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Treatment with daraxonrasib at the phase 3 dose of 300 mg was well tolerated, had favorable dose intensity, and showed efficacy in RAS–mutated PDAC.
Daraxonrasib (RMC-6236), a multi-selective, tri-complex RAS(ON) inhibitor, demonstrated antitumor activity, manageable safety, and a reduction in RAS variant allele frequency (VAF) in circulating tumor DNA (ctDNA) indicative of inhibiting all major variants of oncogenic RAS drivers in patients with RAS-mutated pancreatic ductal adenocarcinoma (PDAC), according to updated findings from a phase 1 study (NCT05379985) presented at the 2025 Genitourinary Cancers Symposium.1
Among patients with metastatic PDAC who received daraxonrasib at the recommended phase 2 dose (RP2D) of 300 mg in the second line (n = 59), the median progression-free survival (PFS) was 8.8 months (95% CI, 8.5-not evaluable [NE]) in those with KRAS G12X–mutated disease (n = 22) and 8.5 months (95% CI, 5.9-NE) in those with RAS-mutated disease (n = 37). The overall response rates (ORR) were 36% and 27% in the KRAS G12X– and RAS-mutated subgroups, respectively; disease control rates (DCR) for these respective groups were 91% and 95%.
Comparatively, at doses ranging from 160 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 with RAS-mutated group (n = 57). In these respective subsets, the ORRs were 29% and 25%; respective DCRs were 91% and 93%.
In both the KRAS G12X– and RAS-mutated patient subsets, the median overall survival (OS) was NE (95% CI, NE-NE; 95% CI, 8.5-NE) at the 300-mg dose and 14.5 months (95% CI, 8.8-NE) at doses ranging from 160 mg to 300 mg. At 300 mg, the 6-month OS rates were 100% (95% CI, 100%-100%) and 97% (95% CI, 79%-100%) in the KRAS G12X– and RAS-mutated patient subsets, respectively. The median follow-up for these respective subsets was 6.1 months and 6.6 months.
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 group. The median follow-up for these respective subsets was 6.2 months and 6.6 months.
A total of 73 patients with metastatic PDAC treated with daraxonrasib at 160 to 300 mg in the second line were evaluable for changes in RAS VAF. A greater than 50% decrease in RAS VAF from baseline was observed in 93% of patients with KRAS G12X mutations (n = 56/60) and 90% of those with RAS mutations (n = 66/73). Moreover, 48% and 45% of patients in these respective subsets experienced a 100% decrease in RAS VAF.
“Daraxonrasib is the first investigational targeted agent designed to directly inhibit all major forms of oncogenic RAS(ON), the common drivers of PDAC,” lead study author Ignacio Garrido-Laguna, MD, PhD, MBA, and colleagues wrote in a poster presentation of the data. “At the phase 3 dose of 300 mg [daily], daraxonrasib exhibited a manageable safety profile, favorable dose intensity, and encouraging overall response rate [ORR], PFS, and OS.”
Garrido-Laguna is a professor of oncology, director of the Phase 1 Program, and co-leader of the GI Oncology Multidisciplinary Disease Group at the University of Utah School of Medicine, and a medical oncologist at Huntsman Cancer Institute in Salt Lake City.
The phase 1 study enrolled patients at least 18 years of age with advanced solid tumors harboring KRAS G12X mutations who previously received standard therapy appropriate for their tumor type and stage. An ECOG performance status of 0 or 1 was required. Those with KRAS G12C mutations or active brain metastases were excluded.
In the dose-escalation phase, oral daraxonrasib was evaluated at once-daily doses of 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 220 mg, 300 mg, and 400 mg. Investigators projected that the lowest dose/exposure range to drive tumor regressions in humans, based on preclinical models, would be between 80 mg and 120 mg. The 160 mg, 220 mg, and 300 mg doses were utilized in the dose-expansion and -optimization portion of the study in metastatic PDAC, with 300 mg selected as the phase 3 dose for monotherapy in the second line.
