An experimental drug that has been shown to double the survival of patients in advanced stages of the disease is about to revolutionize pancreatic cancer treatment, according to oncologists.
The drug, called daraxonrasib, has already undergone an accelerated approval procedure by the Food and Drug Administration (FDA). Last week, the agency announced that it would allow drugmaker Revolution Medicines to administer the drug to patients outside of clinical trials, under an expanded access program.
In April, Revolution Medicines published the first results from its Phase III clinical trial of the drug, which revealed that patients who received daraxonrasib in addition to chemotherapy doubled their survival time compared to those who received chemotherapy alone.
This 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 the progression of tumors for more than eight months and kept patients alive for almost a year and a half.
The results represent an extraordinary advance in the treatment of pancreatic cancer. The disease is usually detected only after it has spread to other parts of the body. Even with chemotherapy, many patients do not live more than a year after diagnosis. Only 3% of patients diagnosed with metastatic pancreatic cancer They are still alive five years lateraccording to the American Cancer Society.
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“We’ve been working very hard and hard to find other ways to treat cancer,” said Dr. Brian Wolpin, who led the new daraxonrasib research and directs the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute in Boston. “It really seems like a watershed moment. It’s going to change the way we think about pancreatic cancer treatment in general.”
Daraxonrasib targets a protein called RASwhich controls the growth of cells in the body. More than 90% of pancreatic cancers have a mutation in the RAS protein gene, which keeps it in a permanent “activated” position, allowing cells to grow uncontrollably.
This protein has long been considered “impossible to treat pharmacologically,” after years of failed attempts to act on the RAS and block it. Daraxonrasib solves the problem by binding to a protein called cyclophilin A inside cells. The duo works like “molecular glue,” Wolpin explained, and is able to adhere to the RAS, preventing it from wreaking further havoc.
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The results published this Wednesday come from a phase 1/2 study, which evaluated the safety of the drug and the appropriate dosage. All 168 patients had advanced pancreatic cancer that had spread to other parts of the body, especially the lung and liver. All had previously received standard chemotherapy.
In patients who received the highest dose of the drug, progression-free survival — that is, the time before the cancer got worse — was about 8.1 months and overall survival was about 15.6 months.
There were side effects, including a blistering rash similar to a severe sunburn, sores in the mouth and throat, and vomiting and diarrhea. (Former Sen. Ben Sasse, R-Neb., who has taken the drug as part of a clinical trial, described the rash as “nuclear” in 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 taking the drug.)
Wolpin said some patients had to temporarily stop taking the medication “so the rash would calm down.”
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Overall, he said, the drug is “much more tolerable than chemotherapy. Most patients much prefer the ability to take one pill a day.” instead of undergoing all those infusions”.
Most of the side effects of daraxonrasib were treated with antibiotics, topical creams, and antidiarrheal medications. They were considered serious in about 30% of patients, and eight people left the trial because of them.
In the Phase III trial, which the research team plans to present later this month at the American Society of Clinical Oncology annual meeting, researchers found that overall survival for the chemotherapy-only group was 6.7 months, compared with 13.2 months for the combination treatment group. What’s more, the Phase III trial included patients without the KRAS gene mutation, suggesting that potentially all pancreatic cancer patients could benefit in some way.
“I think we’re going to stop thinking about chemotherapy as something that needs to be given to everyone,” Wolpin said.
Excitement about the drug’s potential has caught on among doctors who treat patients with pancreatic cancer.
“Those of us who deal with this disease are, frankly, a little skeptical of new data coming out, especially those that get a lot of attention in the mainstream media, because most of the time they are exaggerated,” said Dr. Reza Nazemzadeh, a gastrointestinal medical oncologist at Atrium Health Levine Cancer in Charlotte, North Carolina. “But this is something important. “This drug is the most exciting thing to come out in pancreatic cancer in more than a decade.”
Nazemzadeh was not involved in clinical trials of daraxonrasib, but he has had patients who did join them. Based on his observations, 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 do not use the word ‘revolutionary’ lightly.”said Dr. Sekhar Padmanabhan, 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 the way we care for our patients.”
More than 67,000 people in the United States are expected to be diagnosed with pancreatic cancer this year, according to the American Cancer Society. There is no detection method for this type of cancer and the initial symptoms are usually so vague that the majority of people, 80, are diagnosed in advanced stages of the disease, when it is much more difficult to treat. More than 52,000 people are expected to die from the disease this year.
Dr. Dae Won Kim, a gastrointestinal medical oncologist at Moffitt Cancer Center in Tampa, Florida, who was also not involved in the research, said he hopes the FDA will act 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 colorectal and lung cancers with mutations in the RAS gene.
Although the new research focused on how daraxonrasib works as a second-line therapy – that is, after a patient has already received chemotherapy – scientists are also working to see if it could be used before or alongside chemotherapy from the beginning. Two smaller studies presented at an American Association for Cancer Research meeting in April found survival benefits from giving daraxonrasib as part of first-line therapy.
“That is the direction the field is taking”said Padmanabhan, who was not involved in the research. “It brings hope to a disease for which, for decades, we didn’t have much to offer beyond front-line therapies, which haven’t prolonged life very much. This has the ability to do that.”
