A new drug that targets a gene behind pancreatic cancer has physicians and researchers cautiously optimistic about improved treatment for one of the deadliest cancers.
Revolution Medicines, the pharmaceutical company behind the new drug, will release more in-depth data Sunday on the clinical trial testing of its pill.
The pill is called daraxonrasib, and it’s part of a class of drugs known as RAS inhibitors that target the KRAS gene. Mutations of that gene are found in more than 90% of patients with the most common type of pancreatic cancer, as well as 40 to 45% percent of colorectal cancer patients and up to 30% percent of people with non-small cell lung cancer.
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The five-year survival rate for pancreatic cancer, which is difficult to detect early and among the hardest to treat, once it has spread to other parts of the body is only 3%, and the vast majority of patients are diagnosed when the cancer is more advanced.
But experts not involved with the drug’s development told PBS News that the preliminary data in the daraxonrasib trial are raising hopes for prolonging those patients’ lives.
The early ‘extraordinary’ results in the clinical trial for daraxonrasib
Revolution Medicines released the initial results of the Phase 1 and 2 trial at the end of April with a promising breakthrough: The overall survival rate for people who got daraxonrasib was 13.2 months, nearly double the 6.7 months people survived on standard chemotherapy alone.
Patients received the pill as a “second line” treatment after they’d been treated for their cancer or received standard chemotherapy.
“For that to exceed one year is really extraordinary,” said Dr. Emil Lou, professor of medicine at the University of Minnesota Medical School and medical oncologist.
Among the 168 patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, 26 had the RAS G12 gene mutation, which is the most prevalent KRAS mutation in patients with PDAC.
More than one third of those patients with that mutation had an “objective response” to the drug, meaning their tumor shrank on a CT scan by 30% or more, said Dr. Elizabeth Jaffee, oncology professor and deputy director of Johns Hopkins’ Sidney Kimmel Cancer Center. Within that same group, the drug also extended the amount of time people lived without their cancer progressing. The median amount of time these patients lived was 13.1 months, with 8.5 months of “progression-free survival.”
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The drug also caused severe side effects in about 30% of the patients. Revolution Medicines found that 90% of patients experienced a rash, and about half had diarrhea, or inflammation of the mouth or GI tract.
How one discovery ‘opened up the whole field’
The drug targets the KRAS gene, which is present in as much as 20% or more of all cancers, Lou said.
Researchers have found that when KRAS is dysregulated, or not controllable, it’s constantly overstimulating the rest of the cell it’s in, which can lead to cancer.
KRAS has been considered “undruggable” for decades, said Dr. Despina Siolas, assistant professor of medicine at Weill Cornell Medical College. This is partly because of the gene’s smooth structure, which makes it hard for researchers to find a place for proteins to bind to. KRAS is also inside the cell as opposed to being on the surface.
“You would need a drug that needs to be able to fit this particular structure and penetrate the cell,” Siolas said.
For years, researchers tried to target KRAS because its mutation is present in nearly all PDAC patients, she added.
But in 2013, scientists identified a small pocket in KRAS that wasn’t known before, and pharmaceutical companies collaborated with universities and investigators to develop drugs that can bind to that pocket.
“That just opened up the whole field,” Jaffee said.
“For all the years that I’ve been treating and developing new therapies for pancreatic cancer, it’s still a death sentence.”
Now, daraxonrasib has been shown to target multiple mutations of the KRAS gene, which means physicians won’t have to screen each patient to see which mutation they have, Jaffee said.
“For all the years that I’ve been treating and developing new therapies for pancreatic cancer, it’s still a death sentence,” she said.
Chemotherapy, which can be hard to tolerate, often only gives patients months of life, she added, and even “curable” cancers may still return.
Daraxonrasib has “manageable toxicities” compared to chemotherapy, Jaffee said. The once-daily pill’s side effects include rash, diarrhea, nausea, inflammation, vomiting and fatigue, early results have shown.
What are the drawbacks?
Besides side effects, there are a handful of concerns about daraxonrasib.
The Food and Drug Administration fast-tracked limited approval for the drug on April 30, permitting “expanded access” for eligible patients. But right now, doctors don’t have access to it, Lou said.
While Lou practices at a large, university-based health center, he said most people get cancer treatment in community settings. That difference in access to resources could lead to equity issues.
“There’s no shortage of demand for patients at all stages, at all times since their time of diagnosis, who are anxiously waiting to have it available,” Lou said.
Cost is another concern. It’s not yet clear what the drug’s price will be. Since daraxonrasib is taken daily, patients may need hundreds of pills, and targeted therapies in general are not cheap, Lou said.
Oral targeted therapies in the past 20 years have run “tens of thousands per month,” he said, not to mention the complications in trying to get widespread insurance coverage.
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Siolas said drugs taken orally also require patients to be able to swallow and digest medications, which is not always a given in cancer patients.
What comes next?
Revolution Medicines will unveil the full results of their Phase 3 trial on Sunday at the American Society of Clinical Oncology annual meeting in Chicago.
There are hopes among experts that daraxonrasib, and others in its class, could be used earlier in the treatment process — or potentially alongside targeted immunotherapy or surgery — which may improve both length and quality of life for cancer patients.
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“We’re very hopeful that we’re going to see even better results when we start this drug earlier,” Jaffee said.
Jaffee hopes the trajectory of treatment for pancreatic cancer might someday mirror that of HIV, which was also once a fatal diagnosis. When scientists discovered a treatment for HIV in the late 1980s, then later identified how the disease was resistant to that treatment, they developed more drugs to fight three different pathways at once, she said.
With daraxonrasib, “we’ve hit on the first component of this pathway,” she said. “Now we have to figure out combinations. This will be a little bit more complex, obviously. But a lot of work’s already being done.”
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