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Investigational Drug

RMC-6236

Shows activity

Also known as:

A122

Cancer types include:

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

HealthScout AI Analysis

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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)

Active trials using RMC-6236

Found 7 active trials using this drug:

A Phase 1/2, Multicenter, Open-Label Study to Evaluate Safety, Tolerability & Antitumor Activity of TNG462 in Combination With Other Agents in Patients With Pancreatic or Non-Small Cell Lung Cancer With MTAP Loss & RAS Mutation

Sponsor: Tango Therapeutics, Inc. (industry) Phase: 1/2 Start date: May 31, 2025

HealthScout AI summary: This trial enrolls adults with metastatic pancreatic or non-small cell lung cancer harboring both MTAP loss and a RAS mutation, previously treated with standard therapies, to receive TNG462 (a selective PRMT5 inhibitor exploiting MTAP-deleted tumor vulnerabilities) combined with either RMC-6236 (a multi-RAS mutant inhibitor) or RMC-9805 (a KRAS G12D-selective inhibitor). Prior treatment with RAS-targeted, PRMT5, or MAT2A inhibitors is not allowed.

ClinicalTrials.gov ID: NCT06922591

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)

Sponsor: Revolution Medicines, Inc. (industry) Phase: 3 Start date: Oct. 16, 2024

HealthScout AI summary: Previously treated metastatic PDAC (ECOG 0–1) after one prior 5-FU– or gemcitabine-based regimen, randomized to oral daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor targeting active mutant and wild-type RAS (notably KRAS G12X), versus investigator’s choice of standard chemotherapy. Excludes prior direct RAS-targeted therapy and CNS metastases; endpoints include PFS/OS (primary in RAS G12-mutant population).

ClinicalTrials.gov ID: NCT06625320

A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 193 in Combination With Other Therapies in Subjects With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous MTAP-deletion

Sponsor: Amgen (industry) Phase: 1 Start date: May 29, 2024

HealthScout AI summary: Adults with metastatic or unresectable, MTAP‑deleted pancreatic ductal adenocarcinoma (measurable disease, adequate organs; no prior PRMT5/MAT2A inhibitors and, for the RAS combo, no prior MAPK/KRAS inhibitors) receive AMG 193, an oral MTA‑cooperative PRMT5 inhibitor exploiting MTAP synthetic lethality, combined with either gemcitabine/nab‑paclitaxel, modified FOLFIRINOX, or with RMC‑6236, an oral RAS(ON) tri‑complex inhibitor for RAS‑mutant cohorts. The study explores dose, safety, PK, and preliminary efficacy with expansion in defined PDAC cohorts.

ClinicalTrials.gov ID: NCT06360354

A Platform Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1/2 Start date: May 24, 2024

HealthScout AI summary: This trial enrolls adults with metastatic or unresectable, RAS-mutant colorectal or pancreatic cancer (including KRAS G12D subsets), and tests oral RAS(ON) inhibitors—RMC-6236 (a multi-selective tri-complex RAS inhibitor) and RMC-9805 (a KRAS G12D-selective molecular glue)—either as monotherapy or combined with standard therapies such as mFOLFOX6, mFOLFIRINOX, gemcitabine/nab-paclitaxel, bevacizumab, or cetuximab. All patients must have ECOG 0-1 and adequate organ function.

ClinicalTrials.gov ID: NCT06445062

A Platform Study of RAS(ON) Inhibitor Combinations in Patients With RAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1/2 Start date: Jan. 18, 2024

HealthScout AI summary: This trial enrolls adults with advanced or metastatic RAS-mutated NSCLC (including KRAS G12C and G12D subtypes) who have progressed on standard therapies, testing investigational RAS(ON) inhibitors—RMC-6291 (KRAS G12C-selective), RMC-6236 (multi-selective RAS), and RMC-9805 (KRAS G12D-selective via cyclophilin A tri-complex)—alone or combined with pembrolizumab or platinum-based chemotherapies. Eligible patients must have ECOG 0–1 and adequate organ function.

ClinicalTrials.gov ID: NCT06162221

Phase 1/1b, Multicenter, Open-Label, Study of RMC 9805 in Participants With Advanced KRASG 12D-Mutant Solid Tumors

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1 Start date: Sept. 7, 2023

HealthScout AI summary: This trial enrolls adults with advanced, previously treated KRAS G12D-mutant solid tumors (excluding those with CNS involvement or prior direct RAS inhibitor use) to receive the selective KRAS G12D inhibitor RMC-9805, either as monotherapy or combined with the RAS(ON) multi-selective inhibitor RMC-6236. RMC-9805 acts as a molecular glue inducing covalent modification of KRAS G12D, while RMC-6236 targets multiple active KRAS G12X mutations.

ClinicalTrials.gov ID: NCT06040541

A Multicenter Open-Label Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS

Sponsor: Revolution Medicines, Inc. (industry) Phase: 1 Start date: May 31, 2022

HealthScout AI summary: The trial involves adult patients with advanced solid tumors harboring specific RAS mutations, including KRAS G12, who have progressed after standard therapies, evaluating the safety and tolerability of RMC-6236, an oral selective inhibitor targeting active RAS(ON) with a novel 'tri-complex' mechanism. This investigational drug shows promising early efficacy, especially in KRAS G12X-related pancreatic and non-small cell lung cancers.

ClinicalTrials.gov ID: NCT05379985