Trial: Phase 3 Study of Daraxonrasib (RMC-6236…

Trial Details

Sponsor: Revolution Medicines, Inc. (industry)

Phase: 3

Start date: Oct. 16, 2024

Planned enrollment: 460

Trial ID: NCT06625320

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: RMC-6236 (A122)

Overview

RMC-6236 (generic name: daraxonrasib; also referred to as “A122” in some chemical catalogs) is an oral, noncovalent, multi‑selective RAS(ON) tri‑complex inhibitor in clinical development for RAS‑mutant solid tumors, notably pancreatic ductal adenocarcinoma (PDAC) and non‑small cell lung cancer (NSCLC). In 2025, the FDA granted Breakthrough Therapy Designation for daraxonrasib for previously treated metastatic PDAC with KRAS G12 mutations, and global phase 3 trials are ongoing in PDAC (RASolute 302) and NSCLC (RASolve 301). (pubs.acs.org)

Aliases: Daraxonrasib, RMC‑6236; Compound A122/RAS inhibitor A122 (catalog naming). (pharmacompass.com)

Mechanism of action

Daraxonrasib engages an intracellular chaperone (cyclophilin A) and active, GTP‑bound RAS to form a reversible “tri‑complex” that occupies a composite pocket across the switch I/II regions of RAS, blocking effector binding (e.g., BRAF RBD) and downstream MAPK signaling. The design confers activity across wild‑type and multiple oncogenic RAS variants (e.g., KRAS G12X, G13X, Q61X). (pubs.acs.org)

Clinical development

Phase 1/1b (RMC‑6236‑001; NCT05379985): Multicenter dose‑escalation/expansion in RAS‑mutant solid tumors, including PDAC and NSCLC; clinically active doses explored largely at 120–300 mg once daily. (ascopubs.org)
Phase 3 in PDAC (RASolute 302; NCT06625320): Randomized daraxonrasib vs investigator’s choice chemotherapy in previously treated metastatic PDAC; dual primary endpoints PFS and OS in a KRAS G12X‑focused core population; study start October 2024. (ir.revmed.com)
Phase 3 in NSCLC (RASolve 301; NCT06881784): Randomized daraxonrasib vs docetaxel in previously treated RAS‑mutant NSCLC; first patient dosed May 14, 2025. (revolutionmedicinesclinicaltrial.com)

Efficacy

Pancreatic ductal adenocarcinoma (previously treated)
- ASCO GI 2025 phase 1 update (clinically active doses 160–300 mg QD; data cutoff July 23, 2024): In second‑line PDAC, ORR 29% for KRAS G12X (n=42) and 25% for all RAS‑mutant (n=57); median PFS 8.5 months (KRAS G12X) and 7.6 months (all RAS‑mutant); median OS 14.5 months in both groups. Early and deep ctDNA reductions were common. (ascopubs.org)
- Company synopsis consistent with the above: at daily 160–300 mg, durable PFS/OS were observed; at 300 mg QD (Phase 3 dose), reported median PFS ~8.5–8.8 months in 2L cohorts. (revmed.gcs-web.com)

Non‑small cell lung cancer (previously treated, RAS‑mutant)
- Peer‑reviewed JTO 2025 report (dose range 120–220 mg QD, proposed 200 mg for NSCLC): confirmed ORR 38%, median duration of response 15.5 months, median PFS 9.8 months, median OS 17.7 months in a defined efficacy set; forms the basis for RASolve 301. (jto.org)
- AACR 2025 abstract analyzing ctDNA corroborated the same NSCLC activity metrics at 120–220 mg (confirmed ORR 38%, median PFS 9.8 months, median OS 17.7 months) with manageable safety. (aacrjournals.org)

Earlier multi‑tumor phase 1 snapshot (EORTC‑NCI‑AACR 2024 press summary): ORR 38% in efficacy‑evaluable NSCLC (n=40) and 20% in PDAC (n=46); disease control rates 85% and 87%, respectively. Mutation‑agnostic responses included KRAS G12D/V/R. (ir.revmed.com)

Safety

Across studies, the most frequent treatment‑related adverse events (generally grade 1–2) are dermatologic and gastrointestinal: rash, diarrhea, nausea, vomiting, stomatitis; paronychia and mucosal inflammation also reported. In PDAC (160–300 mg QD; n=127), any‑grade TRAEs ≥10% included rash 91%, diarrhea 48%, nausea 43%, vomiting 31%, stomatitis 31%, fatigue 20%, paronychia 13%, mucosal inflammation 13%, decreased appetite 11%, peripheral edema 10%. (ascopubs.org)

