Revolution Medicines has announced results from 2 phase 1/2 clinical trials evaluating zoldonrasib, its oral RAS(ON) G12D-selective covalent inhibitor, in combination regimens for patients with RAS G12D metastatic pancreatic ductal adenocarcinoma (PDAC). The results, which will be presented in a proffered paper session at the 2026 European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress, include zoldonrasib in combination with Standard of Care chemotherapy in previously untreated patients and zoldonrasib in combination with daraxonrasib, the company’s oral RAS(ON) multi-selective inhibitor, in previously treated patients.

Alan Sandler, MD, CDO, Revolution Medicines, said, “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 2 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.”

RMC-GI-102 (NCT06445062) is an ongoing phase 1/2 trial evaluating zoldonrasib 1200 mg once daily in combination with investigator's choice of Standard of Care chemotherapy in patients with previously untreated metastatic RAS G12D PDAC. Investigator's choice of chemotherapy includes modified FOLFIRINOX (mFFX) or gemcitabine plus nab-paclitaxel (GnP). As of the February 8, 2026 data cutoff, the trial enrolled 41 patients in the zoldonrasib plus mFFX arm and 40 patients in the zoldonrasib plus GnP arm.

Zoldonrasib demonstrated a manageable safety and tolerability profile in combination with standard chemotherapy. The safety profile of zoldonrasib in combination with chemotherapy was broadly consistent with the established profiles of each respective chemotherapy regimen. Grade 3 or greater Treatment-Related Adverse Events (TRAEs) occurred in 61 percent of patients who received the zoldonrasib plus mFFX and 80 percent of patients who received zoldonrasib plus GnP. The most common Grade 3 or greater TRAEs with zoldonrasib plus mFFX were decreased neutrophil count (37 percent), anemia (12 percent), and platelet count decreased (7 percent). The most common Grade 3 or greater TRAEs with zoldonrasib plus GnP were decreased neutrophil count (35 percent), anemia (28 percent), and fatigue (25 percent). No Grade 5 TRAEs were reported in either arm. The mean dose intensity was 86 percent with zoldonrasib plus mFFX and 90 percent with the zoldonrasib plus GnP.

In the trial, zoldonrasib with chemotherapy showed compelling antitumor activity, with an Objective Response Rate (ORR) of 82 percent (95 percent Confidence Interval [CI]: 60, 95) and Disease Control Rate (DCR) of 96 percent (95 percent CI: 77, 100) in the mFFX population, and an ORR of 61 percent (95 percent CI: 42, 78) and DCR of 90 percent (95 percent CI: 74, 98) in the GnP population.

These preliminary safety and clinical activity data support the ongoing RASolute 305 pivotal trial (NCT07621718), a global, randomised, double-blind placebo-controlled phase 3 clinical trial evaluating zoldonrasib plus investigator’s choice of Standard of Care chemotherapy compared with placebo plus investigator’s choice of chemotherapy in patients with previously untreated metastatic RAS G12D PDAC.

RMC-9805-001 (NCT06040541) is a phase 1 trial evaluating zoldonrasib 1200 mg once daily plus daraxonrasib 300 mg once daily in advanced solid tumors with RAS G12D mutations. As of the February 9, 2026 data cutoff, 60 patients with RAS G12D metastatic PDAC who had previously received one or more prior lines of therapy were treated with the combination.

Zoldonrasib plus daraxonrasib demonstrated a manageable safety and tolerability profile that was broadly consistent with the established profile of daraxonrasib monotherapy. Grade 3 or greater TRAEs occurred in 35 percent of patients who received the combination. Among TRAEs occurring in 10 percent or more of all patients, the most common Grade 3 or greater events were rash (12 percent), anemia (10 percent), and stomatitis/mucositis (7 percent). Few patients discontinued due to TRAES; 2 percent discontinued zoldonrasib and 5 percent discontinued daraxonrasib. The mean dose intensity was 88 percent for zoldonrasib and 76 percent for daraxonrasib.

The zoldonrasib plus daraxonrasib combination demonstrated compelling antitumor activity in patients with previously treated metastatic PDAC. In the second line cohort (2L) (N=30), the ORR was 50 percent (95 percent CI: 31-69) and DCR was 97 percent (95 percent CI: 83-100). Median Progression-Free Survival (PFS) in the 2L cohort was 9.6 months (95 percent CI: 7.1-NE), with a 6-month PFS rate of 71 percent.

Median Overall Survival (OS) in the 2L cohort was not yet estimable, with a 6-month OS rate of 89 percent. In the third line and beyond (3L+) cohort (N=30), the ORR was 47 percent (95 percent CI: 28-66) and DCR was 90 percent (95 percent CI: 74-98). Median PFS in the 3L+ cohort was 7.6 months (95 percent CI: 4.6-10.5), with a 6-month PFS rate of 59 percent. Median OS in the 3L+ cohort was 10.5 months (95 percent CI: 6.7-NE), with a 6-month OS rate of 82 percent.

These safety and clinical activity data support the planned pivotal global, phase 3 RASolute 309 clinical trial of zoldonrasib plus daraxonrasib versus GnP in patients with previously untreated RAS G12D metastatic PDAC.