Local Consolidative Therapy and Brigatinib in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of stage IV NSCLC (or recurrentNSCLC not a candidate for definitive multimodality therapy)

2. Documented ALK re-arrangement as detected by: (1) FISH, (2) IHC, (3) tissue NGS, or (4) cfDNA NGS

3. Subjects can be enrolled as (1) TKI naïve or (2) after ≤ 8 weeks of first-linebrigatinib treatment without disease progression.

4. Candidate for local consolidative therapy to at least one site of residual disease

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

6. Males or females aged at least 18 years.

7. Adequate organ function laboratory values, defined as:

8. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L or at least 1500/mm3 or at least 1.5 x 109/L

9. Platelet count at least 75,000/mm3 or at least 75 x 109/L

10. Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline

11. Serum creatinine ≤ 1.5 × ULN or ≥ 60 mL/minute for subjects with creatininelevels > 1.5 × the institutional ULN

12. Serum total bilirubin less than or equal to ≤ 1.5 × ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels > 1.5 × ULN

13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULNexcept for subjects with liver mets for whom ALT and AST should be ≤ 5× ULN

14. International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULNunless subject is receiving anticoagulant therapy as long as PT or partialthromboplastin time (PTT) is within therapeutic range of intended use ofanticoagulants

15. Activated PTT (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulanttherapy as long as PT or PTT is within therapeutic range of intended use ofanticoagulant

16. Female patients of childbearing potential must have a negative pregnancy testdocumented at time of screening.

17. Female patients who:

18. Are postmenopausal for at least 1 year before the screening visit, OR

19. Are surgically sterile, OR

20. If they are of childbearing potential, agree to use a highly effective methodof contraception from the time of signing the informed consent through 4 monthsafter the last dose of study drug, or agree to completely abstain fromheterosexual intercourse

21. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

22. Agree to practice effective barrier contraception during the entire studytreatment period and through 4 months after the last dose of study drug, or

23. Agree to completely abstain from heterosexual intercourse

24. Have normal QT interval on screening ECG evaluation, defined as QT intervalcorrected (Fridericia) (QTcF) of ≤450 milliseconds (msec) in males or ≤470 msec infemales.

25. Voluntary agreement to provide written informed consent and the willingness andability to comply with all aspects of the protocol.

Exclusion Criteria:

1. Have been diagnosed with another primary malignancy other than NSCLC, except foradequately treated non-melanoma skin cancer or cervical cancer in situ; definitivelytreated non-metastatic prostate cancer; or patients with another primary malignancywho are definitively relapse-free with at least 2 years elapsed since the diagnosisof the other primary malignancy.

2. Previously received any prior TKI, including ALK-targeted TKIs. Note: on-goingfirst-line brigatinib use as specified in the Inclusion criteria is allowed.

3. Previously received more than 1 regimen of chemotherapy or immunotherapy for locallyadvanced or metastatic disease. Note that history of consolidative immunotherapyafter concurrent chemoradiotherapy (for locally advanced disease) is allowed.

4. Symptomatic CNS metastasis. Asymptomatic CNS disease requiring increasing dose ofcorticosteroids within 7 days prior to study enrollment is also not permitted.

5. Have current spinal cord compression (symptomatic or asymptomatic and detected byradiographic imaging). Patients with leptomeningeal disease and without cordcompression are allowed.

6. The presence of pulmonary interstitial disease, drug-related pneumonitis, orradiation pneumonitis at screening.

7. Have a known or suspected hypersensitivity to brigatinib or its excipients.

8. Have malabsorption syndrome or other gastrointestinal (GI) illness or condition thatcould affect oral absorption of the study drug.

9. Be pregnant, planning a pregnancy, or breastfeeding.

10. Have significant, uncontrolled, or active cardiovascular disease, specificallyincluding, but not restricted to:

11. Myocardial infarction (MI) within 6 months prior to the first dose of studydrug

12. Unstable angina within 6 months prior to first dose of study drug

13. Decompensated congestive heart failure (CHF) within 6 months prior to firstdose of study drug

14. History of clinically significant atrial arrhythmia (including clinicallysignificant bradyarrhythmia), as determined by the treating physician

15. Any history of ventricular arrhythmia

16. Cerebrovascular accident or transient ischemic attack within 6 months prior tofirst dose of study drug

17. Have uncontrolled hypertension. Patients with hypertension should be under treatmenton study entry to control blood pressure

18. Have an ongoing or active infection, including, but not limited to, the requirementfor intravenous (IV) antibiotics.

19. Have a known history of human immunodeficiency virus (HIV) infection. Testing is notrequired in the absence of history.

20. Have any condition or illness that, in the opinion of the investigator, wouldcompromise patient safety or interfere with the evaluation of the study drug.