Revolution Medicines' Daraxonrasib Doubles Median Survival in Phase 3 Pancreatic Cancer Trial

Revolution Medicines said on May 31 that its oral RAS(ON) inhibitor daraxonrasib roughly doubled median overall survival compared with chemotherapy in the Phase 3 RASolute 302 trial in previously treated metastatic pancreatic ductal adenocarcinoma, according to the company's announcement, distributed by GlobeNewswire and read via Santé Log. The results were presented in a late-breaking plenary session at the American Society of Clinical Oncology (ASCO) annual meeting and published the same day in the New England Journal of Medicine, the company said.

The RASolute 302 results

RASolute 302 (NCT06625320) randomized 500 patients whose metastatic pancreatic cancer had progressed after prior treatment to once-daily oral daraxonrasib 300 mg (248 patients) or the investigator's choice of four chemotherapy regimens (252 patients). AJMC reported that the trial was open-label, ran at 59 sites in North America, Europe and Asia, and enrolled patients who had received one prior line of chemotherapy.

The primary endpoints were overall survival and progression-free survival, assessed by blinded independent central review, in patients whose tumors carry a RAS G12 mutation. At a median follow-up of 8.5 months, median overall survival in that group was 13.2 months on daraxonrasib versus 6.6 months on chemotherapy, a hazard ratio of 0.40 (p<0.0001), according to the company. Results in the full trial population, which included patients without an identified RAS mutation, were similar: 13.2 versus 6.7 months, with a hazard ratio of 0.40.

Median progression-free survival was 7.3 months versus 3.5 months in the RAS G12 group and 7.2 versus 3.6 months overall. Tumors shrank in 33.2% of RAS G12 patients on daraxonrasib versus 11.8% on chemotherapy. Patients on daraxonrasib also had a significantly longer time before their pain, global health status and quality of life worsened, the company said.

"In this global randomized trial, daraxonrasib, an oral RAS(ON) inhibitor, doubled median overall survival compared to standard of care chemotherapy for patients with previously treated metastatic pancreatic cancer," said Brian M. Wolpin of Dana-Farber Cancer Institute, the trial's principal investigator.

Safety

Grade 3 or higher treatment-related adverse events occurred in 43.6% of patients on daraxonrasib and 57.5% on chemotherapy, according to the company. The most frequent severe events on daraxonrasib were rash (14%) and mouth sores, or stomatitis (12%). One treatment-related death, from pneumonitis, was reported in the daraxonrasib arm and none in the chemotherapy arm. Treatment-related side effects led 1.2% of daraxonrasib patients to stop treatment, compared with 11.2% on chemotherapy.

Regulatory plans

Revolution Medicines said it intends to submit the data to regulators, including to the FDA as part of a new drug application under a Commissioner's National Priority Voucher. The FDA has granted daraxonrasib breakthrough therapy and orphan drug designations for previously treated metastatic pancreatic cancer with G12 mutations, and recently authorized an expanded access treatment protocol, the company said.

Daraxonrasib is designed to block the active, signaling form of both normal and mutant RAS proteins. It is being tested in three other Phase 3 trials, including in pancreatic and lung cancer. The drug is investigational and not approved by any regulator.