Daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, is showing promise in patients with RAS-mutant pancreatic ductal adenocarcinoma (PDAC). Findings from a phase 1 trial (NCT05379985) presented at the 2025 ASCO Gastrointestinal Cancer Symposium suggest a correlation between circulating tumor DNA (ctDNA) changes and clinical outcomes.
The study, led by Ignacio Garrido-Laguna, MD, PhD, MBA, explored the safety and efficacy of RMC-6236 and its impact on ctDNA dynamics. While emphasizing the preliminary nature of the phase 1 data, Garrido-Laguna noted that the research aims to understand how ctDNA changes might inform clinical decision-making in the future.
ctDNA Response and Clinical Outcomes
The trial revealed that the majority of patients treated with daraxonrasib experienced a decrease in ctDNA levels. Approximately 50% of patients achieved complete ctDNA eradication. This molecular response was observed across different dose levels of the drug.
Survival Benefit in KRAS G12X Mutants
Interestingly, the study identified a potential survival benefit in patients with KRAS G12X mutations compared to those with other RAS mutations. In patients treated with 300 mg of daraxonrasib, the median progression-free survival (PFS) was 8.8 months (95% CI, 8.5-NE) in the KRAS G12X group versus 8.5 months (95% CI, 5.9-NE) in the broader RAS-mutant group. Similarly, an overall survival (OS) benefit was observed, with 6-month OS rates of 100% and 97% (95% CI, 79%-100%), respectively.
For patients treated with 160 to 300 mg of daraxonrasib, the median OS was 14.5 months (95% CI, 8.8-NE) in the KRAS G12X group and 14.5 months (95% CI, 8.8-NE) in the RAS-mutant group, with 6-month OS rates of 89% (95% CI, 70%-97%) and 91% (95% CI, 71%-96%), respectively.
Future Directions
Garrido-Laguna emphasized the need for further research to fully understand the relationship between ctDNA changes and clinical outcomes. Specifically, future follow-up will focus on how ctDNA dynamics correlate with outcomes in patients with stable disease. "How that translates to improved outcomes for patients with a stable disease is something we will need to understand with future follow-up," he stated.
The ongoing research aims to refine the use of daraxonrasib in RAS-mutant PDAC and potentially personalize treatment strategies based on ctDNA monitoring.
