Brigatinib Before Brain Irradiation Trial (B3i Trial)

Inclusion Criteria: 1. Provision to sign and date the consent form. 2. Stated willingness to comply with all study procedures and be available for the duration of the study. 3. Ability to take and retain oral medications. 4. Age ≥18 years. 5. Patients with ALK+ lung cancer with evidence of ≥1 previously untreated brain metastases on brain MRI. Prior therapy (radiation or surgery) for brain metastases is allowed. However, patients must have ≥1 previously untreated at the time of enrollment. 6. Patients may be ALK TKI naïve OR have had prior crizotinib therapy. 7. Patients may be included if they are asymptomatic from their brain metastases (RTOG/EORTC grade 0) or if they have mild symptoms from their brain metastases not to exceed RTOG/ EORTC grade 1 or 2 (Grade 1: Fully functional status (i.e. able to work) with minor neurological findings, no medication needed; Grade 2: Neurological findings present sufficient to require home care / nursing assistance may be required / medications including steroids/anti-seizure agents may be required) (Cox, James D., et al "Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC)." International Journal of Radiation Oncology• Biology• Physics 31.5 (1995): 1341-1346). 8. Neurologically symptomatic patients must not require immediate surgical or radiation therapy for their symptoms, as decided by an investigator. 9. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 10. Have adequate organ function, as determined by * ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable if liver metastases are present * Total serum bilirubin ≤1.5 × ULN (\<3.0×ULN for patients with Gilbert syndrome) * Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) equation * Serum lipase/amylase ≤1.5 × ULN * Absolute neutrophil count (ANC) ≥1.5 × 109/L * Platelet count ≥75 × 109/L * Hemoglobin ≥9 g/dL 11. For females of childbearing potential, have a negative pregnancy test documented prior to initiating brigatinib. 12. For female and male patients who are fertile, agree to use 2 effective methods of contraception with their sexual partners from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal contraceptives, therefore, women are recommended to use non-hormonal methods of contraception. Highly effective non-hormonal birth control for women of child bearing potential with male partners includes: * Sexual abstinence (no sexual intercourse) * Intrauterine device (IUD) or intrauterine system (IUS) * Bilateral tubal ligation (both tubes tied) * Vasectomized partner 13. Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following: * Practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or completely abstain from heterosexual intercourse. Exclusion Criteria: 1. Patients who have received prior brigatinib therapy or other CNS-penetrant ALK TKIs, including alectinib, lorlatinib, or ceritinib. 2. RTOG/EORTC Acute CNS symptoms, grade 3 and 4 (Grade 3: Neurological findings requiring hospitalization for initial management; Grade 4: Serious neurological impairment that includes paralysis, coma, or seizures \> 3 per week despite medication / hospitalization required). 3. Currently pregnant, planning a pregnancy during the study period, or breastfeeding. 4. Have clinically significant, uncontrolled cardiovascular disease per investigator, specifically including, but not restricted to: 1. Myocardial infarction (MI) within 6 months prior to the first dose of study drug 2. Unstable angina within 6 months prior to first dose of study drug 3. Clinically significant congestive heart failure (CHF) within 6 months prior to first dose of study drug 4. History of clinically significant atrial or ventricular arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician 5. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug 5. Have uncontrolled hypertension per the investigator. Patients with persistent hypertension of systolic ≥140 or diastolic ≥90 mm Hg should be under treatment on study entry to control blood pressure. 6. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis. 7. Have an ongoing or active infection, including, but not limited to, the requirement for intravenous (IV) antibiotics. 8. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history. 9. Have a known or suspected hypersensitivity to brigatinib or its excipients. 10. Additional systemic therapies for the treatment of lung cancer may not be taken concomitantly with brigatinib (eg, TKIs, immunotherapy, chemotherapy). No washout period is required for prior therapy. 11. Have malabsorption syndrome or other GI illness that could affect oral absorption of brigatinib. 12. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of brigatinib. 13. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong cyp3a inducers, or moderate cyp3a inducers within 14 days before enrollment. 14. Had major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. 15. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.