Brigatinib for Lung Cancer

INDICATIONS AND USAGE ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . ALUNBRIG is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. ( 1 , 2.1 )

DOSAGE AND ADMINISTRATION 90 mg orally once daily for the first 7 days; then increase to 180 mg orally once daily. May be taken with or without food. ( 2.2 ) 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with ALUNBRIG based on the presence of ALK positivity in tumor specimens [see Clinical Studies (14) ] . Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage for ALUNBRIG is: 90 mg orally once daily for the first 7 days; then increase the dose to 180 mg orally once daily. Administer ALUNBRIG until disease progression or unacceptable toxicity. If ALUNBRIG is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. ALUNBRIG may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets. If a dose of ALUNBRIG is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of ALUNBRIG at the scheduled time. 2.3 Dosage Modifications for Adverse Reactions ALUNBRIG dosage reductions for adverse reactions are summarized in Table 1. Table 1: Recommended ALUNBRIG Dosage Reductions Dosage Reduction Dosage First Second Third 90 mg once daily 60 mg once daily permanently discontinue N/A Not applicable 180 mg once daily 120 mg once daily 90 mg once daily 60 mg once daily Once reduced for adverse reactions, do not subsequently increase the dosage of ALUNBRIG. Permanently discontinue ALUNBRIG if patients are unable to tolerate the 60 mg once daily dose. Recommendations for dosage modifications of ALUNBRIG for the management of adverse reactions are provided in Table 2. Table 2: Recommended ALUNBRIG Dosage Modifications for Adverse Reactions Adverse Reaction Severity Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4). Dosage Modifications bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal Interstitial Lung Disease (ILD) /Pneumonitis [see Warnings and Precautions (5.1 )] Grade 1 If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline, then resume at same dose. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG. Grade 2 If new pulmonary symptoms occur during the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. Resume at next lower dose (Table 1) and do not dose escalate if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. If ILD/pneumonitis is suspected, resume at next lower dose (Table 1); otherwise, resume at same dose. If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG. Grade 3 or 4 Permanently discontinue ALUNBRIG for ILD/pneumonitis. Hypertension [see Warnings and Precautions (5.2) ] Grade 3 hypertension (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg, medical intervention indicated, more than one antihypertensive drug, or more intensive therapy than previously used indicated) Withhold ALUNBRIG until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume ALUNBRIG at the same dose. Recurrence: withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment. Grade 4 hypertension (life-threatening consequences, urgent intervention indicated) Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or permanently discontinue treatment. Recurrence: permanently discontinue ALUNBRIG for recurrence of Grade 4 hypertension. Bradycardia (HR less than 60 bpm) [see Warnings and Precautions (5.3) ] Symptomatic bradycardia Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ALUNBRIG at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. Bradycardia with life-threatening consequences, urgent intervention indicated Permanently discontinue ALUNBRIG if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Recurrence: permanently discontinue ALUNBRIG. Visual Disturbance [see Warnings and Precautions (5.4) ] Grade 2 or 3 visual disturbance Withhold ALUNBRIG until recovery to Grade 1 or baseline, then resume at the next lower dose (Table 1). Grade 4 visual disturbance Permanently discontinue ALUNBRIG. Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5) ] Grade 3 or 4 CPK elevation (greater than 5× ULN) with Grade 2 or higher muscle pain or weakness Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5× ULN) CPK elevation or to baseline, then resume ALUNBRIG at same dose. Recurrence: Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 2.5× ULN) CPK elevation or to baseline, then resume ALUNBRIG at the next lower dose (Table 1). Lipase/Amylase Elevation [see Warnings and Precautions (5.6) ] Grade 3 lipase or amylase elevation (greater than 2× ULN) Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at same dose. Recurrence: Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Grade 4 lipase or amylase elevation (greater than 5× ULN) Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 1.5× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Hepatotoxicity (Elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) [see Warnings and Precautions (5.7) ] Grade 3 or 4 elevation (greater than 5 × ULN) of either ALT or AST with bilirubin less than or equal to 2 × ULN Withhold ALUNBRIG until recovery to Grade 1 or less (less than or equal to 3× ULN) or to baseline, then resume ALUNBRIG at next lower dose (Table 1). Grade 2 to 4 elevation (greater than 3 × ULN) of ALT or AST with concurrent total bilirubin elevation greater than 2 × ULN in the absence of cholestasis or hemolysis Permanently discontinue ALUNBRIG. Hyperglycemia [see Warnings and Precautions (5.8) ] Grade 3 (greater than 250 mg/dL or 13.9 mmol/L) or 4 If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and resume at the next lower dose (Table 1) or permanently discontinue ALUNBRIG. Other Grade 3 Withhold ALUNBRIG until recovery to baseline, then resume at same dose. Recurrence: withhold ALUNBRIG until recovery to baseline, then resume at next lower dose or discontinue ALUNBRIG (Table 1). Grade 4 Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Perma

WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold ALUNBRIG for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue ALUNBRIG. ( 2.3 , 5.1 ) Hypertension : Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue. ( 2.3 , 5.2 ) Bradycardia : Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue. ( 2.3 , 5.3 ) Visual Disturbance : Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG. ( 2.3 , 5.4 ) Creatine Phosphokinase (CPK) Elevation : Monitor CPK levels regularly during treatment. Based on the severity and with muscle pain or weakness, withhold ALUNBRIG, then resume or reduce dose. ( 2.3 , 5.5 ) Pancreatic Enzymes Elevation : Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose. ( 2.3 , 5.6 ) Hepatotoxicity : Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels regularly during treatment. Based on severity, withhold dose, then resume at lower level. ( 2.3 , 5.7 ) Hyperglycemia : Assess fasting serum glucose prior to starting ALUNBRIG and regularly during treatment. If not adequately controlled with optimal medical management, withhold ALUNBRIG, then consider dose reduction or permanently discontinue, based on severity. ( 2.3 , 5.8 ) Photosensitivity : Advise patients to limit sun exposure. Based on severity withhold ALUNBRIG, then resume at the same dose, reduce the dose, or permanently discontinue. ( 2.3 , 5.9 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients. In Trial ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred within 9 days of initiation of ALUNBRIG (median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1 after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.2 Hypertension In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; Grade 3 hypertension occurred in 13% of patients. In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia [see Warnings and Precautions (5.3) ] . 5.3 Bradycardia In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG. Grade 3 bradycardia occurred in 1 patient (0.7%). In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided [see Warnings and Precautions (5.2) ] . For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.3) ] . 5.4 Visual Disturbance In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance including blurred vision, photophobia, photopsia, and reduced visual acuity were reported in 7.4% of patients receiving ALUNBRIG. In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in 1 patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.5 Creatine Phosphokinase (CPK) Elevation In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients. In ALTA, CPK elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation with Grade 2 or higher muscle pain or weakness. Upon resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at the same dose or at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.6 Pancreatic Enzymes Elevation In ALTA 1L, amylase elevation occurred in 52% of patie

DRUG INTERACTIONS CYP3A Inhibitors : Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG. ( 2.4 , 7.1 ) CYP3A Inducers : Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of ALUNBRIG. ( 2.5 , 7.1 ) 7.1 Effect of Other Drugs on ALUNBRIG Strong or Moderate CYP3A Inhibitors Coadministration of ALUNBRIG with a strong or moderate CYP3A inhibitor increased brigatinib plasma concentrations, which may increase the incidence of adverse reactions [see Clinical Pharmacology (12.3) ] . Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration of strong or moderate CYP3A inhibitors cannot be avoided, modify dose as recommended [see Dosage and Administration (2.4) ] . Strong or Moderate CYP3A Inducers Coadministration of ALUNBRIG with a strong or moderate CYP3A inducer decreased brigatinib plasma concentrations, which may decrease the efficacy of ALUNBRIG [see Clinical Pharmacology (12.3) ] . Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, modify dose as recommended [see Dosage and Administration (2.5) ] .

