A Study to Evaluate the Efficacy of Brigatinib (AP26113) in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

A Randomized Phase 2 Study of AP26113 in Patients With ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.

The drug being tested in this study is called brigatinib (AP26113). Brigatinib was tested to treat people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or were intolerant to crizotinib. This study looked at the efficacy of brigatinib.

The study enrolled 222 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

• Brigatinib 90 mg
• Brigatinib 90 mg -180 mg

All participants were asked to take a tablet, orally once daily until disease progression or intolerable toxicity. Participants in Brigatinib 90 mg - 180 mg received 180 mg with a 7-day lead-in at 90 mg.

This multi-center trial was conducted worldwide. The overall time to participate in this study is up to 3 years. Participants will make multiple visits to the clinic, and 3 months after the End-of-Treatment visit. Follow-up is intended to continue for 2 years after the last participants was enrolled into the study.

Inclusion Criteria:

1. Have histologically or cytologically confirmed locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is anaplastic lymphoma kinase (ALK+).

2. Must meet one of the following two criteria:

   1. Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or
   2. Have documented ALK positivity by a different test and tissue available for the Vysis® FISH test. Tissue should be derived preferably from a biopsy taken after progression with crizotinib. If such a sample is not available, testing may be performed with archived tumor tissue.

3. Had progressive disease while on crizotinib, as assessed by the investigator or treating physician.

4. Have at least 1 measurable lesion per RECIST v1.1. Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy. Brain lesions may not be used as target lesions if they were: 1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical resection.

5. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade ≤2.

6. Are a male or female participants ≥18 years old.

7. Have a life expectancy ≥3 months.

8. Have adequate organ and hematologic function, as determined by:

   1. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN; ≤5 x ULN is acceptable if liver metastases are present)
   2. Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for participants with Gilbert syndrome)
   3. Serum creatinine ≤1.5 x ULN
   4. Serum lipase/amylase ≤1.5 x ULN
   5. Absolute neutrophil count (ANC) ≥1500/µL
   6. Platelets ≥75000/µL
   7. Hemoglobin ≥10 g/dL

9. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

10. Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.

11. For female participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

12. Female and male participants who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation.

13. Must provide a signed and dated informed consent indicating that the participants has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating.

14. Have the willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

1. Received any prior ALK-targeted TKI other than crizotinib.

2. Received crizotinib within 3 days of the first dose of brigatinib (Day 1, Cycle 1).

3. Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except SRS or stereotactic body radiosurgery.

4. Received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib (Day 1, Cycle 1).

5. Have been diagnosed with another primary malignancy within the past 3 years (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, which are allowed within 3 years).

6. Have symptomatic CNS metastases that are neurologically unstable or require an increasing dose of corticosteroids.

7. Have current spinal cord compression.

8. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

   1. Myocardial infarction (MI) within 6 months prior to the first dose of brigatinib
   2. Unstable angina within 6 months prior to first dose
   3. Congestive heart failure (CHF) within 6 months prior to first dose
   4. History of clinically significant (as determined by the treating physician) atrial arrhythmia
   5. Any history of ventricular arrhythmia
   6. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose

9. Have a history or the presence of pulmonary interstitial disease or drug-related pneumonitis.

10. Have an ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.

11. Have a known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.

12. Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose of brigatinib.

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

14. Have malabsorption syndrome or other GI illness that could affect oral absorption of the study drug.

15. Have any condition or illness that, in the opinion of the investigator, would compromise participants safety or interfere with evaluation of the drug study.

16. Be pregnant or breastfeeding.