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 investigational oral inhibitor targeting active (GTP-bound) RAS proteins, including both mutant and wild-type variants. It is being developed for the treatment of cancers driven by RAS mutations, such as pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC).

Mechanism of Action

Daraxonrasib is a macrocyclic, noncovalent pan-RAS inhibitor. It forms a binary complex with cyclophilin A, which then binds with high affinity to active RAS proteins, leading to the formation of a tri-complex. This interaction inhibits RAS signaling pathways that are critical for tumor growth and survival. (guidetopharmacology.org)

Efficacy

Pancreatic Ductal Adenocarcinoma (PDAC):

In a Phase 1 trial involving patients with previously treated, RAS-mutant metastatic PDAC, daraxonrasib demonstrated promising efficacy. At doses ranging from 160 to 300 mg daily, patients achieved a median progression-free survival (PFS) of 7.6 months (95% CI, 5.9 to 11.1) and a median overall survival (OS) of 14.5 months (95% CI, 8.8 to not evaluable). (aacrjournals.org)

Non-Small Cell Lung Cancer (NSCLC):

In a Phase 1 study presented at the 2025 European Lung Cancer Congress, daraxonrasib was evaluated in patients with RAS G12X-mutant NSCLC who had received one or two prior lines of therapy. At doses of 120 to 220 mg daily, the confirmed overall response rate (ORR) was 38%, consisting exclusively of partial responses. The median duration of response was 15.1 months (95% CI, 11.1 to not evaluable), with a median time to response of 1.5 months (range, 1.2 to 6.2). (onclive.com)

Safety

Daraxonrasib has exhibited a manageable safety and tolerability profile in clinical trials. In the NSCLC cohort, treatment-related adverse events (TRAEs) led to dose interruptions in 48% of patients, dose reductions in 27%, and treatment discontinuation in 6%. The most common TRAE was rash, primarily Grade 1 or 2 in severity. Notably, prophylactic measures reduced the incidence of Grade 3 or higher rash. (onclive.com)

In the PDAC cohort, daraxonrasib was well-tolerated at clinically active doses, with no new safety signals observed. (onclive.com)

Further Reading

• Revolution Medicines Reports Fourth Quarter and Full Year 2024 Financial Results and Update on Corporate Progress
• Daraxonrasib Generates Clinical Activity With Manageable Safety in RAS-Mutant NSCLC
• Abstract LB281: Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies

Last updated: Aug 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.