Targeted RAS inhibitor shows promise against pancreatic cancer mutations

"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 the ongoing 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 most lethal cancers because they are not usually diagnosed until advanced stages, when available treatments are generally not effective. Only about a third of patients respond to first-line chemotherapy, and fewer than 10% respond to chemotherapy as a second-line treatment. These patients have an overall survival of just five to seven months.

However, more than 90% of these cancers are driven by RAS mutations, making them potentially able to be treated with RAS-targeted therapies like daraxonrasib.

What are the other key data from this trial?

The primary endpoint for this Phase 1/2 dose expansion and escalation trial was safety. While 96% of patients experienced any-grade adverse effects, only 30% experienced those of grade three or higher. The most common side effects were rash, diarrhea, oral/throat inflammation (stomatitis, mucositis) and fatigue.

Half of the patients treated at the 300 mg. level had dose modifications, but no patients had to discontinue treatment due to adverse effects. It is notable that the current second-line treatment of chemotherapy also has significant adverse effects for patients.

What makes daraxonrasib different from other therapies targeting RAS mutations?

Mutations in RAS proteins, such as KRAS, are known drivers in several cancer types, and there are multiple types of mutations. The most commonly targeted mutation is KRAS G12C, but while this specific mutation is relatively common in some cancer types, it is relatively rare in pancreatic cancer. Additionally, most current RAS therapies target RAS mutations in the "off" state, but KRAS drives pancreatic adenocarcinoma in its "on" state. Daraxonrasib can inhibit RAS in its "on" state and can target multiple RAS variants, suggesting there is more potential use for a therapy of this type in treating pancreatic cancers.

Initial data from this trial, presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, prompted the FDA to grant orphan drug status to daraxonrasib and the ongoing Phase 3 RASolute trial.

Source:

University of Texas M. D. Anderson Cancer Center

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