Summary

This phase III trial compares the effects of stereotactic radiosurgery given in one day called single fraction stereotactic radiosurgery (SSRS) versus stereotactic radiosurgery given over several days called fractionated stereotactic radiosurgery (FSRS) in patients who are receiving immunotherapy with immune checkpoint inhibitors for breast, kidney, small cell lung cancer, non-small cell lung cancer, or melanoma that has spread to the brain (brain metastasis). Immune checkpoint inhibitors are a type of drug that blocks proteins called checkpoints that are made by some types of immune system cells, such as T cells, and some cancer cells. These checkpoints help keep immune responses from being too strong and sometimes can keep T cells from killing cancer cells. When these checkpoints are blocked, T cells can kill cancer cells better. Stereotactic radiosurgery is a type of external radiation therapy that uses special equipment to position the patient and precisely deliver radiation to a tumor. In this trial radiation is delivered to the small areas of brain with metastatic tumor, avoiding the surrounding normal tissue. Giving FSRS may result in fewer side effects than SSRS.

Objectives

PRIMARY OBJECTIVE:
I. To compare the proportion of participants experiencing Grade 2 or higher Adverse Radiation Effects (ARE) within 9 months following randomization to single fraction stereotactic radiosurgery (SSRS) versus (vs) fractionated stereotactic radiosurgery (FSRS) in patients with brain metastases >= 2 cm in diameter or >= 4cc in volume treated with concurrent immune checkpoint inhibitor (ICI) therapy.

SECONDARY OBJECTIVES:
I. To compare the time to the composite endpoint of either local failure of a metastasis treated with stereotactic radiosurgery (SRS) or first Grade 2 or higher ARE between SSRS and FSRS groups.
II. To compare time to local failure between SSRS and FSRS groups.
III. To compare time to neurologic death between groups.
IV. To compare patient-reported brain tumor specific symptom burden using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) between SRSS or FSRS groups at 9 months.

EXPLORATORY OBJECTIVES:
I. To estimate time to first grade 2 or higher ARE, Central Nervous System (CNS) progression-free survival, and overall survival within groups.
II. To compare the proportion of patients requiring increasing or persistent use of steroids between SSRS and FSRS arms.
III. To compare neurocognitive outcomes between SRSS and FSRS groups at 2 and 9 months post-completion of SRS using the Rey Auditory Verbal Learning Test Revised (RAVLT), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT) parts A and B.
IV. To compare cognition failure- or neurologic death-free survival (CFNDFS) between the SSRS and FSRS groups.
V. To compare patient-reported symptom burden using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and a single item (item 5) from the Functional Assessment of Cancer Therapy—General Population (GP5) between SRSS or FSRS groups and over time.
VI. To compare time to significant decline in patient-reported symptom burden (decline in MDASI-BT > 0.5 standard deviation) between SRSS or FSRS groups.
VII. To assess differences in outcomes adjusted for: 1) histology subgroups of Renal Cell Carcinoma (RCC), Melanoma, Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), or breast cancers, 2) type of systemic therapy (ICI monotherapy, dual immunotherapy, chemo-immunotherapy, targeted agent plus ICI), 3) timing of ICI delivery (before versus after SRS), 4) number of lesions, 5) presence of lesions in eloquent brain regions; and 6) presence of extracranial metastases.
VIII. To assess tumor microenvironment changes in patients that undergo a biopsy or resection.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo single fraction stereotactic radiosurgery on study. Patients undergo magnetic resonance imaging (MRI) throughout the study. Additionally, patients may optionally undergo blood sample collection throughout the study.

ARM II: Patients undergo fractionated stereotactic radiosurgery for up to 5 treatments over a few days. Patients undergo MRI throughout the study. Additionally, patients may optionally undergo blood sample collection throughout the study.

Patients are followed for 12 months after the completion of stereotactic radiosurgery.

Eligibility

1. At least one intact brain metastasis or resection cavity >= 2 cm in diameter or >= 4 cc volume. * Patients at initial diagnosis of brain metastases and patients with known brain metastasis treated with systemic therapy alone are eligible. * Patients who have previously undergone SRS for brain metastases are eligible if all MRIs and Digital Imaging and Communications in Medicine (DICOM)-radiation therapy (RT) files from prior SRS courses are available for upload to Transfer of Images and Data (TRIAD) and there are no lesions requiring re-irradiation. ** Prior SRS data upload is NOT required prior to enrollment and randomization ** Both SSRS and FSRS are acceptable * Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice-by-slice contouring on a treatment planning software package can be used to calculate the total tumor volume. * Any extent of non-CNS disease is allowed. There is no requirement for non-CNS disease to be controlled prior to study entry. * For patients considered to be borderline or potentially eligible by size or volume criteria, sites have the option to send in DICOM films for central review screening.
2. Age >= 18 years at the time of enrollment.
3. Total number of brain metastases (including resection cavities) =< 15 on diagnostic MRI; all lesions must be amenable to SSRS and FSRS as determined by the treating radiation oncologist. Treatment must take place at a facility credentialed by the Imaging and Radiation Oncology Core (IROC) for SRS and that offers both SSRS and FSRS as treatment options.
4. Total gross tumor volume must be =< 30 cc. Lesion volume will be approximated by measuring each lesion’s three perpendicular diameters on contrast-enhanced T1 MRI and the product of those diameters will be divided by 2 (V = xyz/2). Direct volumetric measurements by contouring all lesions on all visible slices on treatment planning software is also acceptable. If there is a cavity, only gross residual disease within or adjacent to the cavity is counted toward the 30 cc total volume.
5. Ability to tolerate MRI brain with gadolinium-based contrast.
6. Pathologically confirmed melanoma, renal cell carcinoma, non-small cell lung cancer, small-cell lung cancer, or breast cancer.
7. Has received, is currently receiving, or is anticipated to receive immune checkpoint inhibitor therapy (defined as agent targeted to PD-1/PD-L1 axis) within 30 days of the planned first day of SSRS/FSRS. Dual ICI therapy with PD-1/PD-L1 and CTLA-4 targeted agents are allowed, but patients treated with a single agent CTLA-4 targeted agent only are ineligible. * It is not mandatory to wait for the results of next generation sequencing (NGS) or other molecular tumor testing to determine if the patient is planned to receive ICI if the enrolling physician feels that identification of a mutation that would preclude ICI therapy (such as an EGFR mutation in a patient with NSCLC) is unlikely to be identified.
8. Karnofsky Performance Status (KPS) >= 50.
9. Negative serum or urine pregnancy test within 14 days of randomization for women of child- bearing potential.
10. Ability to understand and the willingness to sign written informed consent.
11. Patients must be able to provide informed consent.
12. Must be able to speak, read and understand English or Spanish.

Treatment Sites in Georgia