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

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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)

Further reading

• Discovery/Mechanism: Discovery of daraxonrasib (RMC‑6236), a RAS(ON) multi‑selective tri‑complex inhibitor (Journal of Medicinal Chemistry, 2025). (pubs.acs.org)
• Translational/preclinical and initial patient responses: Translational and Therapeutic Evaluation of RAS‑GTP Inhibition by RMC‑6236 (PubMed). (pubmed.ncbi.nlm.nih.gov)
• PDAC (phase 1) results: ASCO GI 2025 abstract on safety, efficacy, and ctDNA changes in RAS‑mutant PDAC. (ascopubs.org)
• NSCLC (phase 1) results: Journal of Thoracic Oncology report on safety and activity in RAS‑mutant NSCLC. (jto.org)
• NSCLC biomarker analysis: AACR 2025 Late‑Breaking Abstract LB218 on ctDNA dynamics with daraxonrasib in RAS‑mutant NSCLC. (aacrjournals.org)
• Pivotal NSCLC trial initiation: Company release on RASolve 301 phase 3 study. (ir.revmed.com)
• PDAC phase 3 listing: National Pancreatic Cancer Foundation clinical trial summary for previously treated metastatic PDAC. (npcf.us)

Notes - Efficacy outcomes from peer‑reviewed meeting abstracts and the Journal of Thoracic Oncology report are the most reliable public clinical data as of October 7, 2025; sponsor press materials provide additional, but not yet peer‑reviewed, details for PDAC. (ascopubs.org)

Last updated: Oct 2025

Inclusion Criteria:

* At least 18 years old and has provided informed consent.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Histologically confirmed NSCLC, either locally advanced or metastatic, not amenable to curative surgery or radiotherapy.

* Measurable disease per RECIST v1.1.

* Adequate organ function (bone marrow, liver, kidney, coagulation).

* One to two prior lines of therapy including an anti-PD-1/anti-PD(L)-1 agent and platinum-based chemotherapy.

* Documented RAS mutation status, 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 or docetaxel.

* Untreated central nervous system (CNS) metastases.

* Medically significant comorbidities (significant cardiovascular disease, lung disease, or impaired GI function).

* Ongoing anticancer therapy.

* Pregnancy and/or breastfeeding.