The oral RAS(ON) G12D-selective covalent inhibitor zoldonrasib (RMC-9805) demonstrated compelling antitumor activity and a manageable safety profile when combined with standard-of-care chemotherapy in previously untreated patients and when combined with daraxonrasib (RMC-6236), an oral RAS(ON) multi-selective inhibitor, in previously treated patients with RAS G12D metastatic pancreatic ductal adenocarcinoma (PDAC), according to phase 1/2 data from two trials.1
In the first-line setting, among patients receiving zoldonrasib plus modified FOLFIRINOX (mFFX) in the phase 1/2 RMC-GI-102 trial (NCT06445062), the objective response rate (ORR) was 82% (95% CI, 60%-95%) and the disease control rate (DCR) was 96% (95% CI, 77%-100%).1,2 Among patients receiving zoldonrasib plus gemcitabine and nab-paclitaxel (Abraxane; GnP), the ORR was 61% (95% CI, 42%-78%) and the DCR was 90% (95% CI, 74%-98%).
In the previously treated setting, among patients in the second-line cohort of the phase 1/1b RMC-9805-001 trial (NCT06040541) receiving zoldonrasib plus daraxonrasib (RMC-6236), the ORR was 50% (95% CI, 31%-69%) and the DCR was 97% (95% CI, 83%-100%).1,3
Both datasets were shared during the 2026 ESMO Gastrointestinal Cancers Congress (ESMO GI).¹⁻³
"The results presented at ESMO GI demonstrate compelling proof-of-concept for [both] zoldonrasib-based regimens in RAS G12D–mutant disease," Alan Sandler, MD, chief development officer of Revolution Medicines, stated in a company news release.1 “Together, these findings are the foundation of 2 distinct phase 3 strategies we are pursuing in previously untreated metastatic RAS G12D[–mutant] pancreatic cancer.”
Key Early Efficacy, Safety Data With Zoldonrasib Combos in PDAC
- In the first-line setting, the ORR with zoldonrasib plus mFFX was 82% (95% CI, 60%-95%) and the DCR was 96% (95% CI, 77%-100%). Respective rates with zoldonrasib plus GnP were 61% (95% CI, 42%-78%) and 90% (95% CI, 74%-98%). In the previously treated setting, zoldonrasib plus daraxonrasib produced an ORR of 50% (95% CI, 31%-69%) and DCR of 97% (95% CI, 83%-100%).
- Zoldonrasib demonstrated a manageable safety and tolerability profile in combination with both chemotherapy regimens, as well as with daraxonrasib.
- Together with data from the landmark phase 3 RASolute 302 trial, these findings provide the basis for two planned phase 3 studies: RASolute 305 and RASolute 309.
How were the RMC-GI-102 and RMC-9805-001 trials designed?
RMC-GI-102 is an ongoing phase 1/2 trial evaluating zoldonrasib at a dose of 1200 mg once daily in combination with investigator's choice of either mFFX or GnP in patients with previously untreated metastatic RAS G12D–mutant PDAC.1,2 As of the February 8, 2026, data cutoff, 41 patients had been enrolled in the zoldonrasib plus mFFX arm and 40 patients in the zoldonrasib plus GnP arm.
RMC-9805-001 is a phase 1/1b trial evaluating zoldonrasib at a dose of 1200 mg once daily plus daraxonrasib at a dose of 300 mg once daily in patients with advanced solid tumors harboring RAS G12D mutations. As of the February 9, 2026, data cutoff, 60 patients with RAS G12D–mutant metastatic PDAC who had previously received 1 or more prior lines of therapy were treated with the combination. Patients were analyzed in a second-line cohort (n = 30) and a third-line and beyond cohort (n = 30).1,3
In both studies, the primary end point was safety, as assessed through adverse effects and the rate of dose-limiting toxicities.1-3 Additional efficacy and pharmacokinetic measures served as secondary end points.
What additional efficacy data were reported from RMC-9805-001?
In the second-line cohort, the median progression-free survival (PFS) with zoldonrasib and daraxonrasib was 9.6 months (95% CI, 7.1 months to not estimable [NE]), and the 6-month PFS rate was 71%. The median overall survival (OS) was not yet estimable, and the 6-month OS rate was 89%.