In NSCLC (120–220 mg QD; safety set N=73), common TRAEs were rash (90%), diarrhea (63%), nausea (49%), vomiting (40%), stomatitis (34%); grade 3 TRAEs were infrequent (rash 7%); no grade 4–5 TRAEs observed; dose modifications in 41%, discontinuations in 4%. Prophylaxis appeared to reduce grade ≥3 rash. (jto.org)

Key identifiers

Daraxonrasib (RMC‑6236); investigational, not FDA‑approved. Mechanism and discovery described in Journal of Medicinal Chemistry (2025). (pubs.acs.org)
Phase 1/1b: NCT05379985. Phase 3 PDAC: NCT06625320. Phase 3 NSCLC: NCT06881784. (ascopubs.org)

HealthScout AI Analysis

Goal: Evaluate whether the RAS(ON) inhibitor daraxonrasib (RMC-6236) improves progression-free survival and overall survival versus investigator’s choice of standard chemotherapy in previously treated metastatic PDAC.

Patients: Adults (≥18 years) with histologically or cytologically confirmed metastatic PDAC, ECOG 0–1, measurable disease by RECIST 1.1, adequate organ function, and documented RAS mutation status (mutant or wild type). Prior one line of systemic therapy with a 5-FU–based or gemcitabine-based regimen is required. Key exclusions include prior direct RAS-targeted therapy, CNS metastases, and conditions affecting oral absorption.

Design: Global, multicenter, open-label, randomized phase 3 study with 1:1 allocation to investigational therapy versus investigator’s choice of standard chemotherapy. Primary analysis focuses on the RAS G12-mutant population, with additional analyses in the all-randomized population. Blinded independent central review is used for radiographic endpoints.

Treatments: Experimental arm: Daraxonrasib (RMC-6236), an oral, multi-selective RAS(ON) inhibitor that forms a tri-complex with cyclophilin A and KRAS to block downstream effector binding, targeting active GTP-bound RAS, including mutant and wild-type isoforms, with particular activity in KRAS G12X tumors. In phase 1/1b studies in previously treated PDAC and NSCLC, it showed objective responses (including complete responses) and a median PFS of approximately 8.1 months in second-line KRAS G12X PDAC, with a generally manageable safety profile dominated by low-grade rash, diarrhea, and nausea. These data support advancement to phase 3 and exploration of combinations. Control arm: Investigator’s choice of standard chemotherapy (gemcitabine/nab-paclitaxel, modified FOLFIRINOX, liposomal irinotecan plus 5-FU/leucovorin, or FOLFOX), representing accepted regimens for previously treated metastatic PDAC.

Outcomes: Co-primary endpoints: PFS by BICR per RECIST v1.1 and OS, both in the RAS G12-mutant population. Key secondary endpoints include PFS and OS in the all-patient population; objective response by BICR and by investigator; duration of response and time to response; patient-reported outcomes with time to deterioration on EORTC QLQ-PAN26 and QLQ-C30; safety and tolerability; and pharmacokinetics of RMC-6236.

Burden on patient: Moderate. Participation entails standard oncology visit frequency, imaging for RECIST assessments at typical intervals, and safety monitoring comparable to routine care. The oral investigational agent reduces infusion time burden relative to multi-drug chemotherapy; however, additional protocol-driven assessments, central imaging review schedules, and pharmacokinetic blood draws introduce extra visits and sampling beyond usual practice. No mandatory biopsies are specified, and exclusion of CNS disease limits additional neuroimaging. Overall burden is somewhat higher than routine follow-up for standard therapy due to PK and QoL assessments, but lower procedural burden than intensive multi-agent IV regimens for those randomized to oral therapy.

Last updated: Oct 2025

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Status: Active, not recruiting

RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator's Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)

Trial Details

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Investigational Drug AI Analysis

Show for: RMC-6236 (A122)

Overview

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Clinical development

Efficacy

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Further reading

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Sites (60)

Charité Universitätsmedizin, Campus Berlin Mitte

Nationales Centrum fur

Universitatsklinikum Ulm

Universitatsklinikum Ulm, Zentru

Aichi Cancer Center

Cancer Institute Hospital of JFCR

Kanagawa Cancer Center

National Cancer Center

National Cancer Center Hospital

Osaka International Cancer

Centre Eugene Marquis

Gustave Roussy

Hopital Paul Brousse

Institut Paoli Calmettes

Azienda Ospedaliera

Fondazione IRCCS Istituto Nazionale dei Tumori

IEO-Istituto Europeo di Oncologia

IOV-Istituto Oncologico

Pan-American Center for Oncology Trials

Clinica Universidad de Navarra

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