6 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)]

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*) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N = 273)
Adverse Reactions	ALUNBRIG N = 136		Crizotinib N = 137
Adverse Reactions	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 † Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort ‡ Includes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis § 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 ¶ Included pruritus, allergic pruritus, and generalized pruritus # Include dyspnea and exertional dyspnea Þ Includes Grade 5 events ß Includes hypertension and systolic hypertension à Includes asthenia and fatigue è Includes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face ð Includes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia ø Includes headache and migraine ý Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy £ Includes blood cholesterol increased, hypercholesterolaemia ¥ Includes bradycardia, heart rate decreased, sinus bradycardia Œ Includes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia œ Includes upper respiratory tract infection and viral upper respiratory tract infection Ɖ Includes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters
Gastrointestinal Disorders
Diarrhea	53	2.2	57	2.9
Nausea	30	2.2	58	2.9
Abdominal pain†	24	0.7	33	3.6
Vomiting	21	0.7	44	2.2
Constipation	18	0	42	0
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§	40	2.9	17	0
Pruritus¶	20	0.7	5.8	0.7
Respiratory, Thoracic and Mediastinal Disorders
Cough	35	0	20	0
Dyspnea#	25	2.9	22Þ	3.6
ILD/Pneumonitis	5.1	2.9	2.2	0.7
Pulmonary embolism	2.2	2.2	5.8Þ	2.9
Vascular Disorders
Hypertensionß	32	13	8	2.9
General Disorders and Administration Site Conditions
Fatigueà	32	1.5	40	2.2
Edemaè	18	0.7	48	0.7
Pyrexia	15	0.7	15	0
Musculoskeletal and Connective Tissue Disorders
Myalgiað	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
Headacheø	22	2.2	17	0
Dizziness	15	0.7	20	0.7
Peripheral neuropathyý	11	0.7	18	0
Dysgeusia	2.9	0	14	0
Investigations
Increased Blood cholesterol£	13	0	0.7	0
Cardiac Disorders
Bradycardia¥	12	0.7	23	0
Infections and Infestations
PneumoniaŒ	15Þ	5.1	6.6Þ	2.9
Upper respiratory tract infectionœ	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 DisturbanceƉ	7.4	0	53	0.7

Table 4: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Arm in ALTA 1L (N = 273)
Laboratory Abnormality	ALUNBRIG N = 136†		Crizotinib N = 137†
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per CTCAE version 4.03 † Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test ‡ Elevated blood insulin was also observed in both arms
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‡	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-positive NSCLC who received at least 1 dose of ALUNBRIG in ALTA after experiencing disease progression on crizotinib. Patients received ALUNBRIG 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90→180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90→180 mg group. A total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to 1 year.

The study population (N = 222) characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and CNS metastases at baseline (69%) [see Clinical Studies (14)].

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90→180 mg group permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90→180 mg group) and pneumonia (1.8% in the 90→180 mg group only).

In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90→180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90→180 mg group).

Table 5 and Table 6 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

Table 5: Adverse Reactions in ≥10% (All Grades*) or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N = 219)
Adverse Reactions	90 mg once daily N = 109		90→180 mg once daily N = 110
Adverse Reactions	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 † Includes abdominal distension, abdominal pain, and epigastric discomfort ‡ Includes asthenia and fatigue § Includes dyspnea and exertional dyspnea ¶ Includes one Grade 5 event # Includes headache and sinus headache Þ Includes peripheral sensory neuropathy and paresthesia ß Includes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash à Includes musculoskeletal pain and myalgia è Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment
Gastrointestinal Disorders
Nausea	33	0.9	40	0.9
Diarrhea	19	0	38	0
Vomiting	24	1.8	23	0
Constipation	19	0.9	15	0
Abdominal Pain†	17	0	10	0
General Disorders and Administration Site Conditions
Fatigue‡	29	1.8	36	0
Pyrexia	14	0	6.4	0.9
Respiratory, Thoracic and Mediastinal Disorders
Cough	18	0	34	0
Dyspnea§	27	2.8	21	1.8¶
ILD/Pneumonitis	3.7	1.8	9.1	2.7
Hypoxia	0.9	0	2.7	2.7
Nervous System Disorders
Headache#	28	0	27	0.9
Peripheral NeuropathyÞ	13	0.9	13	1.8
Skin and Subcutaneous Tissue Disorders
Rashß	15	1.8	24	3.6
Vascular Disorders
Hypertension	11	5.5	21	6.4
Musculoskeletal and Connective Tissue Disorders
Muscle Spasms	12	0	17	0
Back pain	10	1.8	15	1.8
Myalgiaà	9.2	0	15	0.9
Arthralgia	14	0.9	14	0
Pain in extremity	11	0	3.6	0.9
Metabolism and Nutrition Disorders
Decreased Appetite	22	0.9	15	0.9
Eye Disorders
Visual Disturbanceè	7.3	0	10	0.9
Infections
Pneumonia	4.6	2.8¶	10	5.5¶
Psychiatric Disorders
Insomnia	11	0	7.3	0

Table 6: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Regimen in ALTA (N = 219)
Laboratory Abnormality	90 mg once daily N = 109		90→180 mg once daily N = 110
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Per CTCAE version 4.0 † Elevated blood insulin was observed in both regimens
Chemistry
Increased aspartate aminotransferase	38	0.9	65	0
Hyperglycemia†	38	3.7	49	3.6
Increased creatine phosphokinase	27	2.8	48	12
Increased lipase	21	4.6	45	5.5
Increased alanine aminotransferase	34	0	40	2.7
Increased amylase	27	3.7	39	2.7
Increased alkaline phosphatase	15	0.9	29	0.9
Decreased phosphorous	15	1.8	23	3.6
Prolonged activated partial thromboplastin time	22	1.8	20	0.9
Hematology
Anemia	23	0.9	40	0.9
Lymphopenia	19	2.8	27	4.5

Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (0.9%).

Other Adverse Reactions from Multiple Clinical Trials

In a pooled clinical trial population consisting of three studies with 274 patients treated with ALUNBRIG at the recommended dose, the following adverse reactions and laboratory abnormalities were reported: white blood cell count decreased (28%), hyponatremia (20%), hypokalemia (19%), decreased platelet count (10%), dry skin (4.7%), pain (3.3%), and musculoskeletal stiffness (1.1%).