Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options.
• Activating RAS mutations are prevalent in over 90% of PDAC tumors.
• Daraxonrasib (RMC-6236) is an investigational oral inhibitor targeting RAS(ON) proteins.

Purpose of the Study:

• To evaluate the safety and efficacy of daraxonrasib in patients with advanced solid tumors, specifically focusing on previously treated RAS-mutated PDAC.
• To determine the recommended Phase 3 dose and assess pharmacokinetic and antitumor activity.

Main Methods:

• A Phase 1-2 study involving 168 patients with previously treated RAS-mutated PDAC.
• Oral administration of daraxonrasib at doses ranging from 10 to 400 mg daily, with 300 mg selected for Phase 3.
• Safety, pharmacokinetics, and antitumor activity were assessed as primary and secondary endpoints.

Main Results:

• In previously treated RAS-mutated PDAC patients (N=168), 96% experienced any grade treatment-related adverse events (TRAEs), with 30% experiencing Grade 3+ TRAEs.
• Common TRAEs included rash, diarrhea, nausea, stomatitis, vomiting, and fatigue.
• In a subgroup with RAS G12 mutations (N=26) receiving second-line daraxonrasib (300 mg), objective response rate was 35%, with a median duration of response of 8.2 months.

Conclusions:

• Daraxonrasib demonstrated antitumor activity in patients with previously treated RAS-mutated PDAC.
• Treatment-related adverse events of Grade 3 or higher occurred in approximately one-third of patients.
• Further investigation in Phase 3 trials is warranted based on these findings.