Daraxonrasib Shows Promise in Pancreatic Cancer: Early Access Program Now Available

An experimental drug called daraxonrasib, which is now being offered through an early access program, has shown promising results for patients with a tough-to-treat form of pancreatic cancer. According to early-stage trial data, about one-third of patients experienced serious side effects, but the drug also helped many patients control their disease.

The study focused on people with pancreatic ductal adenocarcinoma (PDAC) that had already been treated. Among patients with a specific genetic change called a RAS G12 mutation who took the 300-milligram dose—the same dose now being tested in larger phase III studies—35% saw their tumors shrink with second-line treatment. The disease control rate, meaning the cancer stopped growing or shrank, reached 92%, according to researchers led by Dr. Brian Wolpin of the Dana-Farber Cancer Institute in Boston.

For these patients, the benefits lasted a median of 8.2 months. The median time before the cancer worsened, known as progression-free survival (PFS), was 8.5 months. The median overall survival (OS) was 13.1 months.

The findings were published in the New England Journal of Medicine. In the larger group of patients who received daraxonrasib at doses of 300 mg or less, nearly all reported treatment-related side effects of any grade. The most common were rash, diarrhea, and nausea. About 30% of patients had side effects classified as grade 3 or higher, meaning they were serious or severe.

Interest in daraxonrasib has grown recently, especially after Revolution Medicines announced what it called an “unprecedented” improvement in overall survival from the phase III RASolute 302 trial. On Friday, the U.S. Food and Drug Administration (FDA) gave the drug’s maker permission to start an expanded access program, working with licensed doctors to make the drug available to more patients sooner.

The results from this phase I/II study compare very favorably with current chemotherapy options for patients whose metastatic PDAC has already been treated. Standard chemo typically leads to response rates below 10%, median PFS of just 2 to 3 months, and median overall survival of 5 to 7 months.

Dr. Wolpin and his team noted that the drug’s safety profile—mostly mild side effects—combined with its effectiveness supports the ongoing phase III trial.

In a related editorial called “Science Behind the Study,” Dr. Channing Der and Dr. Jen Jen Yeh of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill pointed out a key concern. More than half of the patients in the study stopped treatment because their cancer got worse. The researchers said this “highlights the need to understand the primary and adaptive mechanisms of resistance.”

They added that finding ways to predict which patients will respond and designing combination treatments to overcome resistance “will be essential to improving on the unprecedented responses to this single-agent small-molecule inhibitor in pancreatic ductal adenocarcinoma.”

Two smaller studies of daraxonrasib, presented at a recent American Association for Cancer Research meeting, showed response rates of about 50% to 60% for patients with previously untreated metastatic pancreatic cancer. Those patients received the RAS inhibitor either alone or combined with chemotherapy.

Dr. Wolpin and his team explained why this research matters. Current therapies offer only modest benefits, but more than 90% of PDAC tumors have activating RAS mutations. This “highlights an opportunity for RAS-targeted therapies to expand treatment options for patients with PDAC and to improve patient outcomes.”

The study included 168 patients with RAS-mutated PDAC who received at least one dose of daraxonrasib as a second-line or later treatment. Doses ranged from 10 to 400 mg taken orally once daily. Of these, 83 patients received the 300-mg phase III dose. Treatment was stopped in 150 of the 168 patients, most often because the disease progressed (55% of cases).

Across all dose levels, the median patient age was 65, and 45% were women. About 68% had an ECOG performance status score of 1, meaning they were fully active but had some physical limitations. All patients had stage IV cancer when they entered the study. Liver metastases were present in 67% of patients, and lung metastases in 46%.

Among the trial participants, 89% had RAS G12 mutations. These included KRAS G12D (39%), KRAS G12V (31%), KRAS G12R (17%), and other RAS G12 types (2%). Of the 19 patients with non-RAS G12 mutations, 14 had KRAS Q61H, two had KRAS Q61R, two had KRAS Q61K, and one had KRAS G13D.

The median number of previous cancer treatments among all patients was two. About 42% had received one prior line of therapy, while the rest had received two or more.

For second-line patients with RAS G12, G13, or Q61 mutations who were treated at the 300-mg dose, 29% responded to the drug, and the disease control rate reached 95%. The median duration of response was 8.2 months, with median PFS of 8.1 months and median overall survival of 15.6 months.

For patients with any RAS mutation treated in the third-line or later setting, 20% responded, the disease control rate was 84%, and the median duration of response was 3.3 months.

Treatment-related side effects occurred in 96% of patients, but most were mild (grade 1 or 2). The most common side effects of any grade were rash (88%), diarrhea (46%), nausea (42%), mouth sores or inflammation (40%), vomiting (31%), and fatigue (20%).

Doses were interrupted due to side effects in 37% of patients. Doses were reduced in 21% of patients. Only one patient—less than 1%—stopped treatment completely because of side effects.

Serious treatment-related side effects occurred in 6% of patients, with diarrhea being the most common (2%). No fatal side effects (grade 5 events) were reported.

Source: MedPage Today