Sponsor: Revolution Medicines, Inc. (industry)
Phase: 3
Start date: Oct. 16, 2024
Planned enrollment: 460
RMC-6236, also known as A122, is an investigational oral inhibitor targeting multiple active RAS proteins (RAS(ON) inhibitor). It is being developed for the treatment of solid tumors harboring various KRAS mutations, including G12D, G12V, and G12R.
RMC-6236 functions as a RAS(ON) multi-selective inhibitor, binding directly to active RAS proteins to inhibit their signaling pathways. This approach aims to suppress tumor growth driven by RAS mutations.
In a Phase 1/1b clinical trial, RMC-6236 demonstrated preliminary antitumor activity:
Non–Small Cell Lung Cancer (NSCLC): Among 40 evaluable patients, the objective response rate (ORR) was 38%, including one complete response and 14 partial responses. The disease control rate (DCR) was 85%. Responses were observed across KRAS mutations G12D, G12V, and G12R. (revmed.gcs-web.com)
Pancreatic Ductal Adenocarcinoma (PDAC): In 46 evaluable patients, the ORR was 20%, with nine partial responses. The DCR was 87%. Confirmed responses included tumors with KRAS mutations G12D, G12V, and G12R. (revmed.gcs-web.com)
Updated data for PDAC patients treated with RMC-6236 at doses ranging from 160 mg to 300 mg daily showed:
Second-Line Treatment: Median progression-free survival (PFS) was 8.5 months, and median overall survival (OS) was 14.5 months for patients with KRAS G12X mutations. (ir.revmed.com)
Third-Line or Later Treatment: Median PFS was 4.2 months. (onclive.com)
RMC-6236 was generally well tolerated. Common treatment-related adverse events (TRAEs) included rash and gastrointestinal issues, primarily Grade 1 or 2. Grade 3 TRAEs were rash (6%), stomatitis (2%), and diarrhea (1%). A Grade 4 TRAE involving a large intestine perforation occurred in one PDAC patient. No significant hepatotoxicity signals were observed. (revmed.gcs-web.com)
RMC-6236 Shows Activity With Favorable Toxicity Profile in Previously Treated PDAC
Phase 1 Data Support Further Investigation of RMC-6236 in KRAS-Mutant NSCLC
Last updated: Apr 2025
Goal: To determine whether the RAS(ON) inhibitor daraxonrasib (RMC-6236) improves progression-free survival and overall survival compared with investigator’s choice of standard chemotherapy in previously treated metastatic PDAC.
Patients: Adults (ECOG 0–1) with histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma, measurable disease by RECIST 1.1, adequate organ function, and documented RAS mutation status (mutant or wild type). One prior systemic line with a 5-FU–based or gemcitabine-based regimen is required. Key exclusions include prior direct RAS-targeted therapy, CNS metastases, major recent surgery, and conditions impairing oral drug absorption.
Design: Global, multicenter, open-label, randomized 1:1 Phase 3 trial comparing RMC-6236 versus investigator’s choice of standard-of-care chemotherapy. Stratification and blinded independent central review are used for efficacy assessments; enrollment planned for 460 participants.
Treatments: Experimental: RMC-6236 (daraxonrasib), an oral, multi-selective RAS(ON) inhibitor that forms a tri-complex with cyclophilin A and KRAS, blocking downstream effector binding to active, GTP-bound RAS. It targets both mutant and wild-type canonical RAS isoforms with particular activity in KRAS G12X tumors. In Phase 1/1b studies, RMC-6236 showed encouraging activity in previously treated PDAC, including an objective response rate of approximately 27% and median PFS of about 8 months in KRAS G12X second-line cohorts, with a generally manageable safety profile (predominantly grade 1–2 rash, diarrhea, nausea). Active comparator: Investigator’s choice of standard chemotherapy—gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, liposomal irinotecan plus 5-FU/leucovorin, or FOLFOX, consistent with accepted regimens in the post–first-line setting.
Outcomes: Primary endpoints: PFS by BICR and OS in the RAS G12-mutant population. Key secondary endpoints: PFS and OS in the all-patient population; objective response rate (BICR and investigator) in RAS G12-mutant and all-patient populations; duration of response and time to response; patient-reported outcomes with time to deterioration on EORTC QLQ-PAN26 and QLQ-C30; safety (incidence of adverse events); and pharmacokinetics of RMC-6236. Assessments are planned for up to approximately 3 years.
Burden on patient: Moderate. As a Phase 3 trial, visit frequency and imaging are expected to mirror standard practice in metastatic PDAC, with periodic CT/MRI for RECIST assessments and routine labs. The oral investigational arm may reduce infusion visits compared with chemotherapy; however, on-treatment monitoring, safety labs, and patient-reported outcome questionnaires add visit time. The RMC-6236 arm includes pharmacokinetic blood sampling, particularly early in treatment, increasing blood draw frequency. No mandatory biopsies are specified, and there is no CNS imaging requirement unless clinically indicated, limiting additional procedural burden. Overall, burden is comparable to standard second-line PDAC care with added PK and PRO assessments.
Inclusion Criteria:
* At least 18 years old and has provided informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Histologically or cytologically confirmed PDAC with metastatic disease.
* Measurable disease per RECIST 1.1.
* Adequate organ function (bone marrow, liver, kidney, coagulation)
* Documented RAS mutation status, either mutant or wild-type. RAS mutations defined as nonsynonymous mutations in KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61).
* Able to take oral medications.
Exclusion Criteria:
* Prior therapy with direct RAS-targeted therapy (eg. degraders and/or inhibitors).
* History of or known central nervous system metastatic disease.
* Any conditions that may affect the ability to take or absorb study treatment
* Major surgery within 4 weeks prior to randomization.
* Patient is unable or unwilling to comply with protocol-required study visits or procedures
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