Dr Garrido-Laguna on the Safety of Daraxonrasib in KRAS G12X–Mutated PDAC

"It will be important to have more granularity on...the incidence of grade 2 vs grade 1 [TRAEs] when it comes to these low-grade toxicities, and hopefully with more data, we will all learn in the future."

Ignacio Garrido-Laguna, MD, PhD, MBA, professor of oncology at the University of Utah School of Medicine; and director of the Phase 1 Program, co-leader of the GI Oncology Multidisciplinary Disease Group, and a member of the Experimental Therapeutics Program at Huntsman Cancer Institute, discusses the safety profile of daraxonrasib (RMC-6236) in patients with KRAS G12X–mutated pancreatic ductal adenocarcinoma (PDAC).

Updated safety data from an ongoing phase 1 study (NCT05379985) evaluating daraxonrasib were presented at the 2025 Gastrointestinal Cancers Symposium. Among patients treated at doses ranging from 160 mg to 300 mg (n = 127), treatment-related adverse effects (TRAEs) occurred in 98% of patients with 29% experiencing a grade 3 or higher TRAEs. In the 300-mg cohort (n = 76), the incidence of any-grade TRAEs was 96% with 34% of patients experiencing a grade 3 or higher TRAEs.

Rash was the most frequently reported toxicity, occurring at any grade in 91% of patients in the 160 mg to 300 mg group and 81% in the 300-mg cohort; grade 3 or higher rash as reported in 8% of patients in both groups. Other common any-grade toxicities included diarrhea (160 mg to 300 mg, 48; 300 mg, 53%), nausea (48%; 50%), vomiting (31%; 36%), and stomatitis (30%; 32%).

Dose modifications due to TRAEs were required in 35% of patients treated at 160 mg to 300 mg, with dose interruptions (34%) and reductions (19%) being the most common. In the 300-mg cohort, 42% of patients required a dose modification, including dose interruptions (40%) and reductions (25%). Rash was the primary reason for dose reduction in more than 10% of patients in both cohorts.

Proactive management strategies have been implemented to mitigate the incidence and severity of rash, a common toxicity associated with RAS-targeted therapies, Garrido-Laguna says. Preventive interventions include the use of tetracyclines, mirroring the approach used for managing dermatologic toxicities in patients receiving EGFR inhibitors for metastatic colorectal cancer, he adds. Additional supportive measures include topical steroids, topical antibiotics such as clindamycin, and, in some cases, oral dapsone for more severe presentations.

Although the majority of toxicities were low grade, further analyses could provide additional insight on the incidence of grade 1 vs grade 2 toxicities, giving a more granular look at the toxicity profile of daraxonrasib, Garrido-Laguna notes.