An experimental pancreatic cancer drug that’s been shown to double survival in patients with advanced stages of the disease is poised to revolutionize the way the cancer is treated, oncologists say.
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The drug, called daraxonrasib, has already been fast-tracked for approval by the Food and Drug Administration. Last week, the agency said it would permit the drugmaker Revolution Medicines to give the drug to patients outside of clinical trials in an expanded access program.
In April, Revolution Medicines released early findings from its Phase 3 clinical trial of the drug, which found that patients who got daraxonrasib in addition to chemotherapy saw double the survival time compared with patients who just got chemotherapy.
On Wednesday, results from an earlier phase of the clinical trial were published in the New England Journal of Medicine, showing that in patients whose cancer had spread to other parts of the body, daraxonrasib stopped tumors from getting worse for more than eight months and kept patients alive for up to nearly a year and a half.
The results represent an extraordinary advance in treating pancreatic cancer. The disease is usually found only after it’s spread elsewhere in the body. Even with chemotherapy, many patients don’t live more than a year after diagnosis. Just 3% of patients diagnosed with metastatic pancreatic cancer are alive five years later, according to the American Cancer Society.
“We have been desperately working very hard trying to find other ways to treat the cancer,” said Dr. Brian Wolpin, who led the new research on daraxonrasib and directs the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute in Boston. “This really feels like a watershed moment. It’s going to shift how we think about treatment for pancreatic cancer overall.”
Daraxonrasib targets a protein called RAS, which manages how cells grow in the body. More than 90% of pancreatic cancers have a mutation in the gene for the RAS protein, forcing it into a permanent “on” position, allowing cells to grow out of control.
The protein has long been considered “undruggable,” after years of failed attempts to target and block RAS. Daraxonrasib solves the problem by pairing up with a protein called cyclophilin A inside cells. The duo work like a “molecular glue,” Wolpin said, and are able to glom onto RAS, blocking it from wreaking additional havoc.
The results published Wednesday are from a Phase 1/2 study, which looked at the drug’s safety and the appropriate dose. All of the 168 patients had advanced pancreatic cancer that had spread to other parts of the body, particularly the lung and liver. All previously had standard chemotherapy.
In patients who got the highest dose of the drug, progression-free survival — that is, how long it took before the cancer got worse — was about 8.1 months and overall survival was about 15.6 months.
There were side effects — most notably a blistering rash that looks like a bad sunburn, sores in the mouth and throat, and vomiting and diarrhea. (Former Sen. Ben Sasse, R-Neb., who has taken the drug through a clinical trial, described the rash as “nuclear” on a New York Times podcast last month. Sasse was diagnosed with Stage 4 pancreatic cancer last year and said his tumors have shrunk significantly since he started the drug.)
Wolpin said that some patients had to stop taking the drug temporarily “to let the rash calm down.”
Overall, he said, the drug is “much more tolerable than chemo. Most patients greatly prefer the ability to take a pill every day rather than do all of those infusions.”
Most side effects from daraxonrasib were treated with antibiotics, topical creams and anti-diarrheal medication. They were considered severe in about 30% of patients, and eight people left the trial because of them.
In the Phase 3 trial, which the research team is scheduled to present later this month at the American Society of Clinical Oncology’s annual meeting, the researchers found overall survival for the chemo-only group was 6.7 months, compared with 13.2 months in the combo treatment group. What’s more, the Phase 3 trial included patients without the KRAS mutation — suggesting potentially that all pancreatic cancer patients might benefit in some way.
“I think we’re going to stop thinking of chemotherapy as something that you have to give to everyone,” Wolpin said.
Enthusiasm for the drug’s potential has reverberated among doctors who treat pancreatic cancer patients.
“Those of us who take care of this disease are, frankly, a little cynical about new data that comes out, especially data that gets a lot of press in the general media, because most of the time it is overhyped,” said Dr. Reza Nazemzadeh, a gastrointestinal medical oncologist at Atrium Health Levine Cancer in Charlotte, North Carolina. “But this is a big deal. This drug is the most exciting thing in pancreas cancer in over a decade.”
Nazemzadeh was not involved in daraxonrasib clinical trials but has had patients who did join trials. Anecdotally, he said those patients did well and that the drug gave them more time with their loved ones than they would have had with other therapies.
“I don’t use the word ‘groundbreaking’ lightly,” said Dr. Sekhar Padmanabhan, a surgical oncologist and director of robotic liver, pancreas and bile duct surgery at Vanderbilt University Medical Center. “This is going to have a significant impact on how we take care of our patients.”
More than 67,000 people in the U.S. are expected to be diagnosed with pancreatic cancer this year, according to the American Cancer Society. There is no screening for the cancer and early symptoms are often so vague that the majority of people, 80%, are diagnosed at later stages of the disease, when it’s much more difficult to treat. More than 52,000 people are predicted to die of the disease this year.
Dr. Dae Won Kim, a gastrointestinal medical oncologist at Moffitt Cancer Center in Tampa, Florida, who was also not involved with the research, said he expects the FDA to move quickly to approve the drug.
Mutations in the RAS gene are not limited to pancreatic cancer. Researchers are also studying whether the drug will work in patients with RAS-mutated colorectal and lung cancers.
While the new research focused on how daraxonrasib works as a second-line therapy — that is, after a patient has already gone through chemotherapy — scientists are also working to see if it could be used either before or alongside chemo from the get-go. Two smaller studies presented at a meeting of the American Association for Cancer Research in April found survival benefits to giving daraxonrasib as part of first-line therapy.
“That’s the direction that the field is going,” Padmanabhan, who wasn’t involved with the research, said. “It brings hope to a disease that for decades we didn’t really have much to offer beyond first-line therapies that haven’t prolonged life very much. This has the capacity to do that.”
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