Trial: Study of Daraxonrasib (RMC-6236) in Pre…

Trial Details

Sponsor: Revolution Medicines, Inc. (industry)

Phase: 3

Start date: March 18, 2025

Planned enrollment: 420

Trial ID: NCT06881784

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: daraxonrasib

Overview

Daraxonrasib (RMC-6236) is an oral, noncovalent, RAS(ON) multi‑selective inhibitor in clinical development for RAS‑mutant solid tumors, including pancreatic ductal adenocarcinoma (PDAC) and non‑small cell lung cancer (NSCLC). It is being evaluated in a multicenter phase 1/1b study (NCT05379985) and multiple phase 3 trials in PDAC and NSCLC. (revmedclinicaltrials.com)

Mechanism of action

Modality: tri‑complex inhibitor that binds cyclophilin A (CypA) and active, GTP‑bound RAS to form a composite binding pocket, thereby blocking effector (e.g., RAF) engagement and downstream signaling. The approach is designed to inhibit multiple mutant and wild‑type RAS isoforms. (pubs.acs.org)
Target coverage: preclinical/medicinal chemistry data indicate activity across common RAS mutations (e.g., KRAS G12X, G13X, Q61X) and RAS wild type. (pubs.acs.org)

Efficacy

Pancreatic ductal adenocarcinoma (previously treated) - Phase 1 (RMC‑6236‑001; data cutoff July 23, 2024): in patients with RAS‑mutant PDAC treated at 160–300 mg once daily, the confirmed+pending ORR was 29% (95% CI, 16–45) in KRAS G12X (n=42) and 25% (95% CI, 14–38) in any RAS mutation (n=57). Median PFS was 8.5 months (95% CI, 5.3–11.7) and 7.6 months (95% CI, 5.9–11.1), respectively; median OS was 14.5 months (95% CI, 8.8–NE) in both groups. Early and deep declines in mutant RAS ctDNA were reported (>50% decrease in 93–95% of evaluable patients). (ascopubs.org)

Additional company‑sponsored update (2025, supports ongoing registrational efforts): at 300 mg QD in second‑line PDAC, confirmed ORR 29–35%, DCR 92–95%, median PFS 8.1–8.5 months, and median OS 13.1–15.6 months; in an initial first‑line cohort (n=38 with adequate follow‑up), ORR 47% and DCR 89%. Note: these are sponsor communications pending peer‑reviewed publication. (ir.revmed.com)

Non‑small cell lung cancer (previously treated) - Phase 1 (NSCLC cohorts; data cutoff Sept 30, 2024): at 120–220 mg once daily in RAS‑mutant NSCLC (G12X‑enriched) after 1–2 prior lines, confirmed ORR was 38%, median PFS 9.8 months (95% CI, 6–12.3), median OS 17.7 months (95% CI, 13.7–NE); median duration of response 15.5 months. Based on tolerability, 200 mg daily was selected for further NSCLC development. (jto.org)

Exploratory ctDNA analysis in RAS‑mutant NSCLC showed that early reductions, including complete clearance, associated with clinical activity on daraxonrasib. (aacrjournals.org)

Pivotal trials - NSCLC: RASolve 301, a global randomized phase 3 trial of daraxonrasib vs docetaxel in previously treated RAS‑mutant NSCLC (core G12X cohort; dual primary endpoints PFS and OS) began dosing in May 2025. (ir.revmed.com) - PDAC: a randomized phase 3 trial in second‑line metastatic PDAC (RASolute 302) is ongoing; clinical listings describe a global, open‑label design comparing daraxonrasib to investigator’s‑choice chemotherapy. (npcf.us)

Safety

PDAC (phase 1; 160–300 mg QD): most common treatment‑related AEs (any grade) were rash (91%), diarrhea (48%), nausea (43%), vomiting (31%), stomatitis (31%), fatigue (20%), paronychia (13%), mucosal inflammation (13%), decreased appetite (11%), and peripheral edema (10%). (ascopubs.org)
NSCLC (phase 1; 120–220 mg QD): any‑grade TRAEs in ≥20% included rash (90%), diarrhea (63%), nausea (49%), vomiting (40%), stomatitis (34%). Grade ≥3 events were uncommon; grade 3 rash occurred in 7%; no grade 4/5 TRAEs were reported. Mean relative dose intensity was 88%, and prophylaxis appeared to lower grade 3 rash incidence. (jto.org)

TrialFetch AI Analysis

Goal: Evaluate whether the RAS(ON) inhibitor daraxonrasib (RMC-6236) improves progression-free survival and/or overall survival compared with docetaxel in previously treated RAS-mutant NSCLC.

Patients: Adults (ECOG 0–1) with histologically confirmed locally advanced or metastatic NSCLC not amenable to curative therapy, measurable disease by RECIST v1.1, adequate organ function, and 1–2 prior systemic regimens including anti–PD-1/PD-(L)1 and platinum chemotherapy. Enrollment requires a documented nonsynonymous RAS mutation (KRAS, NRAS, or HRAS at codons G12, G13, or Q61). Key exclusions include prior direct RAS-targeted therapy or docetaxel, untreated CNS metastases, significant comorbidities, ongoing anticancer therapy, and pregnancy or breastfeeding.

