Revolution Medicines: zoldonrasib combos active in RAS G12D PDAC

Revolution Medicines presented Phase 1/2 clinical data for zoldonrasib-based combination regimens in RAS G12D metastatic pancreatic ductal adenocarcinoma (PDAC) at the ESMO Gastrointestinal Cancers Congress 2026 on 2 July, reporting meaningful antitumour activity across both first-line and second-line-plus settings.

The Redwood City, California company is building a portfolio of oral RAS(ON) inhibitors targeting specific oncogenic RAS variants. Zoldonrasib (RMC-9805) is designed as a G12D-selective covalent inhibitor, while daraxonrasib (RMC-6236) is a multi-selective agent targeting a broader range of RAS genotypes. The two drugs were evaluated both with standard chemotherapy and with each other.

First-line combination with chemotherapy

In the RMC-GI-102 trial (NCT06445062), 81 previously untreated patients received zoldonrasib 1,200 mg once daily alongside either modified FOLFIRINOX (mFFX) or gemcitabine plus nab-paclitaxel (GnP). As of a February 2026 data cutoff, the objective response rate (ORR) in the mFFX arm was 82% (95% CI: 60-95), with a disease control rate (DCR) of 96%. In the GnP arm, ORR was 61% (95% CI: 42-78) and DCR was 90%.

Grade 3 or greater treatment-related adverse events occurred in 61% of the mFFX arm and 80% of the GnP arm, driven primarily by neutropenia and anaemia. No Grade 5 events were reported. Mean dose intensity exceeded 85% in both arms, suggesting the combinations were broadly manageable, though the higher-grade toxicity rate in the GnP arm warrants close monitoring in the pivotal setting.

RAS(ON) inhibitor doublet in later lines

In the Phase 1 RMC-9805-001 trial (NCT06040541), 60 patients with previously treated RAS G12D metastatic PDAC received zoldonrasib plus daraxonrasib. In the second-line cohort (n=30), ORR was 50% and median progression-free survival was 9.6 months, with a six-month overall survival rate of 89%. In the third-line-and-beyond cohort (n=30), ORR was 47% and median PFS was 7.6 months. Grade 3 or greater adverse events occurred in 35% of patients; discontinuation rates were low at 2% for zoldonrasib and 5% for daraxonrasib.

Alan Sandler, chief development officer at Revolution Medicines, said the findings represented "compelling proof-of-concept for two zoldonrasib-based regimens in RAS G12D disease" and described them as the foundation of two distinct Phase 3 strategies: the ongoing RASolute 305 trial and the planned RASolute 309 trial.

Market context and competitive landscape

Pancreatic cancer remains one of oncology's most resistant indications. Around 90% of PDAC cases harbour RAS mutations, with G12D accounting for roughly 40% of those. Until recently, no approved targeted therapy existed for this subtype, leaving chemotherapy as the standard of care with limited long-term benefit.

The data presented at ESMO GI build directly on the Phase 3 RASolute 302 readout for daraxonrasib in second-line PDAC, which Revolution Medicines has previously described as the first clinical validation of RAS(ON) inhibition in this setting. The FDA has granted daraxonrasib Breakthrough Therapy Designation and Orphan Drug Designation for previously treated metastatic PDAC, and it has been selected for the FDA Commissioner's National Priority Voucher pilot programme.

The company's G12D programme places it ahead of most competitors in this specific genotype. Amgen's sotorasib and Mirati's adagrasib are approved for G12C, a different mutation that is rare in PDAC. No other RAS G12D inhibitor has yet reported comparable Phase 1/2 combination data in pancreatic cancer at a major congress, though the space is attracting interest from larger pharmaceutical groups monitoring Revolution Medicines' progress. Investors will focus on the pace of enrolment in RASolute 305 and the timeline for initiating RASolute 309 as the next material milestones.