SAFETY PROFILE

Adverse Reactions in ≥10% (All Grades^a) 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^b	24	0.7	33	3.6
Vomiting	21	0.7	44	2.2
Constipation	18	0	42	0
Stomatitis^c	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^d	40	2.9	17	0
Pruritus^e	20	0.7	5.8	0.7
Respiratory, Thoracic and Mediastinal Disorders
Cough	35	0	20	0
Dyspnea^f	25	2.9	22^r	3.6
ILD/Pneumonitis	5.1	2.9	2.2	0.7
Pulmonary embolism	2.2	2.2	5.8^r	2.9
Vascular Disorders
Hypertension^g	32	13	8	2.9
General Disorders and Administration Site Conditions
Fatigue^h	32	1.5	40	2.2
Edemaⁱ	18	0.7	48	0.7
Pyrexia	15	0.7	15	0
Musculoskeletal and Connective Tissue Disorders
Myalgia^j	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^k	22	2.2	17	0
Dizziness	15	0.7	20	0.7
Peripheral neuropathy^l	11	0.7	18	0
Dysgeusia	2.9	0	14	0
Investigations
Increased blood cholesterol^m	13	0	0.7	0
Cardiac Disorders
Bradycardiaⁿ	12	0.7	23	0
Infections and Infestations
Pneumonia^o	15^r	5.1	6.6^r	2.9
Upper respiratory tract infection^p	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^q	7.4	0	53	0.7

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

^bIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort.

^cIncludes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis.

^dIncludes 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.

^eIncludes pruritus, allergic pruritus, and generalized pruritus.

^fIncludes dyspnea and exertional dyspnea.

^gIncludes hypertension and systolic hypertension.

^hIncludes asthenia and fatigue.

ⁱIncludes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face.

^jIncludes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia.

^kIncludes headache and migraine.

^lIncludes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy.

^mIncludes blood cholesterol increased, hypercholesterolemia.

ⁿIncludes bradycardia, heart rate decreased, sinus bradycardia.

^oIncludes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia.

^pIncludes upper respiratory tract infection and viral upper respiratory tract infection.

^qIncludes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters.

^rIncludes Grade 5 events.

Laboratory Abnormalities in ≥20% (All Grades^a) of Patients by Arm in ALTA 1L (N=273)

Laboratory Abnormality	ALUNBRIG (n=136)^b		crizotinib (n=137)^b
	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^c	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

^aPer NCI CTCAE v4.0.

^bDenominator for each laboratory parameter may vary and is defined as the number of patients who had both baseline and post-baseline test.

^cElevated blood insulin was also observed in both arms.

Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG^® (brigatinib). 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%).

The median duration of treatment with ALUNBRIG was 24.3 months.
The median relative dose intensity was 97% for ALUNBRIG.

Interstitial lung disease/pneumonitis

In the first-line phase 3 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 the post-crizotinib phase 2 trial (ALTA): ILD/pneumonitis occurred in 9.1% of patients. 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%

See the Recommended Dose Modifications for Adverse Reactions

Indication

ALUNBRIG^® (brigatinib) 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.

Important safety Information

Warnings and Precautions

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 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 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 90180 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% of patients. Monitor for new or worsening respiratory symptoms (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 of the full Prescribing Information 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.

Hypertension
In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; 13% of patients experienced Grade 3 hypertension. In ALTA, hypertension was reported in 11% of patients in the 90 mg group and 21% of patients in the 90180 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. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia
In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG; one patient (0.7%) experienced Grade 3 bradycardia. 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 90180 mg group. One patient (0.9%) in the 90 mg group experienced Grade 2 bradycardia. 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. 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.

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 treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90180 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.

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 90180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% of patients in the 90180 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 per Table 2 of the full Prescribing Information.

Pancreatic Enzyme Elevation
In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients who received ALUNBRIG. Lipase elevations occurred in 59% of patients and Grade 3 or 4 lipase elevation occurred in 17% of patients. In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hepatotoxicity
In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients who received ALUNBRIG. Alanine aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4 ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious adverse reaction of hepatocellular injury. In ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of patients in the 90180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90180 mg group. Grade 3 or 4 AST elevations occurred in 0.9% of patients in the 90 mg group and did not occur in any patients in the 90180 mg group. Grade 3 or 4 ALT elevations did not occur in any patients in the 90 mg group and in 2.7% of patients in the 90180 mg group. Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during the first 3 months. Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with bilirubin less than or equal to 2 × ULN. Upon resolution or recovery to Grade 1 or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a next lower dose per Table 2 of the full Prescribing Information. Permanently discontinue ALUNBRIG for Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation greater than 2 times the ULN in the absence of cholestasis or hemolysis.

Hyperglycemia
In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 7.5% of patients. In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG dosage per Table 1 of the full Prescribing Information or permanently discontinuing ALUNBRIG.

Photosensitivity
In ALTA 1L, 3.7% of patients who received ALUNBRIG experienced photosensitivity, with 0.7% of patients experiencing Grade 3 to 4 reactions. In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group and 0.9% of patients in the 90180 mg group experienced photosensitivity. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90180 mg group. Advise patients to limit sun exposure while taking ALUNBRIG, and for at least 5 days after discontinuation of treatment. Advise patients, when outdoors, to wear a hat and protective clothing, and use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Based on the severity, withhold ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently discontinue.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

Adverse Reactions

The most common adverse reactions (≥25%) with ALUNBRIG were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

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.

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.

Use in Specific Populations

Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose. ALUNBRIG may cause reduced fertility in males.

Lactation: Advise patients not to breastfeed.

Hepatic Impairment: Reduce the dose of ALUNBRIG for patients with severe hepatic impairment.

Renal Impairment: Reduce the dose of ALUNBRIG for patients with severe renal impairment.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

SAFETY PROFILE

Adverse Reactions in ≥10% (All Grades^a) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N=273)

Laboratory Abnormalities in ≥20% (All Grades^a) of Patients by Arm in ALTA 1L (N=273)

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In Vitro: ALUNBRIG Inhibited 17
ALK-Inhibitor—Resistant Mutations^1,2

Adverse Reactions in ≥10% (All Gradesa) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N=273)

Laboratory Abnormalities in ≥20% (All Gradesa) of Patients by Arm in ALTA 1L (N=273)

Adverse Reactions in ≥10% (All Grades^a) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N=273)

Laboratory Abnormalities in ≥20% (All Grades^a) of Patients by Arm in ALTA 1L (N=273)