Design: Global, multicenter, open-label, randomized phase 3 trial with 1:1 allocation to daraxonrasib versus docetaxel. Primary endpoints are assessed in the RAS G12X-confirmed population, with additional analyses in the overall RAS-mutant population. Planned enrollment is 420 participants.

Treatments: Daraxonrasib (RMC-6236) oral monotherapy. Daraxonrasib is a macrocyclic, noncovalent pan-RAS inhibitor that targets the active, GTP-bound state of RAS by forming a tri-complex with cyclophilin A and RAS, thereby suppressing downstream signaling. Early-phase studies have shown clinical activity in RAS-mutant NSCLC with a confirmed objective response rate of approximately 38% and a median duration of response around 15 months, and manageable toxicity dominated by low-grade rash with occasional dose modifications. Docetaxel is an established cytotoxic taxane used as standard second-line therapy in advanced NSCLC.

Outcomes: Co-primary endpoints: Investigator-assessed PFS and overall survival in the RAS G12X-confirmed population. Key secondary endpoints include PFS and OS in the broader RAS-mutant population; objective response rate, duration of response, and time to response by Investigator and by blinded independent central review; PFS and ORR by BICR; patient-reported outcomes via EORTC QLQ-LC13 and QLQ-C30 (time to deterioration and changes from baseline); safety and tolerability; and pharmacokinetics of daraxonrasib.

Burden on patient: Moderate. As a phase 3 randomized study, visit frequency, imaging schedules, and safety labs are similar to standard care for previously treated metastatic NSCLC. The docetaxel arm requires routine infusion visits and supportive care, which adds clinic time. The oral daraxonrasib arm reduces infusion visits but includes periodic PK blood sampling and close monitoring for dermatologic and other adverse events, which may increase early-therapy visit density. No protocol-mandated invasive biopsies are described; CNS imaging and RECIST assessments are expected at typical intervals (about every 6–9 weeks initially), resulting in a burden comparable to standard second-line management with some additional blood draws for PK in the experimental arm.

Last updated: Oct 2025

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Sites (83)

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AZ Delta

Roeselare, 8800, Belgium

[email protected] / +32 (0)51 23 72 07

Status: Recruiting

AZ Groeninge

Kortrijk, 8500, Belgium

RASolve 301: Phase 3 Multicenter, Open Label, Randomized Study of RMC-6236 Versus Docetaxel in Patients With Previously Treated Locally Advanced or Metastatic RAS[MUT] NSCLC

Trial Details

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Show for: daraxonrasib

Overview

Mechanism of action

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TrialFetch AI Analysis

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Sites (83)

AZ Delta

AZ Groeninge

Grand Hôpital de Charleroi - Les Viviers

CHU Brest - Hôpital Morvan

CHU Strasbourg - Nouvel Hôpital Civil

Hopital Nord - CHU Marseille

Institut régional du Cancer de Montpellier

CHU Rennes Hôpital Pontchaillou

CHU de Grenoble - Hôpital Albert Michallon

CHU Nantes - Hôpital Guillaume et René Laënnec

Institut de Cancerologie de l Ouest

Centre Leon Berard

Hopital Albert Calmette - CHU Lille

Hôpital Bichat - Claude Bernard

Hopital Louis Pradel

Centre Hospitalier Intercommunal de Créteil

LKI Lungenfachklinik Immenhausen

Hong Kong United Oncology Centre

Mater Private Hospital

IEO Istituto Europeo di Oncologia

Istituto Clinico Humanitas

Istituto Nazionale Tumori Fondazione G. Pascale

Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)

Istituto Nazionale dei Tumori Regina Elena IRCCS

Aichi Cancer Center Hospital

Fujita Health University Hospital

NHO Shikoku Cancer Center

National Hospital Organization Hokkaido Cancer Center

Hyogo Cancer Center

Kanazawa University Hospital

Kanagawa Cancer Center

Tohoku University Hospital

Nara Medical University Hospital

Niigata Cancer Center

Kindai University Hospital

Shizuoka Cancer Center

Cancer Institute Hospital of JFCR

National Cancer Center Hospital

Wakayama Medical University Hospital

Antoni van Leeuwenhoek

Radboudumc

Amsterdam UMC, Locatie VUMC

Erasmus Medisch Centrum

Aidport Sp. z o.o.

INSTYTUT GENETYKI I IMMMUNOLOGII GENIM sp. z o.o.

Pan American Center for Oncology Trials

National University Hospital

Hospital Universitari Dexeus

Hospital Universitario La Paz

HFR Fribourg/Kantonsspital Fribourg

Kantonsspital St. Gallen

Universitätsspital Basel

Taipei Medical University Hospital

Kaohsiung Medical University Chung-Ho Memorial Hospital

National Cheng Kung University Hospital

Alabama Oncology

MemorialCare Long Beach Medical Center

Yale University, Smillow Cancer Center

BRCR Global

Cancer Care Centers of Breevard

Cleveland Clinic Martin North

Florida Cancer Specialists & Research Institute - East

Florida Cancer Specialists & Research Institute - North

Florida Cancer Specialists & Research Institute - South

The University of Kansas Cancer Center