RAS Inhibitor Offers Pancreatic Cancer Survivors Renewed Hope 

What began as a minor, nagging pain in her abdomen became an unbearable stabbing sensation that landed Debby Orcutt in the hospital. For months, she and her primary care physician thought the pain was the result of constipation, but hospital physicians suspected it could be cancer. 

As she waited in the hospital room with her husband, Orcutt struggled to process the possibility. “I didn’t want to believe it,” she says. “I was floored.” Her entire life, she tried to live a healthy lifestyle, abstaining from drinking and smoking. There was almost no history of cancer in her family. 

Her local priest came to visit, a leader of the church in Worcester that she had attended for forty years. To her surprise, one of the first things he said as he looked out the hospital room window was, “You’re going to be okay.” 

He had no way of knowing this. In fact, Orcutt was diagnosed with pancreatic cancer, which has historically been difficult to treat. There is no screening for the disease, and, like Orcutt’s stomach pain, early symptoms are vague and difficult to identify. About 80% of patients are diagnosed at later stages, when the disease is much more difficult to treat. When physicians discovered Orcutt’s cancer, it had already spread to her liver. 

Just 3% of patients diagnosed with metastatic pancreatic cancer are alive five years later, according to the American Cancer Society. But her priest’s words became a source of hope. “I’ll never forget it,” she says. “That positive attitude stuck with me, and I tried to hold on to it.” 

She saw that reflected in her care team at Dana-Farber, which moved quickly to begin treatment. Fortunately, the priest also turned out to be correct. When standard chemotherapy didn’t halt the cancer’s growth, her Dana-Farber team offered her a clinical trial on a drug called daraxonrasib. At the time, it was a promising new kind of drug called a RAS-inhibitor that targets a protein which mutated in most pancreatic cancers. This RAS protein controls how cells grow, and in many pancreatic cancers it is continuously turned on, allowing cells to grow uncontrollably.  

The protein has proven difficult to target, evading researchers for years. Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber, and his team worked with biotechnology company Revolution Medicines to help crack the puzzle with daraxonrasib. By pairing up with a protein called cyclophilin A inside cells, Wolpin says daraxonrasib works like a “molecular glue” and can attach to RAS, effectively turning it off. 

When it was offered, Orcutt had no idea if it would help her. She joined the trial because she was confident in her team, and she felt motivated by the idea of contributing to research on the disease.  

“You get undivided attention from multiple people,” she says. “You’ve got all these brilliant people looking at lab work, especially at Dana-Farber. So I said, ‘Why not? 
That’s how I felt.” 

It proved to be a life-saving decision. Her tumors shrank significantly. The spot on her liver has vanished, and the tumor on her pancreas has shrunk by 80 percent. 

She was part of a cohort of patients with metastatic pancreatic cancer who experienced similar results. Recently published in the New England Journal of Medicine, the trial showed that, on average, daraxonrasib stopped tumors from getting worse for more than eight months and kept patients alive for up to nearly a year and a half. This represents double the current survival rate of patients with advanced stages of the disease, an extraordinary advance in treating pancreatic cancer. 

“We have been working very hard trying to find other ways to treat this cancer besides chemotherapy,” Wolpin says. “This feels like a watershed moment. I believe it’s going to shift how we think about treatment for pancreatic cancer overall.” 

This success has led to daraxonrasib being fast-tracked for approval by the Food and Drug Administration. The hard work by investigators and clinicians at Dana-Farber has given Orcutt more time with her family, a husband who she has been with for 47 years, two adult children and their spouses, and her five grandchildren. 

Every day is precious to Orcutt. She spends many mornings helping her grandchildren get ready for school and getting them on the bus. In return, her family drives her to appointments at Dana-Farber. Despite some side effects from her treatment, Orcutt stays busy tending to her home, cultivating her garden, cooking homemade meals, canning vegetables and sauce, and making jams. 

“I feel blessed,” Orcutt says, advising other people to be realistic about their situations, but to hold their heads high. “Don’t lose hope.”