The FDA has accepted a new drug application (NDA) seeking the approval of daraxonrasib (RMC-6236), an oral RAS(ON) multi-selective inhibitor, for the treatment of patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).¹
The agent was selected for the FDA Commissioner's National Priority Voucher pilot program, intended to accelerate the review of medicines that address key national health priorities. Under the program, review time is anticipated to be 1 to 2 months.2
The NDA is based on
In the overall population, which included patients with and without an identified tumor RAS mutation, the median OS was 13.2 months (95% CI, 10.0-NE) for daraxonrasib (n = 248) vs 6.7 months (95% CI, 5.8-8.0) for chemotherapy (n = 252; HR, 0.40; 95% CI, 0.30-0.53; P = 4.6×10⁻¹¹).
"The FDA's acceptance of the daraxonrasib NDA is an important step in the regulatory review process and brings us closer to the possibility of offering patients a new targeted medicine for previously treated metastatic pancreatic cancer," Mark A. Goldsmith, MD, PhD, chief executive officer and chairman of Revolution Medicines, stated in a news release.1 "These findings underscore the potential for daraxonrasib to become a new standard of care and to help define a new class of RAS-targeted medicines for this disease."
Daraxonrasib is an investigational, oral, RAS(ON) multi-selective, noncovalent tri-complex inhibitor that suppresses RAS signaling by blocking the interaction between RAS(ON) proteins and their downstream effectors.3,4 The agent binds intracellular cyclophilin A to form a binary complex that engages GTP-bound RAS mutantations, including variants with G12, G13, and Q61 mutations, as well as RAS wild-type.
More than 90% of PDAC tumors harbor an oncogenic RAS mutation, and no RAS-targeted therapies are currently approved for patients with pancreatic cancer.
RASolute 302 enrolled adult patients with metastatic PDAC who had received one prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting, had an ECOG performance status of 0 or 1, and had documented tumor RAS mutational status by local testing.3
A total of 500 patients were randomly assigned 1:1 to receive oral daraxonrasib at 300 mg once daily (n = 248) or investigator's choice of 1 of 4 cytotoxic chemotherapy regimens (n = 252): gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, nanoliposomal irinotecan (Onivyde) plus fluorouracil and leucovorin, or FOLFOX. Patients were stratified by ECOG performance status, metastatic disease at diagnosis, liver metastases at baseline, and tumor RAS mutational status.
The dual primary end points were OS and PFS by blinded independent central review (BICR) in the RAS G12–mutant population. Key secondary end points included OS and PFS in the overall population, objective response rate (ORR), and time to deterioration in patient-reported outcomes.
The trial also met its key secondary end points. Among patients evaluated by BICR, the median PFS in the RAS G12–mutant population was 7.3 months (95% CI, 6.3-8.1) with daraxonrasib vs 3.5 months (95% CI, 2.9-3.8) with chemotherapy (HR, 0.45; 95% CI, 0.34-0.59; P = 3.2×10⁻⁹); in the overall population, the median PFS was 7.2 months (95% CI, 5.7-7.5) vs 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P = 5.2×10⁻⁸).
The confirmed ORR by BICR was 33.2% vs 11.8%, respectively, in the RAS G12–mutant population, with respective rates of 31.6% and 11.2% in the overall population, favoring daraxonrasib (P < .0001).
Daraxonrasib also significantly delayed the time to deterioration in the symptom of pain (9.2 vs 3.8 months; HR, 0.51; 95% CI, 0.37-0.71; P < .0001) and in global health status/quality of life (5.7 vs 2.6 months; HR, 0.60; 95% CI, 0.46-0.79; P = .0002) compared with chemotherapy in the overall population.
Among 241 patients treated with daraxonrasib, the median dose intensity was 93.1%. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 43.6% of patients in the daraxonrasib arm vs 57.5% in the chemotherapy arm, and serious TRAEs were reported in 10.8% vs 18.7%, respectively.
TRAEs led to treatment discontinuation in 1.2% of patients treated with daraxonrasib vs 11.2% of those treated with chemotherapy. One grade 5 TRAE (treatment-related pneumonitis) occurred in the daraxonrasib arm, and none occurred in the chemotherapy arm.
The most common any-grade TRAEs with daraxonrasib were rash (85%), diarrhea (58%), stomatitis (53%), nausea (46%), and vomiting (37%); grade 3 or higher rates for these TRAEs were 14%, 5%, 12%, 2%, and less than 1%, respectively. The median time on treatment was 6.2 months with daraxonrasib vs 1.5 to 3.2 months across the chemotherapy regimens.
