For decades, the RAS family of proteins had a reputation in cancer biology: don’t bother. The molecules were too smooth, too slippery, too structurally defiant for any drug to grab hold of. Scientists called them “undruggable” — and meant it.

Then came a packed conference room in Chicago, a standing ovation, and a number that made oncologists emotional: 13.2 months.

On May 31, researchers presented results from a Phase 3 trial of 500 patients with RAS-driven pancreatic cancer. A drug called daraxonrasib nearly doubled survival in patients with advanced disease — from 6.7 months on chemotherapy to 13.2 months — reducing the risk of death by 60%. The findings, published simultaneously in the New England Journal of Medicine, represent the most significant advance in pancreatic cancer treatment in over a decade.

“After more than a decade without major advances in treatment for pancreatic cancer, seeing this is really emotional,” Ecaterina Dumbrava, an oncologist at the University of Texas MD Anderson Cancer Center, told Nature. The audience gave the presentation a long standing ovation.

Why RAS Was Off-Limits

RAS proteins act as molecular on-off switches controlling cell growth and division. When mutations jam them in the “on” position, tumors flourish. More than 90% of pancreatic cancers carry RAS mutations, as do significant proportions of lung and colorectal cancers.

But drugs work by fitting into pockets and grooves on a protein’s surface. RAS proteins are unhelpfully smooth — no pockets, no obvious handholds. For decades, the target sat there, driving some of the deadliest cancers on Earth, defying every attempt to drug it.

The first crack appeared in 2021, when the US approved a drug targeting one specific mutation in one member of the RAS family, a protein called KRAS. It was a proof of concept, but a narrow one — suitable for only a fraction of patients, and tumors quickly grew resistant.

Daraxonrasib, developed by Revolution Medicines in Redwood City, California, takes a fundamentally different approach. Rather than targeting a single mutation, it switches off all three members of the RAS family. In the RASolute 302 trial, which enrolled 500 patients with previously treated metastatic pancreatic cancer, the drug worked across a wide range of RAS variants — including patients whose tumors carried no identified RAS mutation at all.

The Numbers

The trial results are striking. Patients receiving daraxonrasib lived a median of 13.2 months, compared with 6.7 months for those on standard chemotherapy. Progression-free survival — the time before the cancer worsened — was 7.2 months versus 3.6 months. Tumors shrank in roughly a third of patients on the drug, compared with about 11% on chemotherapy.

The safety profile was generally manageable. Grade 3 or higher treatment-related adverse events occurred in 43.6% of daraxonrasib patients versus 57.5% on chemotherapy. The most common severe side effects were rash and mouth sores. Only 1.2% of patients stopped treatment due to side effects, compared with 11.2% in the chemotherapy group.

Colin Weekes, an associate professor of medicine at Mass General Brigham Cancer Institute, described the results as a “game-changing situation.” But he cautioned in an interview with The ASCO Post that “it’s not a benign drug.” The rash and stomatitis can be challenging, particularly for patients outside academic centers who may lack access to specialized supportive care.

What Comes Next

The implications reach beyond pancreatic cancer. Daraxonrasib is already being tested in non-small cell lung cancer, and is designed to also target colorectal cancer — both frequently driven by RAS mutations. A separate Phase 3 trial, RASolute 303, is evaluating the drug as a first-line treatment — potentially moving it earlier in the disease course.

Mark Goldsmith, chief executive officer of Revolution Medicines, described the result as “not previously reported in any Phase 3 clinical trial in any line of therapy for this disease.” In a disease where five-year survival sits at roughly 3%, according to Revolution Medicines, those words carry real weight.

The breakthrough is also reviving optimism about other supposedly undruggable targets. The protein MYC, which drives roughly 70% of all cancers, has a similarly smooth surface and has resisted drug development for decades. Researchers at Oregon Health and Science University are now using artificial intelligence to screen for compounds that might bind to MYC. A company called cosMYC, co-founded by a cancer researcher who has studied the protein for more than 40 years, recently raised financing partly on the momentum generated by the first KRAS drug.

“Sometimes the very first molecule just shows that it’s possible,” said Kevan Shokat, a chemical biologist at the University of California, San Francisco.

Daraxonrasib may be that proof’s most convincing argument yet.

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