The study’s key end points included safety and tolerability, pharmacokinetics, antitumor activity, and pharmacodynamic changes in ctDNA. Notably, analyses of plasma samples for changes in RAS VAF in ctNDA were conducted at baseline and on day 1 of cycle 2 or cycle 3.
Previously reported results from the phase 1 trial demonstrated an ORR of 20% and DCR of 87% with daraxonrasib among efficacy-evaluable patients with KRAS G12X–mutated PDAC (n = 46).2 The median time to response was 3.3 months (range, 0.2-10.9), and the median time on treatment was 3.3 months (range, 0.2-10.9). Notably, reduction in KRAS VAF in ctDNA correlated with clinical response across tumor types. The agent was well-tolerated at clinically active doses.
The current analysis comprised safety data, updated efficacy results, and findings from exploratory analyses of early ctDNA reduction.1
At the data cutoff of July 23, 2024, a total of 127 patients with PDAC received the agent at doses ranging from 160 mg to 300 mg, and 76 received the 300 mg dose. The median age in this cohort was 64 years (range, 30-86) and the majority of patients were male (56%), had an ECOG performance status of 1 (64%), had baseline liver metastases (67%), and had stage IV disease at the time of diagnosis (52%). Patients received a median of 2 prior anticancer therapies (range, 1-11). In the metastatic setting, 1% of patients received 0 prior line of therapy, 45% received 1 prior line, and 54% received 2 or more prior lines of therapy.
KRAS G12X mutations were present in 84% of patients; this comprised KRAS G12D (32%), KRAS G12V (32%), other KRAS G12X mutations (20%); 16% of patients had other RAS mutations.
Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 98% and 96% of patients in the 160-mg-to-300-mg group vs the 300-mg group, respectively. Grade 3 or higher TRAEs occurred in 29% and 34% of patients in these respective groups. One grade 4 TRAE of decreased platelet count occurred at the 300-mg dose level. No grade 5 TRAEs were reported at the 300-mg dose.
The most common TRAEs observed in patients treated with 160 mg to 300 mg of daraxonrasib were rash (any grade, 91%; grade ≥3, 8%), diarrhea (48%; 2%), nausea (43%; 0%), vomiting (31%; 0%), stomatitis (31%; 3%), fatigue (20%; 1%), paronychia (13%; 1%), mucosal inflammation (13%; 1%), decreased appetite (11%; 1%), peripheral edema (10%; 0%), decreased platelet count (9%; 2%), and dry skin (9%; 0%). Other select TRAEs included anemia (9%; 6%), increased alanine aminotransferase levels (8%; 2%), increased aspartate aminotransferase levels (7%; 2%), and decreased neutrophil count (6%; 2%).
TRAEs led to dose interruptions or reductions in 34% and 19% of patients treated with 160 mg to 300 mg of daraxonrasib, respectively. These respective rates were 40% and 25% in the 300-mg cohort. No patients experienced TRAEs necessitating discontinuation. Rash was the most common any-grade TRAE that led to dose reduction in 11% and 13% of patients in the respective groups. The average dose intensity was 92% across the 160 mg to 300 mg doses, and 89% at the 300 mg dose. Median dose intensity was 99% and 97% in these respective groups.
“These results support the ongoing RASolute 302 study [NCT06625320], a global randomized phase 3 clinical trial of daraxonrasib as second-line treatment vs chemotherapy in patients with previously treated metastatic PDAC,” study investigators concluded.
The study will enroll approximately 460 patients with confirmed PDAC, receipt of 1 prior line of therapy in the metastatic setting, and an ECOG performance status of 0 or 1.3 Upon enrollment, patients will be randomly assigned 1:1 to receive either 300 mg of daraxonrasib once daily (n = 230) or investigator’s choice of standard-of-care gemcitabine/nab-paclitaxel, modified FOLFIRINOX, NALIRIFOX, or FOLFOX (n = 230).
The study’s primary end points will be PFS and OS among patients with KRAS G12X mutations. Key secondary end points will include PFS, OS, ORR, duration of response, and quality of life in the overall patient population.