Repotrectinib in ROS1-positive Non-small Cell Lung Cancer Patients With Active Brain Metastasis

Inclusion Criteria: Patients will be included in the study only if they meet all the following criteria: 1. Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures. 2. Female or male patients ≥ 18 years of age at the time of signing ICF. 3. Patients must be capable to swallow capsules intact (without chewing, crushing, or opening). 4. Histologically documented NSCLC. 5. Patients may have active brain metastases with or without related symptoms. 6. No indication for immediate local therapy (neurosurgery, brain radiotherapy) of brain metastases per local investigator. Note: in case of immediate local therapy is needed, the study's medical monitor should be consulted. 7. Type II leptomeningeal disease per European Association of Neuro-Oncology (EANO) - European Society for Medical Oncology (ESMO) Clinical Practice Guidelines are allowed. 8. Patients with confirmed ROS1 rearrangement. Prior to study enrollment, patients must have had confirmation of ROS1 rearrangement, which should have been determined locally by a certified laboratory using methods such as fluorescent in situ hybridization (FISH), next generation sequencing (NGS), quantitative PCR (qPCR), or immunohistochemistry (IHC). 9. Measurable disease according to RANO-BM criteria, with at least one measurable brain lesion of ≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI). 10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 11. Minimum life expectancy of ≥ 6 weeks at screening. 12. No limit in number of prior chemotherapies, immunotherapy or other non-ROS1 TKI regimens. De novo patients can also be included. 13. Patients may have previously received up to one prior line of anti-ROS1 TKI-based treatment. 14. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 15. If feasible, archival tumor biopsy sample at baseline (from primary tissue or any metastatic site) should be provided. 16. Patient has adequate bone marrow, liver, and renal function: I. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 28 days before first study treatment dose): White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 8.0 g/dL (≥ 4.96 mmol/L). II. Hepatic: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) \< 1.5. III. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min/1.73 m2 based on Cockcroft-Gault glomerular filtration rate estimation for patients with creatinine levels above institutional normal. 17. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). 18. Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 2 months after the last dose of study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same period. Note: Due to a potential loss of effectiveness of hormonal contraceptives caused by interaction with study intervention, if WOCBP use hormonal contraceptives (including oral hormonal contraceptives), they must use either another form of non-hormonal highly effective contraception or a reliable barrier method. 19. Male participants who are sexually active with a WOCBP partner must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the study drug. Male participants must not donate or bank sperm during this same period. 20. Patient must be accessible for treatment and follow-up. Exclusion Criteria: Any patient meeting ANY of the following criteria will be excluded from the study: 1. Major surgery within four weeks of the start of treatment. 2. Type I leptomeningeal disease per ESMO-EANO guidelines. 3. Have received prior radiotherapy within two weeks before the first dose of Study treatment (four weeks in case of radiation therapy of the central nervous system). Participants must have recovered from all radiation-related toxicities, not require steroids, and not have had radiation pneumonitis. 4. Treatment with approved or investigational cancer therapy within14 days prior to initiation of Study treatment. 5. Any of the following cardiac criteria: I. Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) \> 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value. II. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec). III. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval. 6. Clinically significant cardiovascular disease (either active or wi