Regulatory & Policy

FDA begins review of Revolution's RAS(ON) inhibitor for pancreatic cancer

Edited by Robert McTiernan··3 min read
FDA begins review of Revolution's RAS(ON) inhibitor for pancreatic cancer

The US Food and Drug Administration has accepted for review Revolution Medicines' New Drug Application (NDA) for daraxonrasib (RMC-6236), an oral RAS(ON) multi-selective inhibitor, in patients with previously treated metastatic pancreatic ductal adenocarcinoma. The Redwood City, California-based company said the filing is supported by the Phase III RASolute 302 trial, which compared daraxonrasib with standard-of-care chemotherapy in patients whose tumors carried RAS G12 mutations as well as those without an identified mutation.

Pancreatic cancer remains one of the least treatable solid tumors, with a five-year survival rate near 3% and few therapies specifically targeting the biology that drives most cases. More than 90% of pancreatic ductal adenocarcinoma tumors harbor RAS mutations, yet no approved drug has directly inhibited RAS across this disease. Existing targeted options are narrow: olaparib is limited to the roughly 5% of patients with germline BRCA mutations, and zenocutuzumab addresses NRG1 fusion-positive tumors, a rare subset. Second-line treatment otherwise relies on cytotoxic chemotherapy regimens such as irinotecan liposome plus fluorouracil, which produce median survival of roughly four to six months.

Daraxonrasib works by binding the active, GTP-bound state of RAS proteins—both wild-type and a broad set of mutant forms—blocking their interaction with downstream signaling effectors. That multi-selective mechanism distinguishes it from earlier KRAS-directed drugs such as sotorasib and adagrasib, which are restricted to the G12C mutation and have limited relevance in pancreatic cancer, where G12C is uncommon.

In RASolute 302, daraxonrasib met all primary and key secondary endpoints, including improvements in overall survival and progression-free survival that the company has characterized as unprecedented for this setting, alongside a manageable safety profile and delayed deterioration in pain and quality of life compared with chemotherapy. Full results were presented at the 2026 American Society of Clinical Oncology Annual Meeting and published simultaneously in The New England Journal of Medicine. The trial's design, enrolling patients regardless of RAS mutation status, reflects the drug's mechanism and could support use across a broader population than mutation-restricted competitors.

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The NDA was submitted on a rolling basis under the FDA Commissioner's National Priority Voucher pilot program, intended to accelerate review of medicines addressing national health priorities. Daraxonrasib previously received Breakthrough Therapy and Orphan Drug designations for this indication. In parallel, the European Medicines Agency's Committee for Medicinal Products for Human Use has opened a phased review of the drug, evaluating data in stages ahead of a full marketing authorization application, with orphan designation and high-priority status under the EMA's Cancer Medicines Pathfinder project.

If cleared, daraxonrasib would become the first RAS(ON) multi-selective inhibitor available to patients with previously treated metastatic PDAC, addressing a population for which second-line options remain sparse and largely reliant on chemotherapy. Revolution Medicines is separately advancing zoldonrasib, a G12D-selective RAS(ON) inhibitor, in combination and monotherapy settings for the same disease, indicating a broader strategy to layer RAS-targeted agents across genotypes and treatment lines rather than relying on a single asset. The FDA has not disclosed a target review date for the daraxonrasib application.

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