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A Study of Stereotactic Radiosurgery (SRS) and Standard Treatment in People with EGFR-Mutated Lung Cancer That Has Spread to the Brain, ICON-RT Trial
Trial Status: active
This phase II clinical trial studies the effect of adding consolidative stereotactic radiosurgery (SRS) to standard treatment in comparison to standard therapy alone for the treatment of patients with non-small cell lung cancer (NSCLC) that has spread to the brain (metastasis) and whose cancer has a change (mutation) in the epidermal growth factor receptor (EGFR) gene. Osimertinib and SRS are both standard treatments for brain metastasis, but most patients with NSCLC either receive osimertinib alone or SRS when they are first diagnosed with brain metastasis to target all the brain metastasis visible on a magnetic resonance imaging (MRI) scan at that time. SRS is a type of radiation therapy that uses imaging scans combined with computer guidance to deliver a very precise and high dose of radiation. SRS can accurately target a very small area of the body, such as a particular part of the brain where tumor cells are growing. Because it is so precise, SRS limits radiation exposure to the rest of the brain. Osimertinib is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs are substances that block the action of enzymes called tyrosine kinases. Tyrosine kinases are a part of many cell functions, including cell signaling, growth, and division. Osimertinib blocks mutated EGFR proteins found on tumor cells. By blocking these proteins, osimertinib may help slow or stop the growth of tumor cells. Undergoing treatment with osimertinib plus SRS may work better than in treating patients already receiving standard therapy for their EGFR mutated NSCLC that has spread to the brain.
Inclusion Criteria
PATIENT SCREENING: Age ≥ 18 years
PATIENT SCREENING: Non-small cell lung cancer (NSCLC) with somatic activating mutation in EGFR diagnosis, confirmed at enrolling institution
PATIENT SCREENING: At least one intact brain metastasis measuring ≥ 1 cm measurable by Response Assessment in Neuro-Oncology Criteria-Brain Metastases (RANO-BM) at baseline prior to TKI therapy initiation
PATIENT SCREENING: Either TKI-naïve or started TKI ≤ 3-months prior (with documented start date and available imaging prior to TKI start)
PATIENT RANDOMIZATION: Presence of detectable and non-progressing BM lesions on imaging consistent with viable residual disease
Exclusion Criteria
PATIENT SCREENING: Unable to undergo contrast-enhanced MRI brain
PATIENT SCREENING: Evidence of leptomeningeal disease on MRI total spine and/or lumbar puncture cytology. The latter are not mandated by protocol but are rather at the discretion of the treating medical team as clinically indicated
PATIENT SCREENING: Neurologic symptoms or presence of a lesion in the brainstem, motor strip, or other eloquent brain area that is felt to warrant immediate intervention with SRS
PATIENT SCREENING: Active hematologic malignancy or a second solid tumor histology with known CNS tropism
PATIENT SCREENING: Patients who have undergone a therapeutic craniotomy for resection of one or more symptomatic brain metastasis are ineligible unless one or more additional intact BM remain unresected, and meets size criteria (e.g., a patient with removal of a 3cm symptomatic brain metastasis, but has an additional 1.25cm lesion remaining post-operatively, remains eligible for the study)
PATIENT SCREENING: Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
PATIENT SCREENING: Pregnant women or women who are breastfeeding or of childbearing potential. If the risk of contraception exists, male and female subjects must use highly effective contraception throughout the study and for at least 3 months after last treatment. Highly effective contraception includes either 2 barrier methods (diaphragm, condom by the partner, copper intrauterine device, sponge, or spermicide), or 1 barrier method and 1 hormonal method (any oral, subcutaneous, intrauterine, or intramuscular registered and marketed contraceptive agent that contains an estrogen and/or a progesterone agent)
PATIENT RANDOMIZATION: Progressive disease (PD) with multiple lesions and/or other features that would warrant a change in systemic therapy, as determined by the primary treating provider
PATIENT RANDOMIZATION: Presence of BM not deemed safely treatable with SRS, as determined by a radiation oncologist
PATIENT RANDOMIZATION: More than 20 visible residual brain metastases at the time of enrollment (i.e. after initial treatment with TKI). However, no upper limit on the number of visible brain metastases is set at the time of initial diagnosis prior to treatment with TKI. For example, a patient who had 35 visible brain metastases at the time of diagnosis, but after three months of treatment with TKI had 10 visible brain metastases remaining will be eligible for enrollment and randomization
Additional locations may be listed on ClinicalTrials.gov for NCT06741085.
I. Estimate intracranial progression-free survival (iPFS) from time of randomization of continuing TKI alone versus (vs) TKI plus consolidative SRS for epidermal growth factor receptor mutation-positive (EGFRm) NSCLC patients with residual, non-progressing brain metastasis (BM) after 3-months of upfront TKI therapy, and compare between study arms.
SECONDARY OBJECTIVES:
I. Estimate time to central nervous system (CNS) progression and compare between study arms.
II. Describe patient-reported quality of life (PR-QOL) at 9 months post-randomization, and compare between study arms.
III. Estimate overall survival and compare between study arms.
EXPLORATORY OBJECTIVES:
I. Describe PR-QOL at 3 and 6 months post-randomization.
II. Estimate time to local CNS failure.
III. Estimate time to distant CNS failure.
IV. Estimate time to salvage craniotomy, whole brain radiotherapy (WBRT), or hospital admission for neurologic indications.
V. Estimate time to change in systemic therapy.
VI. Explore associations between tissue and blood-based genomic and transcriptional biomarkers and CNS outcomes in EGFRm NSCLC BM treated with TKI or TKI plus consolidative SRS.
VII. Estimate iPFS separately by study arm in the following subgroups: by type of mutation (EGFR exon [Ex]19 vs. Other), size of BM (< 2cm vs ≥ 2cm), number of BM (< 2 vs ≥ 2 measurable lesions).
OUTLINE:
ARM I (SCREENING): Patients receive osimertinib or another SOC systemic TKI therapy for 3 months prior to randomization on study.
RANDOMIZATION: Patients are randomized to 1 of 2 arms.
ARM II: Patients receive osimertinib on study. Salvage SRS, whole brain radiation therapy (WBRT), systemic therapy or other standard treatments may be administered to patients who have evidence of CNS or systemic progression on study. Patients undergo computed tomography (CT), MRI, and blood collection throughout the study. Patients may also undergo positron emission tomography (PET)/CT throughout the study.
ARM III: Patients receive osimertinib followed by consolidative SRS over 1-5 treatment fractions on study, as per the discretion of the treating radiation oncologist. Salvage SRS, WBRT, systemic therapy or other standard treatments may be administered to patients who have evidence of CNS or systemic progression. Patients undergo CT, MRI, and blood collection throughout the study. Patients may also undergo PET/CT throughout the study.
After completion of study treatment, patients are followed up at 3, 6, and 9 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
