New medicines called RAS inhibitors are dramatically changing the way pancreatic cancer will be treated over the coming years. They are a beacon of hope for patients with the disease.
There are several oral RAS inhibitors for pancreatic cancer in late phase clinical trials, including one that has been given an initial regulatory green light for expanded access in previously treated metastatic pancreatic cancer. Dozens of RAS inhibitors are in or are being considered for evaluation in clinical trials.
“I don’t think we’ve ever been in a circumstance like this in oncology where you have dozens of different agents for such an important target all coming to the clinic at the same time,” says Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber, who has been leading clinical development of an important RAS inhibitor called daraxonrasib. “It is unprecedented.”
What is RAS and why is it important in pancreatic cancer?
The RAS family of proteins is known to be mutated in ways that drive the growth of many forms of cancer. Between 90 and 95 percent of patients with pancreatic cancer have tumors with a mutant form of a RAS family protein called KRAS.
Dana-Farber science has shown that KRAS mutations are sufficient to initiate pancreatic cancer, making KRAS inhibitors a potentially valuable tool for nearly every patient with pancreatic cancer. Drugs that inhibit KRAS are commonly referred to as RAS inhibitors.
What is a RAS inhibitor?
RAS inhibitors are medicines that block the ability of mutant RAS proteins to turn on growth signals in tumor cells. For a long time, RAS proteins were “undruggable,” but that changed over the last decade. Several pharmaceutical companies have developed new medicines that target individual RAS mutants, such as KRAS G12C (common in lung cancers) and KRAS G12D (common in pancreatic cancer), and agents that target multiple RAS mutants, called pan-RAS inhibitors.
Two mutation-specific KRAS G12C inhibitors are approved by the U.S Food and Drug Administration (FDA) for forms of colorectal and lung cancer and pan-RAS inhibitors are currently under regulatory review for pancreatic cancer.
Will I be given a RAS inhibitor?
While the FDA has granted expanded access to daraxonrasib for patients with advanced, previously treated pancreatic cancer, most RAS inhibitors for pancreatic cancer are available only through clinical trials at this time. There are many RAS inhibitors being evaluated for patients in a range of different scenarios.
Consult with your care team to determine if there is a trial that would be a good fit for you.
What are the side effects of RAS inhibitors for pancreatic cancer?
Side effects will vary depending on the RAS inhibitor.
The drug daraxonrasib can cause a skin rash or diarrhea, though the severity varies. Most patients experience a mild rash, some have no rash, and others may develop a more painful rash.
Side effects like these can be managed with supportive medicines, dose modifications, and other approaches. Work with your care team to manage side effects.
“Compared to chemotherapy, the side effects of this oral medicine are much more manageable,” says Dana-Farber gastrointestinal oncologist and clinical investigator Brandon Huffman, MD.
Talk with your care team about what to expect.
What research is underway related to RAS inhibitors for pancreatic cancer?
An astonishing number of clinical trials are underway to evaluate the safety and efficacy of RAS inhibitors in patients with pancreatic cancer.
For instance, the drug daraxonrasib is being tested in several patient groups:
- In combination with chemotherapy as first-line treatment in patients with newly diagnosed metastatic pancreatic cancer.
- As a therapy after surgery for early-stage pancreatic cancer to reduce the risk of recurrence.
- As a potential therapy prior to surgery for early-stage pancreatic cancer.
There may also be an opportunity to test daraxonrasib in patients at high risk of pancreatic cancer, or patients with precancerous pancreatic lesions, since it is known that RAS mutations initiate the cancer.
“Could we treat these patients before they have cancer and clear out those early lesions, wiping the slate clean so to speak?” asks Andrew Aguirre, MD, PhD, co-director of the Center for RAS Therapeutics and Associate Director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber.
There are also many other RAS targeted treatments that are being tested in clinical trials for pancreatic cancer, including:
- Drugs that inhibit or degrade the RAS mutant protein.
- T cell therapy that targets RAS mutations.
- RAS-targeted vaccines.
Dana-Farber investigators like Wolpin, Huffman, and Aguirre are working closely with researchers and pharmaceutical companies to determine which novel agents are most promising and most likely to benefit patients.
In addition, laboratory researchers are at work at Dana-Farber and elsewhere looking for novel opportunities for combining RAS inhibitors in new ways, such as with immunotherapies, and for developing innovative medicines related to RAS inhibition.