Phase 3 Study of RMC-6236 in Previously Treated NSCLC Patients with RAS Mutations

This is a Phase 3, multicenter, open-label, randomized study for people with advanced non-small cell lung cancer (NSCLC) that has a change (mutation) in a gene called RAS. NSCLC is the most common type of lung cancer, and when it has spread, current treatments often do not work well. After the usual first-line treatments, such as chemotherapy or immune-based therapy, options are limited. Standard second-line treatments like docetaxel (a chemotherapy drug) or docetaxel plus ramucirumab provide only modest benefit. While a few drugs are available for one specific mutation (KRAS G12C), there are no approved treatments for most other RAS mutations. Because about 30% of NSCLC patients have a RAS mutation, this represents a large unmet need.

The investigational drug RMC-6236 is designed to block the activity of the RAS protein when it is “switched on,” which drives cancer growth. By blocking this protein, the drug may slow or stop the cancer from growing. In this study, subjects will be randomly assigned to receive either RMC-6236 (a pill taken daily) or docetaxel (given by intravenous infusion every three weeks). Subjects have a 50/50 chance of assignment to either treatment.

The goals of the study are to find out if RMC-6236 helps subjects live longer without their cancer getting worse (progression-free survival, PFS) and live longer overall (overall survival, OS) compared to standard chemotherapy. Researchers will also measure how many subjects’ tumors shrink and carefully monitor safety.

The anticipated result is that RMC-6236 will improve outcomes for subjects with RAS-mutant NSCLC, offering a new treatment option where few currently exist.

The study’s primary outcomes are progression-free survival (PFS) and overall survival (OS) in the RAS G12X-C population, measured from randomization to disease progression or death, and from randomization to death, respectively. Secondary outcomes include PFS and OS in the RAS (MUT) population; objective response rates, duration of response, and time to response in both RAS G12X-C and RAS (MUT) populations, assessed by investigators and blinded independent central review (BICR); quality of life measures using EORTC QLQ-LC13 and QLQ-C30 questionnaires, including changes in symptom scales, global QoL, functioning domains, and time to symptom deterioration; safety and tolerability, including adverse events and clinical laboratory changes; and pharmacokinetics of daraxonrasib in the RAS (MUT) population. All outcomes will be assessed up to approximately 4 years.

In order to participate you must meet the following criteria:

• Have an ECOG Performance Status of 0 or 1, without significant decline within 2 weeks of screening; rescreening is required if PS >1 for any reason before randomization.
• Have histologically confirmed NSCLC, either locally advanced or metastatic, not amenable to curative surgery or radiotherapy.
• Have evidence of progressive disease (PD) per RECIST v1.1 from prior therapy or intolerance to prior therapy.
• Have measurable disease assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST v1.1 based on site Investigator/radiology assessment. Irradiated lesions are not considered measurable unless they have progressed after radiation.

You will be excluded from the study if any of the following criteria apply to you:

• Have had previous RAS-directed therapy.
• Have other driver mutations, such as epidermal growth factor receptor (EGFR) or serine/threonine protein kinase B-Raf (BRAF) mutation, anaplastic lymphoma kinase (ALK) mutation, reactive oxygen species-1 (ROS-1), tropomyosin receptor kinase (TRK) fusion, or other identifiable driver mutation for which an approved targeted therapy is available.
• Have untreated CNS metastases or leptomeningeal disease. Treated CNS metastases are allowed if ALL of the following conditions are met:
  • Radiation therapy ended ≥2 weeks before randomization (stable disease confirmed by scan performed after CNS-directed treatment has been completed).
  • No evidence of clinical or radiographic progression by a CNS imaging performed within 4 weeks of randomization.
  • Stable residual neurological symptoms Grade ≤2 and on a stable dose of steroids and/or anticonvulsant therapy (if applicable) for ≥2 weeks before randomization.
• Have other cancers that have been diagnosed or treated ≤3 years before randomization, except:
  • Cancers for which no systemic anticancer treatment is required and were treated with successful definitive resection (eg, non-melanoma skin cancer, carcinoma in situ of the breast or cervix, or other in situ cancers).
  • Cancers that have been treated with curative intent judged by Investigator to have a low risk for recurrence during trial participation (eg, <5% risk of recurrence within 5 years).

This is a partial list of eligibility requirements. To inquire about your eligibility, please call the contact number provided. If you wish to inquire via email, please include the title of the study in your message.