Skip to content

Daraxonrasib + Zoldonrasib (RMC-9805) — RAS-class expansion in metastatic PDAC

Headline: Revolution Medicines' RAS(ON) program delivered the most consequential PDAC signal in a decade at ASCO GI 2026 — daraxonrasib (pan-RAS) + chemo combination updates, plus zoldonrasib (RMC-9805, selective KRAS-G12D(ON)) Phase 1 expansion with ORR 30%, DCR 80%, and 86% of evaluable patients with >50% ctDNA KRAS-G12D decline (39% with complete molecular clearance). Sets up the Rasolute-302 Phase 3 Plenary LBA5 readout at ASCO 2026 on May 31.

At a glance

  • Sponsor / PI / institution: Revolution Medicines; presented by Eileen O'Reilly (MSK) and Mark Sausen / Andrew Hendifar (Cedars-Sinai)
  • NCT ID: NCT05379985 (daraxonrasib RMC-6236-001); NCT06040541 (zoldonrasib RMC-9805-001)
  • Phase / arms / N: Phase 1/2 dose-expansion combined readout; daraxonrasib monotherapy + chemo-combo cohorts; zoldonrasib monotherapy at 1200 mg QD / 600 mg BID PDAC expansion (~50 evaluable PDAC pts)
  • Primary endpoint(s): Safety, RP2D, ORR, DCR, ctDNA clearance
  • Indication / line: 1L+ metastatic RAS-mutant PDAC (daraxonrasib); KRAS-G12D-mutant PDAC (zoldonrasib)
  • Comparator: None (single-arm Phase 1/2)
  • Session: Day 2 (Fri Jan 9, 2026), Pancreatic General Session, Moscone West

Headline result

Zoldonrasib delivered an ORR of 30% and DCR of 80% in evaluable KRAS-G12D PDAC patients, with 86% achieving >50% ctDNA KRAS-G12D allele-frequency decline and 39% reaching complete molecular clearance — the first selective G12D(ON) inhibitor activity signal in PDAC. Daraxonrasib + chemo expansion data confirmed the durability profile underlying the April 13, 2026 Rasolute-302 topline (mOS 13.2 vs 6.7 mo, HR 0.40, p<0.0001).

Mechanism / class

Daraxonrasib (RMC-6236) is a pan-RAS(ON) tri-complex inhibitor that traps active GTP-bound RAS in a non-productive complex with cyclophilin A. Zoldonrasib (RMC-9805) is a covalent KRAS-G12D(ON)-selective tri-complex variant of the same chemotype — first selective G12D drug to reach the clinic with PDAC efficacy.

Trial design deep dive

Study architecture. Two parallel single-arm Phase 1/2 dose-expansion programs: daraxonrasib (RMC-6236-001) in pan-RAS-mutant PDAC across monotherapy and chemo-combination cohorts; zoldonrasib (RMC-9805-001) in KRAS-G12D-mutant PDAC at 1200 mg QD vs 600 mg BID. No randomization at this stage; the Phase 3 randomized comparator (Rasolute-302) reads at ASCO 2026 Plenary (May 31).

Endpoint definitions. Investigator-assessed ORR per RECIST 1.1 as primary efficacy; DCR, DoR, PFS, and safety as secondary. ctDNA KRAS-G12D allele-frequency dynamics tracked as exploratory pharmacodynamic readout with prespecified thresholds (>50% decline; complete molecular clearance defined as variant allele frequency below assay LOD). No BICR for Phase 1/2 dose-expansion.

Key subgroup analyses.

  • KRAS-G12D vs G12V vs G12R subsets (daraxonrasib): activity reported across G12 variants — discussant framing emphasized G12-subgroup parity as differentiating from G12C-selective era.
  • Prior lines of therapy (1L vs 2L+ daraxonrasib): Rasolute-302 was 2L+ post-gemcitabine/nab-paclitaxel or FOLFIRINOX; 1L combo cohorts are exploratory.
  • ctDNA responders vs non-responders: 86% of zoldonrasib-evaluable patients with >50% ctDNA G12D decline; 39% complete molecular clearance — clearance correlated with radiographic response.
  • Performance status (ECOG 0 vs 1): TBD — not broken out publicly for this dose-expansion.

Comparator context. SOC 2L+ PDAC remains liposomal irinotecan + 5-FU (NAPOLI-3) or 5-FU/leucovorin with historical mOS ~6-7 months. Daraxonrasib Rasolute-302 topline (mOS 13.2 vs 6.7 mo) doubles control benchmark.

FDA / regulatory implications. Daraxonrasib carries FDA Breakthrough Therapy Designation in 2L+ metastatic PDAC (granted 2024). BLA filing pending Rasolute-302 full data presentation at ASCO 2026 Plenary; accelerated approval pathway feasible Q3-Q4 2026. Zoldonrasib remains pre-pivotal.

Discussant takeaway

Eileen O'Reilly framed the RAS-class signal as the inflection point for PDAC — the first credible molecular-targeted PDAC story since gemcitabine. Discussant framing of toxicity (rash, GI) and G12-subgroup parity will carry directly into the Rasolute-302 Plenary discussant slot at ASCO May 31.

Practice-changing verdict

Foundation, not yet practice-changing. The Phase 1/2 expansion data here is the scientific premise for the Rasolute-302 Plenary readout at ASCO 2026 (May 31). If RASolute-302 reads as toplined, full RAS-class entry into 2L+ PDAC SOC is imminent; zoldonrasib then defines a G12D-selective second wave.

Sources