Overall survival is the time from randomisation until death from any cause. In the RASolute 302 trial, patients assigned to the oral RAS(ON) inhibitor lived a median 13.2 months, compared with 6.7 months for those assigned to investigator's-choice chemotherapy, according to the NEJM paper and the American Society of Clinical Oncology.
The hazard ratio for death was 0.40, according to Revolution Medicines' detailed results and ASCO's release. A hazard ratio compares the rate at which an event occurs between two groups over time; here, the reported figure means the daraxonrasib group had a lower death rate during follow-up than the chemotherapy group. The trial also reported median progression-free survival, the time before the cancer worsens or the patient dies, of 7.2 months with daraxonrasib versus 3.6 months with chemotherapy in the overall study population.
The result is clinically important because pancreatic ductal adenocarcinoma has few effective second-line treatments once metastatic disease has progressed after earlier therapy. ASCO said the study was the first Phase 3 trial of a RAS(ON) multi-selective inhibitor in this setting. RAS refers to a family of signalling proteins that help regulate cell growth; mutations in that pathway are common drivers of pancreatic cancer.
Brian Wolpin of Dana-Farber Cancer Institute, the study's lead investigator, said through ASCO that the trial was designed to test whether the drug could work better and with fewer side effects than available chemotherapies. Dana-Farber said the trial showed substantial survival prolongation regardless of RAS mutation status.
The trial population is important. These were patients with metastatic disease that had already been treated, so the result applies first to second-line care rather than to newly diagnosed pancreatic cancer. Metastatic means the cancer has spread beyond the pancreas; second-line means treatment after a previous regimen has stopped working or is no longer suitable.
The safety results also favoured the drug on several headline measures, though toxicity was not absent. Revolution Medicines reported grade 3 or higher treatment-related adverse events in 43.6% of patients receiving daraxonrasib and 57.5% receiving chemotherapy. Grade 3 or higher means a severe or medically significant adverse event. The company reported one grade-5 pneumonitis, a fatal lung inflammation, in the daraxonrasib group.