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the prescribing information: Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1) ] Hypertension [see Warnings and Precautions (5.2) ] Bradycardia [see Warnings and Precautions (5.3) ] Visual Disturbance [see Warnings and Precautions (5.4) ] Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5) ] Pancreatic Enzymes Elevation [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Hyperglycemia [see Warnings and Precautions (5.8) ] Photosensitivity [see Warnings and Precautions (5.9) ] The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-217-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Advanced ALK-positive NSCLC Without Prior ALK-targeted Therapy In ALTA 1L, the safety of ALUNBRIG was evaluated in 136 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy [see Clinical Studies (14) ] . The median duration of treatment with ALUNBRIG when administered as 90 mg orally once daily for the first 7 days; then increased to 180 mg orally once daily, was 24.3 months. A total of 106 (78%) patients were exposed to ALUNBRIG for greater than or equal to 6 months including 92 (68%) patients exposed for greater than or equal to 1 year. The median relative dose intensity was 97% for ALUNBRIG. The study population (N = 275) characteristics were: median age 59 years (range: 27 to 89), age less than 65 years (68%), female (55%), White (59%), Asian (39%), Stage IV disease (93%), NSCLC adenocarcinoma histology (96%), never smoker (58%), ECOG Performance Status (PS) 0 or 1 (95%), and CNS metastases at baseline (30%) [see Clinical Studies (14) ] . Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%). In ALTA 1L, 13% of patients receiving ALUNBRIG permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (2.2%). In ALTA 1L, 38% of patients required a dose reduction due to adverse reactions. The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%) and hypertension (2.2%). Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA 1L. Table 3: Adverse Reactions in ≥10% (All Grades Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 ) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N = 273) Adverse Reactions ALUNBRIG N = 136 Crizotinib N = 137 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Disorders Diarrhea 53 2.2 57 2.9 Nausea 30 2.2 58 2.9 Abdominal pain Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort 24 0.7 33 3.6 Vomiting 21 0.7 44 2.2 Constipation 18 0 42 0 Stomatitis Includes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis 13 0.7 8.8 0 Dyspepsia 8 0 16 0.7 Gastroesophageal reflux disease 0.7 0 11 0 Skin and Subcutaneous Tissue Disorders Rash Includes dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis contact, drug eruption, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption, urticaria 40 2.9 17 0 Pruritus Included pruritus, allergic pruritus, and generalized pruritus 20 0.7 5.8 0.7 Respiratory, Thoracic and Mediastinal Disorders Cough 35 0 20 0 Dyspnea Include dyspnea and exertional dyspnea 25 2.9 22 Includes Grade 5 events 3.6 ILD/Pneumonitis 5.1 2.9 2.2 0.7 Pulmonary embolism 2.2 2.2 5.8 2.9 Vascular Disorders Hypertension Includes hypertension and systolic hypertension 32 13 8 2.9 General Disorders and Administration Site Conditions Fatigue Includes asthenia and fatigue 32 1.5 40 2.2 Edema Includes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face 18 0.7 48 0.7 Pyrexia 15 0.7 15 0 Musculoskeletal and Connective Tissue Disorders Myalgia Includes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia 28 0 23 0 Back pain 21 0.7 17 1.5 Arthralgia 14 0 12 0 Pain in extremity 5.1 0 15 0.7 Nervous System Disorders Headache Includes headache and migraine 22 2.2 17 0 Dizziness 15 0.7 20 0.7 Peripheral neuropathy Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy 11 0.7 18 0 Dysgeusia 2.9 0 14 0 Investigations Increased Blood cholesterol Includes blood cholesterol increased, hypercholesterolaemia 13 0 0.7 0 Cardiac Disorders Bradycardia Includes bradycardia, heart rate decreased, sinus bradycardia 12 0.7 23 0 Infections and Infestations Pneumonia Includes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia 15 5.1 6.6 2.9 Upper respiratory tract infection Includes upper respiratory tract infection and viral upper respiratory tract infection 12 0 10 0 Nasopharyngitis 8 0 11 0 Urinary tract infection 5.9 0.7 8.8 2.2 Metabolism and Nutrition Disorders Decreased Appetite 8.8 0.7 19 2.9 Eye Disorders Visual Disturbance Includes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters 7.4 0 53 0.7 Table 4: Laboratory Abnormalities in ≥20% (All Grades Per CTCAE version 4.03 ) of Patients by Arm in ALTA 1L (N = 273) Laboratory Abnormality ALUNBRIG N = 136 Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test Crizotinib N = 137 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatine phosphokinase 81 24 68 4.8 Increased aspartate aminotransferase 72 4.5 70 5.2 Increased lipase 59 17 36 9.8 Hyperglycemia Elevated blood insulin was also observed in both arms 56 7.5 37 3.7 Increased alanine aminotransferase 52 5.2 77 13 Increased amylase 52 6.8 25 3 Decreased phosphorous 41 3.7 39 6 Increased alkaline phosphatase 36 3 49 1.5 Increased creatinine 25 0 33 0 Potassium increased 24 1.5 31 3.7 Increased calcium 22 0 1.5 0 Decreased magnesium 21 0 6.9 0 Decreased albumin 15 0.8 52 3.7 Decreased calcium 15 0 67 1.5 Hematology Hemoglobin decreased 41 2.3 36 1.5 Lymphocyte count decreased 42 9.3 30 5.4 Neutrophil count decreased 12 0 34 6.8 Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (3.7%). ALK-positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib The safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-