Dr Garrido-Laguna on the Safety and Efficacy of Daraxonrasib in KRAS-Mutated PDAC

“We feel the PFS data are remarkable. [The median] PFS in the second-line setting for patients with metastatic PDAC, [which was 8.8] months, compares very positively with historical controls. In the second-line setting, we typically see PFS in the range of 3 months.”

Ignacio Garrido-Laguna, MD, PhD, MBA, professor, oncology, director, Phase 1 Program, and co-leader, GI Oncology Multidisciplinary Disease Group, University of Utah School of Medicine, discusses updated safety and efficacy data with the use of daraxonrasib (RMC-6236) in patients with KRAS-mutated pancreatic ductal adenocarcinoma (PDAC).

In previously reported findings from a phase 1 study (NCT05379985), the RAS(ON) multi-selective, tri-complex inhibitor daraxonrasib demonstrated efficacy and had a manageable safety profile in patients with PDAC harboring KRAS G12X or other RAS mutations. Updated safety and efficacy data from the study, along with exploratory analyses of early circulating tumor DNA reduction with daraxonrasib, were presented during the 2025 Gastrointestinal Cancers Symposium.

Findings showed that among patients with metastatic PDAC treated at the recommended phase 2 dose (RP2D) of 300 mg in the second-line setting (n = 59), the median progression-free survival (PFS) was 8.8 months (95% CI, 8.5-not evaluable [NE]) in the KRAS G12X–mutated subgroup (n = 22) and 8.5 months (95% CI, 5.9-NE) in the broader RAS-mutated cohort (n = 37), Garrido-Laguna begins. Given that second-line PFS in PDAC typically ranges around 3 months, these data indicate a substantial improvement over historical controls, he notes. The overall response rates (ORRs) in the KRAS G12X– and RAS-mutated subsets were 36% and 27%, respectively, with disease control rates (DCRs) of 91% and 95%, respectively.

Across all patients treated at doses of 160 mg to 300 mg, the median PFS was 8.5 months (95% CI, 5.3-11.7) in the KRAS G12X–mutated group (n = 42) and 7.6 months (95% CI, 5.9-11.1) in the RAS-mutated group (n = 57). The respectiveORRs were 29% and 25%, and the DCRs were 91% and 93%, respectively.

At 300 mg, the median overall survival (OS) was NE (KRAS G12X–mutated group, 95% CI, NE-NE; RAS-mutated group, 95% CI, 8.5-NE), with 6-month OS rates of 100% (95% CI, 100%-100%) and 97% (95% CI, 79%-100%) in the KRAS G12X– and RAS-mutated subsets, respectively.

For patients treated at doses ranging from 160 mg to 300 mg, the 6-month OS rates were 89% (95% CI, 70%-97%) in the KRAS G12X–mutated group and 91% (95% CI, 77%-96%) in the RAS-mutated cohort, with median follow-ups of 6.2 and 6.6 months, respectively. Although the median OS has not yet been reached in patients treated at the 300-mg dose, ongoing follow-up is expected to further support the promising survival benefit observed with daraxonrasib, Garrido-Laguna concludes.