daraxonrasib

Shows activity

Cancer types include:

colon cancer non-small cell lung cancer pancreas cancer rectal cancer small cell lung cancer

TrialFetch AI Analysis

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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)

Active trials using daraxonrasib

Found 3 active trials using this drug:

A Phase 1/2 Open-Label, Multicenter Study of RAS(ON) Inhibitors in Combination With Ivonescimab With or Without Other Anti-Cancer Agents in Patients With Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1/2 Start date: Jan. 30, 2026

TrialFetch AI summary: Adults with locally advanced/metastatic solid tumors harboring KRAS/NRAS/HRAS mutations (ECOG 0–1, measurable disease) who have progressed on/intolerant to standard therapy are eligible for dose exploration, with expansions in previously untreated non-squamous NSCLC without another actionable driver and in solid tumors/CRC with ≤2 prior advanced lines (HNSCC excluded). Patients receive an oral RAS(ON) inhibitor—daraxonrasib (pan-RAS(ON)), elironrasib (KRAS G12C(ON)), or zoldonrasib (KRAS G12D(ON))—combined with ivonescimab (PD-1/VEGF bispecific antibody), with select cohorts adding platinum/pemetrexed chemotherapy, cetuximab, or additional RAS(ON) inhibitor.

ClinicalTrials.gov ID: NCT07397338

Phase 1/1b, Multicenter, Open-Label, Study of RMC-5127 in Patients With Advanced KRAS G12V-Mutant Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1 Start date: Jan. 8, 2026

TrialFetch AI summary: Eligible patients are adults with locally advanced/metastatic KRAS G12V–mutant solid tumors (ECOG 0–1, measurable disease) that have progressed on or are intolerant to standard therapies. Treatment is oral RMC-5127, a KRAS G12V–selective RAS(ON) inhibitor (cyclophilin A–enabled tri-complex), given alone or combined with oral daraxonrasib (pan-RAS(ON) inhibitor) or with cetuximab.

ClinicalTrials.gov ID: NCT07349537

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

Sponsor: Revolution Medicines, Inc. (industry) Phase: 3 Start date: March 18, 2025

TrialFetch AI summary: Adults with locally advanced or metastatic NSCLC harboring KRAS, NRAS, or HRAS mutations (codons 12, 13, or 61) and previously treated with anti-PD-(L)1 and platinum-based chemotherapy (but not RAS inhibitors or docetaxel) are randomized to receive either daraxonrasib, an oral pan-RAS(ON) inhibitor targeting active GTP-bound RAS, or standard docetaxel.

ClinicalTrials.gov ID: NCT06881784