In the third-line and beyond cohort, the ORR was 47% (95% CI, 28%-66%) and the DCR was 90% (95% CI, 74%-98%). The median PFS was 7.6 months (95% CI, 4.6-10.5), with a 6-month PFS rate of 59%. The median OS was 10.5 months (95% CI, 6.7-NE), and the 6-month OS rate was 82%.
What were the safety data from both studies?
In RMC-GI-102, zoldonrasib demonstrated a manageable safety and tolerability profile in combination with both chemotherapy regimens, with a safety profile broadly consistent with those of each respective chemotherapy backbone.1,2 Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 61% of patients receiving zoldonrasib plus mFFX and 80% of those receiving zoldonrasib plus GnP. No grade 5 TRAEs were reported in either arm.
The most common grade 3 or greater TRAEs with zoldonrasib plus mFFX were decreased neutrophil count (37%), anemia (12%), and platelet count decrease (7%). The most common grade 3 or greater TRAEs with zoldonrasib plus GnP were decreased neutrophil count (35%), anemia (28%), and fatigue (25%). The mean dose intensity was 86% with zoldonrasib plus mFFX and 90% with zoldonrasib plus GnP.
In RMC-9805-001, zoldonrasib plus daraxonrasib demonstrated a manageable safety and tolerability profile broadly consistent with the established profile of daraxonrasib monotherapy. Grade 3 or greater TRAEs occurred in 35% of patients.1,3 Among TRAEs occurring in 10% or more of all patients, the most common grade 3 or greater events were rash (12%), anemia (10%), and stomatitis/mucositis (7%). Few patients discontinued due to TRAEs; 2% discontinued zoldonrasib and 5% discontinued daraxonrasib. The mean dose intensity was 88% for zoldonrasib and 76% for daraxonrasib.²
What are the next steps for zoldonrasib development?
Both datasets build on the landmark phase 3 RASolute 302 trial (NCT06625320), results from which were presented at the 2026 ASCO Annual Meeting and provided clinical validation of RAS(ON) inhibition in metastatic PDAC. In this trial, daraxonrasib reduced the risk of death by 60% compared with standard chemotherapy in patients with previously treated metastatic PDAC (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10-10) and almost doubled the median OS (13.2 vs 6.6 months [HR, 0.40; 95% CI, 0.30-0.54; P < .0001]).4
Additionally, data from RMC-GI-102 support the ongoing phase 3 RASolute 305 trial (NCT07621718), a global, randomized, double-blind, placebo-controlled study evaluating zoldonrasib plus investigator's choice of standard-of-care chemotherapy vs placebo plus investigator's choice of chemotherapy in patients with previously untreated metastatic RAS G12D PDAC.¹
Moreover, results from RMC-9805-001 support the planned pivotal global phase 3 RASolute 309 trial, which will evaluate zoldonrasib plus daraxonrasib vs GnP in patients with previously untreated RAS G12D metastatic PDAC. These 2 phase 3 strategies represent distinct but complementary approaches to RAS G12D-directed therapy—one anchored in cytotoxic chemotherapy combination and one in a RAS(ON) inhibitor doublet—across the treatment continuum.
References
- Revolution Medicines presents phase 1/2 clinical data for zoldonrasib combination regimens in patients with RAS G12D metastatic pancreatic cancer at ESMO Gastrointestinal Cancers Congress 2026. News release. Revolution Medicines. July 2, 2026. Accessed July 9, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-phase-12-clinical-data-zoldonrasib/
- Wainberg ZA, Strickler JH, Bekaii-Saab TS, et al. Safety and efficacy of zoldonrasib plus chemotherapy in patients with first line RAS G12D metastatic pancreatic cancer. Presented at: 2026 ESMO Gastrointestinal Cancers Congress; July 2, 2026; Barcelona, Spain. Abstract 340O.
- Rahma OE, Wainberg ZA, Yaeger R, et al. Safety and efficacy of zoldonrasib plus daraxonrasib in patients with second line-plus RAS G12D metastatic pancreatic cancer. Presented at: 2026 ESMO Gastrointestinal Cancers Congress; July 2, 2026; Barcelona, Spain. Abstract 341O.
- Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA4005. doi:10.1200/JCO.2026.44.17_suppl.LBA4005.
