Revolution Medicines has unveiled striking new late-stage clinical data for its RAS-targeted pipeline in metastatic pancreatic cancer, showcasing two combination strategies built around its oral RAS(ON) G12D-selective inhibitor, zoldonrasib.

 

The results come from two Phase 1/2 trials evaluating zoldonrasib both alongside standard chemotherapy in first-line patients and in combination with daraxonrasib in previously treated disease.

 

The Phase 3 RASolute 302 results provided clinical validation of RAS(ON) inhibition with daraxonrasib in second line metastatic pancreatic cancer and established a strong foundation for evaluating this therapeutic approach across additional RAS genotypes, treatment settings and combination strategies. 

 

The results presented at ESMO GI demonstrate compelling proof-of-concept for two zoldonrasib-based regimens in RAS G12D disease: combination with standard of care chemotherapy in previously untreated patients and a RAS(ON) inhibitor doublet with daraxonrasib in previously treated patients. 

 

"Together, these findings are the foundation of two distinct Phase 3 strategies we are pursuing in previously untreated metastatic RAS G12D pancreatic cancer: the ongoing RASolute 305 trial evaluating zoldonrasib plus standard of care chemotherapy, and the planned RASolute 309 trial evaluating the combination of zoldonrasib plus daraxonrasib,” said Alan Sandler, chief development officer of Revolution Medicines.

 

In first-line metastatic RAS G12D pancreatic ductal adenocarcinoma, zoldonrasib was tested with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel. As of a February 8, 2026 cutoff, 81 patients had been enrolled across both arms.

 

The safety profile was described as manageable and broadly consistent with chemotherapy alone. 

 

Grade 3 or higher treatment-related adverse events occurred in 61% of patients in the FOLFIRINOX arm and 80% in the gemcitabine/nab-paclitaxel arm, with no treatment-related deaths reported. Dose intensity remained high at 86% and 90%, respectively.

 

In the second study, heavily pretreated patients received zoldonrasib in combination with daraxonrasib, another oral RAS(ON) inhibitor. Among 60 patients with metastatic pancreatic cancer, the regimen showed manageable toxicity and relatively low discontinuation rates.

 

Grade 3 or higher adverse events occurred in 35% of patients, with rash, anemia, and stomatitis/mucositis among the most common severe toxicities. Dose intensity remained 88% for zoldonrasib and 76% for daraxonrasib.

 

Efficacy data were particularly notable in later-line disease. In second-line patients, the objective response rate was 50% with a disease control rate of 97%, while median progression-free survival reached 9.6 months. In third-line and beyond patients, response rates remained robust at 47%, with median progression-free survival of 7.6 months and median overall survival of 10.5 months.