021, the first 

 inhibitor was approved to treat non-small cell lung cancer with 

 mutations, but with longer follow-up, it has become clear that 

-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 

 inhibition for pancreatic cancer, which remains one of the deadliest and most difficult forms of cancer to treat,” said co-corresponding senior author 

, the Hanna Wise Professor in Cancer Research and director of the 

 inhibitors have had limited impact in cancer care, this research shows that newer 

 inhibition tools may have an immune stimulatory effect, making them ideal to pair with immunotherapy for longer and better treatment response.”

, director of the Abramson Cancer Center, who is also co-corresponding author on this study, showed that a small molecule inhibitor specifically targeting 

 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.

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 

 inhibitors (including that in the previous study) to target the active or ON-state of multiple forms of 

“The benefit of this ‘multi-selective’ approach is that the inhibitors are designed to inhibit multiple 

 mutations, so if the cancer mutates, and another type of 

 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. 

Click here for more information about the study

“We’re hopeful that we’re starting to crack the code on immunotherapy and 

 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.

Information for patients interested in joining a clinical trial:

visit Penn Medicine's Abramson Cancer Center Clinical Trial Information Service online

 or call 1-855-216-0098 to speak to a clinical trial navigator.

Editor’s note: Vonderheide is an inventor on patents relating to cancer cellular immunotherapy and KRAS immune epitopes.

Articles

Researchers have found that combining immunotherapy with a new type of inhibitor targeting multiple KRAS mutations significantly prolongs the suppression of pancreatic cancer in preclinical models. This combination strategy, which includes the investigational agent daraxonrasib, shows promise for future clinical trials. The multi-selective inhibitors target the active state of various RAS mutations, potentially overcoming resistance seen with single-target KRAS inhibitors. The approach reshapes the tumor microenvironment, enhancing immune cell infiltration and making tumors more receptive to immunotherapy, offering hope for improved treatment outcomes in pancreatic cancer.

A preclinical study offers a foundation for a combination strategy in future clinical trials for KRAS mutations.


Immunotherapy May Boost KRAS-Targeted Therapy in Pancreatic Cancer

Cancer patients spend a lot of time on their care. Meeting with doctors and other members of their health care team, getting labs and other tests, picking up prescriptions, and undergoing treatment all takes time. So does getting to and from each appointment, sitting in the waiting room between each appointment, and so on.

In recent years, cancer researchers have worked to quantify the level of “time toxicity” or time spent commuting to, waiting for, and receiving cancer treatment. Now, for the first time, a pilot study has shown it’s possible to use digital technology to safely reduce the amount of time some patients spend receiving care. With a simple text-messaging system, patients saved more than an hour at each visit captured by the study, which was led by researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center, and published in 

“Patients with cancer spend an enormous amount of time engaging with the health care system, and for patients with advanced cancer in particular, that time is precious,” said senior author Ronac Mamtani, MD, section chief of Genitourinary Cancers. “We developed a safe and effective platform that—for certain patients—could really challenge the status quo and give them quality time back.”

Inspired by the efficiency of the TSA pre-check line to bypass long lines at the airport, Mamtani and former Penn oncology fellow and lead author Erin M. Bange, MD, MSCE, now an assistant professor at Memorial Sloan Kettering Cancer Center, developed a text message-based platform using the Center for Health Care Transformation and Innovation’s Way to Health platform to obtain patient reported-symptoms and make sure patients are ready for immunotherapy treatment. Patients receiving immunotherapy for cancer treatment are currently required to complete bloodwork and meet with their health care team in the office before every infusion to confirm they have not developed any concerning symptoms that might signal a reaction to the immunotherapy and a need to pause treatment. The pre-treatment symptom check is a necessary safety measure that many patients treated with immunotherapy pass with flying colors, given the relatively low rate of side effects for immunotherapy compared to traditional chemotherapy.

In this pilot clinical trial, patients receiving single-agent immunotherapy for solid tumor cancers at Penn Medicine’s Abramson Cancer Center were enrolled and randomized to either an in-person pre-infusion symptom check in the office with their provider, or to complete a 16-question symptom check, estimated to take less than five minutes, via the text message platform. If their labs were normal and no symptoms were reported, patients were given the option to fast-track and bypass the in-person visit, proceeding directly to their immunotherapy infusion. The 16 patients who were fast-tracked saved more than 60 minutes per visit, including 30 minutes less wait time, than the 15 patients who were randomized to continue with the usual in-person visit.

More importantly, the fast-track system was safe, with no difference in post-infusion hospital visits or health-related quality of life impact compared to usual care.

“Considering that patients who consented for the study told us that saving even 45 minutes per visit would significantly impact their lives, we were excited to see that our first test of this tool surpassed expectations, giving patients even more time back each time they went in for treatment,” Bange said.

While patient-reported outcomes have been used in other studies to assess various quality of life measures, the authors note that this study is the first time digital patient-reported outcomes have been used to streamline cancer care delivery.

A total of 19 additional patients who reported their symptoms via the text message platform were eligible for fast-track, but ended up continuing with the in-person visit instead, due to patient preference, provider preference, or other care coordination issues. The study team emphasized that some patients may prefer to continue in-person visits, and the team’s vision for the text message platform is to be an option for patients who want to use it, rather than a one-size-fits-all approach.

The team also conducted focus groups with health care providers to better understand any concerns about the fast-track process and potential barriers to broader implementation.

“Our goal is to ultimately test this strategy in a pragmatic trial, where it’s used in a real-world setting and not the controlled setting of a traditional clinical trial, but we want to be sure that we have the best-designed tool to effectively meet both provider and patient needs, so we’re taking time to assess the feedback and refine our approach before moving forward,” Mamtani said. “Cancer patients are repeatedly asked to hurry up and wait while getting care. What we’re trying to address is just the tip of the iceberg in terms of giving patients valuable time back to focus on living.”

The study was supported by an ASCO Conquer Cancer Young Investigator Award, Marjorie and Bryan Weingarten Fellowship Grant, the Health Network Foundation, and the National Institutes of Health/National Cancer Institute (P30CA016520).

A pilot study demonstrated the potential of digital technology to reduce "time toxicity" for cancer patients by using a text-messaging system to streamline pre-infusion symptom checks. This approach allowed patients to bypass in-person visits, saving over an hour per visit without compromising safety or quality of life. The study, conducted by researchers from the Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center, highlights the importance of patient-reported outcomes in optimizing cancer care delivery. Future research aims to refine and expand this strategy in real-world settings.

In pilot study, patients saved over an hour of time at every treatment visit.

Penn Medicine

Articles

Immunotherapy May Boost KRAS-Targeted Therapy in Pancreatic Cancer

Text Message Tool Addresses "Time Toxicity" for Patients With Cancer