OBSERVE: A Pilot Study Of Omission Of Brain Metastasis Stereotactic Radiosurgery Following Resection With CNS-Active Systemic Therapy

Eligibility Criteria 1. Age ≥ 18 years. 2. ECOG performance status ≤ 2. 3. Participants with a resected brain metastasis with gross total resection and pathologic confirmation of NSCLC or melanoma. Gross total resection must be confirmed based on a review of the operative report, pathology, and all post-operative images available at the time of enrollment. 4. Brain metastasis resection occurred ≤ 5 weeks ago. 5. Additional prior surgeries, including Laser Interstitial Thermal Therapy (LITT), to the same or nearby location are permitted, provided that residual disease or local recurrence is confirmed pathologically at the most recent resection. 6. The resected lesion has never previously been targeted by radiotherapy. 7. 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, and agreement that the intracranial cavity does not or will not require immediate post-operative radiation (i.e. it is judged to be safe to omit post-operative radiation). This BM-MDT evaluation can take place in clinic or during a multidisciplinary conference, either before or after the surgical resection. If the BM-MDT evaluation was before the surgical resection, there can be no new findings in the interim (e.g. during or after the surgical resection) that would change the BM-MDT's recommendation, as determined by one or more of the patient's treating physicians. 8. Documentation by the patient's primary medical oncologist of a planned study systemic therapy regimen consisting of one of the following: dual-agent immune checkpoint inhibitors (e.g. ipilimumab and nivolumab) for melanoma, osimertinib for EGFR Mutant (e.g. Exon 19 deletion; L858R) NSCLC, and brigatinib, alectinib, or lorlatinib for ALK rearranged/fusion positive NSCLC. As new agents are approved, other highly-CNS active tyrosine kinase inhibitors for participants with NSCLC may be included at the discretion of the principal investigator. 9. For a participant with more than one recently resected brain metastasis that meets eligibility criteria #3-#7 above, it is permissible (but not mandated) for more than one surgical cavity to proceed without immediate post-operative radiation. All other intracranial disease must proceed with treatment according to standard-of-care practices at the time of enrollment. This may include treatment with SRS or observation if clinically appropriate. 10. Regarding prior systemic therapy: 1. For participants with melanoma: no prior disease progression on any immune checkpoint inhibitor agent and ≥ 6 months between the last dose of any immune checkpoint inhibitor agent and initiation of the study systemic therapy regimen. 2. For participants with EGFR Mutant NSCLC: no prior disease progression on any EGFR-targeted tyrosine kinase inhibitor and ≥ 6 month between the last dose of any EGFR-targeted tyrosine kinase inhibitor and initiation of the study systemic therapy regimen. 3. For participants with ALK rearranged/fusion positive NSCLC: no prior disease progression on any ALK-targeted tyrosine kinase inhibitor and ≥ 6 month between the last dose of any ALK-targeted tyrosine kinase inhibitor and initiation of the study systemic therapy regimen. 11. 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. Subjects that have previously received or are currently planned for whole brain radiotherapy. 3. Prior unacceptable toxicity on one or more of the agents comprising the planned study systemic therapy. 4. Cognitively impaired 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. 5. Participant unable to receive a brain MRI (implanted metal devices or foreign bodies) or MRI contrast. 6. Pregnancy or plans to become pregnant during the duration of the study.