RASolute 302 — Daraxonrasib (RMC-6236) vs chemotherapy, 2L metastatic pancreatic cancer (RAS-mutant and RAS-WT)¶

Abstract: LBA5 · Session: Plenary, Sun May 31, 2026, 3:21 p.m. CT, Hall B1 · Presenter: Brian M. Wolpin, MD, MPH (Dana-Farber Cancer Institute) · Embargo: lifted 7:00 AM CT May 31, 2026

At a glance¶

Sponsor: Revolution Medicines
PI / presenter: Brian M. Wolpin, MD, MPH (Dana-Farber Cancer Institute)
NCT ID: NCT06625320
Phase: 3 (global, multicenter, open-label, randomized, registrational)
Design: Daraxonrasib 300 mg PO once daily vs investigator's choice of standard-of-care cytotoxic chemotherapy; randomized 1:1; ECOG PS 0–1; median age 66
N: 500 (daraxonrasib n=248; chemotherapy n=252) — previously treated metastatic PDAC across a broad range of RAS variants (RAS G12 mutations plus RAS wild-type)
Primary endpoint(s): OS and PFS (both met)
Comparator: Investigator's choice standard-of-care chemotherapy
Indication: Metastatic pancreatic ductal adenocarcinoma (PDAC)
Line: Second-line (previously treated with one prior chemotherapy line)

Headline result¶

In the intent-to-treat population, daraxonrasib nearly doubled median overall survival versus chemotherapy: 13.2 vs 6.7 months (HR 0.40; P<0.0001) — a ~60% reduction in the risk of death. Median PFS was 7.2 vs 3.6 months and ORR 31.6% vs 11.2%. In the RAS G12–mutant subgroup (daraxonrasib n=228; chemotherapy n=231), the OS benefit was identical in magnitude (HR 0.40; 95% CI 0.30–0.54; P = 5.9 × 10⁻¹⁰), with median PFS 7.3 vs 3.5 months and ORR 33.2% vs 11.8%. Grade ≥3 adverse events were less frequent with daraxonrasib (43.6% vs 57.5%), as were AE-related discontinuations (1.2% vs 11.2%). Median follow-up 8.5 months. The agent was generally well tolerated with no unexpected safety findings, and the results were simultaneously published in the New England Journal of Medicine. Widely framed as the headline of the meeting (standing ovation; "transformative" / "unprecedented" in trade coverage). This is the first positive randomized phase 3 of a RAS-targeted agent in PDAC.

Mechanism / class¶

Daraxonrasib (RMC-6236) is an oral, multi-selective RAS(ON) inhibitor that targets the active (GTP-bound) state of multiple RAS variants (including G12X mutations and wild-type RAS) by forming a tri-complex with cyclophilin A — rather than a single allele (contrast G12C-only inhibitors). Activity in RAS wild-type tumors is consistent with the broad RAS-pathway dependence of PDAC. It is investigational with no prior approvals; RASolute 302 is its first pivotal Phase 3 readout. RASolute 303 is the ongoing first-line registrational trial.

Discussant takeaway¶

The pancreatic discussant framed toxicity management and the durability of the OS benefit as the open questions; the magnitude (HR 0.40) was treated as practice-defining for 2L PDAC, a setting with near-static outcomes for a decade. Framed as the first RAS(ON) multi-selective inhibitor to deliver a Phase 3 OS benefit in pancreatic cancer; described by investigators and ASCO press materials as "unprecedented" for this historically chemo-refractory disease.

Practice-changing?¶

Yes — pending FDA filing. A doubling of median OS (13.2 vs 6.7 mo, HR 0.40) in 2L metastatic PDAC — a setting with minimal effective options — is the strongest signal in this disease in years, with a favorable tolerability profile and simultaneous NEJM publication. It redefines 2L mPDAC and establishes pan-RAS inhibition as a viable class in a tumor where targeted therapy has historically failed. Practice change awaits regulatory action; FDA granted expanded access (May 1, 2026) ahead of approval.

Cross-links¶

AACR 2026 / 2025: RAS-inhibitor preclinical and RAS(ON) mechanism sessions (see AACR 2026 clinical-trials / mechanism axis).
Other ASCO 2026 trials: KRAS-G12D early-phase combos (RMC-9805 and degrader combos) — the early-line extension of the same class; see ASCO 2026 themes.
JPM 2026: Revolution Medicines featured on the JPM 2026 stage; daraxonrasib was the lead value-driver of the preview cycle.