RAS Inhibitor Daraxonrasib Nearly Doubles Survival in Metastatic Pancreatic Cancer Trial

A Phase 3 trial of daraxonrasib, an oral inhibitor of the RAS oncogene pathway, has shown the largest survival improvement reported to date in previously treated metastatic pancreatic cancer, according to results published May 31 in the New England Journal of Medicine and presented concurrently at the American Society of Clinical Oncology annual meeting.

The RASolute 302 trial, run by Revolution Medicines, compared daraxonrasib 300 mg orally once daily against investigator's choice of intravenous cytotoxic chemotherapy. As reported in the NEJM, the trial enrolled 500 patients who had already received at least one prior line of treatment for metastatic pancreatic ductal adenocarcinoma (PDAC). That's a harder population to move the needle on than treatment-naive patients, which makes the magnitude of the benefit notable.

In the intent-to-treat population, the trial reported a median overall survival of 13.2 months for daraxonrasib versus 6.7 months for chemotherapy, a hazard ratio of 0.40 with p less than 0.0001. Both coprimary endpoints, progression-free survival and overall survival, were met. The investigators considered the first interim analysis results final.

The mechanism matters here. More than 90 percent of pancreatic cancer tumors carry mutations in a RAS gene, according to reporting in The Scientist. Daraxonrasib works as a RAS(ON) multi-selective inhibitor, meaning it targets the active, GTP-bound form of RAS rather than a specific mutation subtype, which is a different approach from earlier KRAS G12C-specific drugs that covered a narrower slice of patients.

The safety data warrant attention alongside the efficacy numbers. Data from the earlier Phase 1/2 trial published in NEJM showed that treatment-related adverse events of any grade were reported in 96 percent of the 168 PDAC patients who received daraxonrasib, according to reporting in Targeted Oncology. Grade 3 or higher events occurred in roughly 30 percent of patients. The most common adverse events included rash, diarrhea, nausea, stomatitis, vomiting, and fatigue. Revolution Medicines characterized the profile as manageable and said no new safety signals emerged in the Phase 3 data.

The FDA has already allowed expanded access to daraxonrasib for PDAC ahead of formal approval, a step it took after reviewing the Phase 3 topline readout. Revolution Medicines said it intends to file a New Drug Application under a Commissioner's National Priority Voucher, per a company statement reviewed by OncLive.

A few caveats are worth naming. RASolute 302 was an open-label trial, which means blinding was not maintained at the treatment level, though progression-free survival was assessed by blinded independent central review. The trial was run and funded by Revolution Medicines, the drug's developer. That's standard for a late-stage registrational trial but it's the context readers should carry into any headline claiming practice-changing results.

Pancreatic cancer remains one of the most lethal solid tumors, in large part because most patients are diagnosed at a late stage. A doubling of median overall survival in the second-line setting is a clinically meaningful effect size by most standards in this disease. Whether it translates into long-term survival benefit for a meaningful fraction of patients, rather than a shift in the median, is the question the longer follow-up data will need to answer.

Sources cited:
- New England Journal of Medicine (RASolute 302 trial) (https://www.nejm.org/doi/10.1056/NEJMoa2605555)
- Revolution Medicines press release via OncLive (https://www.onclive.com/view/daraxonrasib-yields-significant-survival-advantages-vs-chemotherapy-in-metastatic-pancreatic-cancer)
- The Scientist (https://www.the-scientist.com/daraxonrasib-drug-doubles-pancreatic-cancer-survival-rate-in-phase-3-trial-74578)
- Targeted Oncology (https://www.targetedonc.com/view/daraxonrasib-pdac-data-published-in-nejm-as-fda-allows-expanded-access)
- ClinicalTrials.gov (NCT06625320) (https://clinicaltrials.gov/study/NCT06625320)