Zoldonrasib Combinations Show Compelling Antitumor Activity in RAS G12D–Mutant Metastatic PDAC

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 (Rasonque), an oral RAS(ON) multiselective inhibitor, in previously treated patients with RAS G12D–mutant metastatic pancreatic ductal adenocarcinoma (PDAC), according to phase 1/2 data from 2 trials.¹

In the first-line setting, among patients receiving zoldonrasib plus modified FOLFIRINOX (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin; mFOLFIRINOX; n = 22) 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; n = 31), 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 (n = 30), the ORR was 50% (95% CI, 31%-69%), and the DCR was 97% (95% CI, 83%-100%).^1,3

Both data sets were shared during the 2026 European Society for Medical Oncology 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 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.”

How were the RMC-GI-102 and RMC-9805-001 trials designed?

RMC-GI-102 is an ongoing trial evaluating zoldonrasib at a dose of 1200 mg once daily in combination with investigator’s choice of either mFOLFIRINOX or gemcitabine plus nab-paclitaxel 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/mFOLFIRINOX arm, and 40 patients had been enrolled in the zoldonrasib/gemcitabine/nab-paclitaxel arm.

RMC-9805-001 is a 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.^1,3 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).

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 plus daraxonrasib was 9.6 months (95% CI, 7.1-not estimable [NE]), and the 6-month PFS rate was 71% (95% CI, 50%-84%).³ The median overall survival (OS) was NE (95% CI, NE-NE), and the 6-month OS rate was 89% (95% CI, 71%-97%).

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% (95% CI, 39%-74%). The median OS was 10.5 months (95% CI, 6.7-NE), and the 6-month OS rate was 82% (95% CI, 62%-92%).

What is the safety profile of zoldonrasib in PDAC?

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.² Grade 3 or greater treatment-related adverse effects (TRAEs) occurred in 61% of patients receiving zoldonrasib plus mFOLFIRINOX and 80% of those receiving zoldonrasib plus gemcitabine and nab-paclitaxel. No grade 5 TRAEs were reported in either arm.

The most common grade 3 or greater TRAEs with zoldonrasib plus mFOLFIRINOX were decreased neutrophil counts (37%), anemia (12%), and decreased platelet counts (7%). The most common grade 3 or greater TRAEs with zoldonrasib plus gemcitabine and nab-paclitaxel were decreased neutrophil counts (35%), anemia (28%), and fatigue (25%). The mean dose intensity of zoldonrasib was 86% in the mFOLFIRINOX arm and 90% in the gemcitabine and nab-paclitaxel arm.

In RMC-9805-001, zoldonrasib plus daraxonrasib demonstrated a manageable safety and tolerability profile broadly consistent with the established profile of daraxonrasib monotherapy.³ Grade 3 or greater TRAEs occurred in 35% of patients. Among TRAEs occurring in 10% or more of all patients, the most common grade 3 or greater TRAEs were rash (12%), anemia (10%), and stomatitis/mucositis (7%). Few patients discontinued treatment due to TRAEs; 2% of patients discontinued zoldonrasib, and 5% of patients discontinued daraxonrasib. The mean dose intensity was 88% for zoldonrasib and 76% for daraxonrasib.

What are the next steps for zoldonrasib development?

Both data sets build on the landmark phase 3 RASolute 302 trial (NCT06625320), results from which were presented at the 2026 American Society of Clinical Oncology Annual Meeting and provided clinical validation of RAS(ON) inhibition in metastatic PDAC.⁴ In this trial, daraxonrasib (n = 228) reduced the risk of death by 60% compared with standard chemotherapy (n = 231) in patients with previously treated metastatic RAS G12-mutated PDAC (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10^-10) and almost doubled the median OS (13.2 months [95% CI, 10.0-NE] vs 6.6 months [95% CI, 5.4-8.2]).

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–mutant PDAC.¹

Moreover, results from RMC-9805-001 support the ongoing pivotal global phase 3 RASolute 309 trial (NCT07805954), which is evaluating zoldonrasib plus daraxonrasib vs gemcitabine and nab-paclitaxel in patients with previously untreated RAS G12D-mutant metastatic PDAC.

References

1. 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/
2. Wolpin BM, Pant S, Spira A, et al. Wainberg ZA, Strickler JH, Bekaii-Saab TS, et al. Safety and efficacy of zoldonrasib (RMC-9805) plus chemotherapy in patients (pts) with 1L RAS G12D metastatic pancreatic adenocarcinoma (MPDAC). Ann Oncol. 2026;37(suppl 1):S122-S123. doi:10.1016/j.annonc.2026.05.381
3. Azad NS, Kim D, Oberstein P, et al. Safety and efficacy of zoldonrasib (RMC-9805) plus daraxonrasib (RMC-6236) in patients with 2L+ KRAS G12D metastatic pancreatic adenocarcinoma (mPDAC). Ann Oncol. 2026;37(suppl 1):S122-S124. doi:10.1016/j.annonc.2026.05.382
4. 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):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5