Daraxonrasib, an oral RAS inhibitor approved by the FDA for metastatic pancreatic cancer on Aug. 26 doubled median overall survival compared with chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC), according to a phase 3 randomized trial.
The international RASolute 302 trial, published in The New England Journal of Medicine, included 500 patients at 59 sites in six countries. First author Eileen M. O'Reilly, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center, New York, and colleagues randomly assigned 248 patients to receive daraxonrasib once daily and 252 to receive chemotherapy selected by the investigator. Ninety-two percent of patients had RAS G12 mutations.
Eligible patients had mPDAC that had progressed after previous chemotherapy or shortly after neoadjuvant or adjuvant therapy. Patients also had measurable disease and good performance status. Chemotherapy options included gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, FOLFOX, or liposomal irinotecan plus fluorouracil and leucovorin.
The two primary endpoints were overall survival and progression-free survival among the 459 patients with RAS G12 mutations. Median overall survival was 13.2 months with daraxonrasib vs. 6.6 months with chemotherapy, representing a 60% lower likelihood of death. In the overall study population, median overall survival was 13.2 months vs. 6.7 months, also representing a 60% lower likelihood of death.
Median progression-free survival was 7.3 months with daraxonrasib vs. 3.5 months with chemotherapy among patients with RAS G12 mutations, representing a 55% lower likelihood of disease progression or death. In the overall study population, median progression-free survival was 7.2 months vs. 3.6 months, representing a 51% lower likelihood.
Tumor responses also favored daraxonrasib. Among patients with RAS G12 mutations, 33% responded to daraxonrasib vs. 12% to chemotherapy. In the overall study population, response rates were 32% and 11%, respectively.
Overall survival generally favored daraxonrasib across patient subgroups, including those based on performance status, stage at diagnosis, liver metastases, previous treatment, and RAS mutation status. However, the authors cautioned that these findings were exploratory, particularly for uncommon RAS mutations and tumors without an identified RAS mutation because few patients were in these groups.
Patient-reported outcomes also favored daraxonrasib. Among patients with RAS G12 mutations, pain took a median of nine months to worsen with daraxonrasib vs. 3.7 months with chemotherapy. Overall health and quality of life took a median of 5.6 months to worsen vs. 2.4 months. Similar results were seen in the overall study population.
Grade 3 or higher adverse events occurred in 62% of patients receiving daraxonrasib vs. 70% receiving chemotherapy. Treatment-related grade 3 or higher events occurred in 44% vs. 58%, respectively. The most common treatment-related events of any grade with daraxonrasib were rash in 86% of patients, diarrhea in 58%, and stomatitis in 53%. Treatment-related adverse events led to treatment discontinuation in 1% of patients receiving daraxonrasib vs. 11% receiving chemotherapy. One patient receiving daraxonrasib died from treatment-related pneumonitis.
For physicians, the findings suggest that sustained RAS inhibition may offer an alternative to chemotherapy after initial treatment of mPDAC, particularly for patients with RAS G12 mutations. Limitations included the open-label design, which may have influenced adverse-event reporting and treatment decisions. Fifteen percent of patients assigned to chemotherapy never started treatment, and small patient numbers limited conclusions about uncommon RAS subtypes.
The authors concluded that the findings “support daraxonrasib as a clinically meaningful advance” for previously treated mPDAC.
Revolution Medicines, which is developing daraxonrasib, funded the study, helped develop the study protocol, and performed and validated the statistical analyses.Individual author disclosures are available with the full article.