Targeted therapy with the RAS inhibitor daraxonrasib showed the potential to improve patient outcomes over current standard treatments for patients with RAS-mutated pancreatic cancer, according to results of a Phase 1/2 trial led by investigators at The University of Texas MD Anderson Cancer Center.
The study, published today in The New England Journal of Medicineled by David Hong, MD, vice president of Investigational Cancer Therapeutics. Thirty-eight patients received 300 mg. daraxonrasib dose. The response rate was 29% and the median overall survival was 15.6 months, a significant improvement over historical response rates to second-line chemotherapy.
“This trial provides a really strong signal that this targeted therapy has the potential to extend the overall survival of these patients,” Hong said. “We saw rapid and durable responses, and the manageable overall safety profile supports continued evaluation of daraxonrasib.”
What is the significance of this study of daraxonrasib in pancreatic cancer?
This study investigated daraxonrasib in pancreatic adenocarcinomas, which make up more than 90% of all pancreatic cancers. They are among the deadliest cancers because they are usually not diagnosed until advanced stages, when available treatments are generally not effective. Only about one-third of patients respond to first-line chemotherapy, and less than 10% respond to chemotherapy as second-line therapy. These patients have an overall survival of only five to seven months.
However, more than 90% of these cancers are due to RAS mutations, making them potentially amenable to RAS-targeted therapies such as daraxonrasib.
What are the other key findings from this trial?
The primary endpoint for this Phase 1/2 dose extension and escalation trial was safety. While 96% of patients experienced adverse events of any grade, only 30% experienced those of grade three or higher. The most common side effects were rash, diarrhea, inflammation of the mouth/throat (stomatitis, mucositis) and fatigue.
Half of the patients were treated with 300 mg. level had dose modifications, but no patients had to discontinue treatment due to adverse events. It is noteworthy that the current second-line treatment of chemotherapy also has significant adverse effects for patients.
What makes daraxonrasib different from other treatments that target RAS mutations?
Mutations in RAS proteins, such as KRAS, are known drivers of various types of cancer, and there are multiple types of mutations. The most commonly targeted mutation is KRAS G12C, but while this particular mutation is relatively common in certain types of cancer, it is relatively rare in pancreatic cancer. Furthermore, most current RAS therapies target RAS mutations in the “off” state, but KRAS drives pancreatic adenocarcinoma to its “on” state. Daraxonrasib can inhibit the RAS in its “on” state and can target multiple RAS variants, suggesting that there is greater potential use for a therapy of this type in the treatment of pancreatic cancers.
Initial data from this trial, presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium, prompted the FDA to grant orphan drug status to daraxonrasib and the ongoing Phase 3 RASolute trial.
