Rasonque OK’d Across KRAS Mutations Despite Clinical Response Differences

FDA granted approval to Revolution Medicines' Rasonque (daraxonrasib) for metastatic pancreatic cancer despite substantial differences in treatment responses among patients with different KRAS mutations and limited evidence of effectiveness in patients without RAS mutations, according to a newly released approval document. The 321-page review shows that FDA considered restricting the indication based on mutation status but ultimately supported broader use, citing a substantial overall survival benefit, limited treatment alternatives and the difficulty of interpreting small subgroup analyses.

FDA approved Rasonque on 8/26 under its Commissioner's National Priority Voucher program (see earlier story). The review documents illustrate how the agency balanced strong overall efficacy findings against uncertainty about treatment effects in smaller molecular subgroups.

In the pivotal 500-patient RASolute 302 trial, the objective response rate among patients with KRAS G12V mutations was 50%, compared with 24% for G12D mutations, the most common mutation type in pancreatic cancer, and 7% for G12R mutations. The corresponding chemotherapy response rates were 15%, 10% and 14%, respectively.

The evidence was particularly limited for patients with RAS wild-type tumors. Only 16 patients in the pivotal trial had such tumors, and FDA reported conflicting progression-free survival estimates depending on whether assessments were conducted by independent reviewers or investigators.

Blinded independent central review produced a progression-free survival hazard ratio of 1.92, numerically favoring chemotherapy, while investigator assessment produced a hazard ratio of 0.62, favoring Rasonque. FDA said the small population and inconsistent findings reduced the reliability of those estimates.

Nevertheless, reviewers supported including both RAS-mutated and wild-type tumors in the indication, citing the overall survival findings, preclinical evidence and substantial unmet medical need.

FDA also extended the approved indication to patients who cannot receive multiagent systemic chemotherapy, a first-line population not enrolled in the pivotal trial. Reviewers justified that decision based on Rasonque's tolerability relative to combination chemotherapy and the limited alternatives available to those patients.

Across the overall trial population, median survival was 13.2 months with Rasonque versus 6.7 months with chemotherapy, representing a hazard ratio of 0.40 (95% CI 0.30–0.53).