EXCLAIM: Exploring Combined Local and Systemic Approaches In Brain Metastasis: a Multi-cohort Randomized Phase II Study Evaluating Initial Response to Systemic Therapy and Subsequent Integration of Stereotactic Radiosurgery in Patients With Low-risk Brain Metastases and Central Nervous System-active

Inclusion Criteria:

1. Age ≥ 18 years.
2. Evaluation by a brain metastasis multidisciplinary team (BM-MDT) consisting of a medical oncologist (can be the patient's primary medical oncologist), a radiation oncologist who regularly performs SRS, and a neurosurgeon. This evaluation can take place in clinic or during a multidisciplinary conference.
3. Life expectancy \> 6 months as estimated by BM-MDT.
4. BM-MDT agreement that the planned systemic therapy regimen may provide intracranial benefit (SD, PR, or CR in the CNS).
5. BM-MDT agreement that the patient's BM does not require immediate local therapy (surgery and/or radiation therapy); i.e. it is judged to be safe to omit local therapy as initial BM management.
6. The patient's BM are amenable to SRS as initial local therapy as determined by BM-MDT.
7. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.
8. Histologically confirmed metastatic cancer with at least one measurable metastasis in the brain (≥ 5 mm).
9. At least one measurable intracranial target lesion which was not previously treated with SRS. Regrowth in a cavity of previously excised lesion will not qualify as a measurable lesion. Growth or change in a lesion previously irradiated will not qualify as a measurable lesion.
10. Prior SRS and prior excision of BM is permitted if other measurable non irradiated lesions as described in #9 remain.
11. The resection cavity of excised BM must have received appropriate radiation therapy (pre or post operative SRS, brachytherapy) or have been observed for \>6 months after resection without evidence of local cavity recurrence.
12. Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions either without systemic corticosteroids or requiring ≤ 2 mg dexamethasone daily for symptom resolution.
13. ECOG performance status ≤ 1.
14. Documented agreement by the patient's primary medical oncologist with the appropriateness of planned SST regimen.
15. This study will allow non-English speaking subjects to be enrolled. Verbal Translation Preparative Sheet (VTPS) will be used if a translated consent form is not available in the subject's language. The consent form will be translated into the language of the subject after 2 or more occurrences. This will apply to any MD Anderson patient.

Exclusion Criteria:

1. History of known leptomeningeal involvement (radiographic or cytological).
2. Small cell lung cancer, lymphoma, or leukemia histology.
3. Non-small cell lung cancer histology with targetable oncogenic driver mutation with planned initiation of highly CNS active targeted therapy (eg osimertinib, brigatinib, alectinib, or lorlatinib).
4. Subjects previously treated with WBRT.
5. Any intact BM size \> 3 cm. After surgical excision and appropriate radiation therapy to the cavity, patients may enroll if additional eligible lesions are present.
6. Prior disease progression on one or more of the agents comprising SST.
7. Exposure to one or more agents comprising SST within the last 30 days.
8. Prior unacceptable toxicity during treatment with one or more agents comprising SST.
9. Subjects with a major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled.
10. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful treatment of superficial bladder cancer, in situ cervical cancer, ductal carcinoma in situ, or other in-situ cancers. Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible.
11. Skin Cancer Exclusion: Please note that localized cutaneous basal cell carcinoma and squamous cell carcinoma is not an exclusion criterion regardless of treatment status. Biopsy proven metastatic disease from these histologies is an exclusion criterion if this constitutes a second cancer.
12. Patient weight \>450 pounds.
13. Patient had prior SRS to any intracranial lesion \<15mm from a metastasis on the screening MRI. Prior MRIs and DICOMs will be used to make this determination.
14. Patient unable to receive a brain MRI (implanted metal devices or foreign bodies) or MRI contrast.
15. Any BM with a significant hemorrhagic component (defined as MRI T1 intrinsic hyperintensity comprising ≥ 25% of maximal lesion diameter).