Study of Safety and Efficacy of Brigatinib Plus Chemotherapy or Brigatinib Only in Advanced ALK-Positive Lung Cancer (MASTERPROTOCOL ALK)

Inclusion Criteria:

1. Subjects must have signed and dated an IRB/IEC approved written informed consentform in accordance with regulatory and institutional guidelines. This must beobtained before the performance of any protocol related procedures that are not partof normal subject care. Subjects must be willing and able to comply with scheduledvisits, treatment schedule, and laboratory testing.

2. Patients diagnosed with histologically or cytologically confirmed locally advancednot eligible to a local treatment or metastatic NSCLC (Stage IIIB, IIIC or IVaccordingly to 8th classification TNM, UICC 2015).

3. Patients are eligible for trial entry on the basis of locally determined ALKtesting. ALK Immunohistochemistry (IHC) assay (3+ only), DNA-based or RNA-based nextgeneration sequencing (NGS) assay, nCounter Nanostring assay or ALK FISH performedlocally are accepted ALK testing assays. If ALK rearrangement diagnostic isperformed using IHC and the result is + or 2+, a confirmation with a second methodperformed locally (DNA-based or RNA-based NGS assay, nCounter Nanostring assay orALK FISH performed) is required.

4. All Patients must have at least one measurable target lesion according to RECISTv1.1 per investigator assessment. The radiological assessment has to be done withinthe timelines indicated.

5. Patients with asymptomatic and neurologically stable CNS metastases (includingpatients controlled with less than 10mg/day of methylprednisolone within the lastweek prior to study entry) will be eligible.

6. Tumor Sample Requirement: sufficient tumor tissue for central analysis should beavailable (tumor block or a minimum of 10 unstained slides of 4 µm of analyzabletissue).

7. Age ≥18 years.

8. Life expectancy of at least 12 weeks, in the opinion of the Investigator.

9. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

10. Adequate Bone Marrow Function, including: Absolute Neutrophil Count (ANC) ≥1.5 x 109/L; Platelets ≥100 x 109/L; Hemoglobin ≥9 g/dL.

11. Adequate Pancreatic Function, including: Serum lipase ≤3.0 ULN.

12. Adequate Renal Function, including: Estimated creatinine clearance ≥45 mL/min ascalculated using the standard method of the institution.

13. Adequate Liver Function, including: Total serum bilirubin ≤1.5 x ULN (<3.0 × ULN forpatients with Gilbert syndrome); Aspartate Aminotransferase (AST) and AlanineAminotransferase (ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver metastasesinvolvement.

14. Participants must have recovered from toxicities related to prior anticancer therapyto CTCAE Grade ≤ 1.

15. Participants must have recovered from effects of any major surgery, or significanttraumatic injury, at least 35 days before the first dose of treatment.

16. Have normal QT interval on screening ECG evaluation, defined as QT intervalcorrected (QTc) of ≤450 milliseconds (msec) in males or ≤470 msec in females.

17. Female patients who: are postmenopausal for at least 1 year before the screeningvisit, OR are surgically sterile, OR if they are of childbearing potential, agree topractice 2 effective methods of contraception, at the same time, one of them beingnonhormonal, from the time of signing the informed consent through 6 months afterthe last dose of study drug, or agree to completely abstain from heterosexualintercourse.

18. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:agree to practice effective barrier contraception during the entire study treatmentperiod and through 6 months after the last dose of study drug, or agree tocompletely abstain from heterosexual intercourse.

19. Willingness and ability to comply with the study scheduled visits, treatment plans,laboratory tests and other procedure.

20. Participant has national health insurance coverage.

Exclusion Criteria:

1. Previously received an investigational antineoplastic agent for NSCLC.

2. Previously received any prior TKI, including ALK-targeted TKIs.

3. Known molecular co-alteration i.e. activating EGFR/BRAF/KRAS/MET mutation andROS1/RET/NTRK fusion.

4. Previously received neo-adjuvant or adjuvant systemic chemotherapy or consolidationimmunotherapy if completion of (neo) adjuvant/consolidation therapy occurred <12months prior to randomization.

5. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM)according to MRI data and/or in case of documented cerebral spinal fluid (CSF)positive cytology.

6. Spinal cord compression.

7. Patients with symptomatic or neurologically instable CNS metastases.

8. Major surgery within 30 days of study entry. Minor surgical procedures (e.g., portinsertion, mediastinoscopy, surgical procedure for re-sampling) are not excluded,but sufficient time at investigator discretion should have passed for wound healing.

9. Radiation therapy within 2 weeks of study entry. Stereotactic or small field brainirradiation must have completed at least 2 weeks prior to study entry. Whole brainradiation must have completed at least 4 weeks prior to study entry.

10. Active and clinically significant bacterial, fungal, or viral infection includinghepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), oracquired immunodeficiency syndrome (AIDS)-related illness.

11. Have significant, uncontrolled, or active cardiovascular disease, specificallyincluding, but not restricted to: a) myocardial infarction within 6 months prior tothe first dose of study drug; b) unstable angina within 6 months prior to the firstdose of study drug; c) congestive heart failure within 6 months prior to the firstdose of study drug; d) any history of ventricular arrhythmia; e) history ofclinically significant atrial arrhythmia or clinically significant bradyarrhythmiaas determined by the treating physician; f) cerebrovascular accident or transientischemic attack within 6 months prior to the first dose of study drug.

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

13. History of grade 3 or 4 of interstitial fibrosis or interstitial lung diseaseincluding a history of pneumonitis, hypersensitivity pneumonitis, interstitialpneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosisand radiation pneumonitis.

14. Presence of interstitial fibrosis of any grade at baseline.

15. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the investigator, would make the patientinappropriate for entry into this study.

16. Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer,in situ cervical cancer, papillary thyroid cancer, DCIS of the breast or localizedand presumed cured prostate cancer) within the last 3 years.

17. Active inflammatory gastrointestinal disease, malabsorption syndrome, chronicdiarrhea, symptomatic diverticular disease or previous gastric resection or lapband.

18. Current use or anticipated need for food or drugs prohibited.

19. Patients presenting with abnormal Left Ventricular Ejection Fraction (LVEF) byechocardiogram or Multi-Gated Acquisition Scan (MUGA) according to institutionallower limits.

20. Have a known or suspected hypersensitivity to brigatinib, carboplatin or pemetrexedor their excipients.

21. Female patients who are both lactating and breastfeeding or have a positive serumpregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

22. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strongcyp3a inducers, or moderate cyp3a inducers within 14 days before enrolment.