Safety

Safety and Tolerability Studied in 219 Treated ALK+ NSCLC Patients

Serious adverse events occurred in 38% of patients in the 90-mg arm and 40% of patients in the 90180-mg arm. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90-mg arm, and 7.3% in the 90180-mg arm) and interstitial lung disease (ILD)/pneumonitis (4.6% overall, 1.8% in the 90-mg arm and 7.3% in the 90180-mg arm)
- Fatal adverse reactions occurred in 3.7% of patients, consisting of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, and urosepsis (1 patient each)
Most common adverse reactions (≥25% of any grade) in the 90-mg arm were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90180-mg arm were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%)
Median duration of treatment was 7.5 and 7.8 months in the 90-mg arm and 90180-mg arm, respectively

Discontinuation Rates

In ALTA, permanent discontinuation of ALUNBRIG^® (brigatinib) due to adverse reactions occurred in 2.8% of patients in the 90-mg arm and 8.2% of patients in the 90180-mg arm
The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90-mg arm and 1.8% in the 90180-mg arm) and pneumonia (1.8% in the 90180-mg arm only)

Dose Modifications

14% of patients required a dose reduction due to adverse reactions (7.3% in the 90-mg arm and 20% in the 90180-mg arm)
The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (CPK) for both regimens (1.8% in the 90-mg arm and 4.5% in the 90180-mg arm)

Adverse Reactions in ≥10% (All Grades)^a or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Adverse Reactions	90 mg once daily (n=109)		90180 mg once daily (n=110)
Adverse Reactions	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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^b	17	0	10	0
General Disorders and Administration Site Conditions
Fatigue^c	29	1.8	36	0
Pyrexia	14	0	6.4	0.9
Respiratory, Thoracic, and Mediastinal Disorders
Cough	18	0	34	0
Dyspnea^d	27	2.8	21	1.8^e
ILD/Pneumonitis	3.7	1.8	9.1	2.7
Hypoxia	0.9	0	2.7	2.7
Nervous System Disorders
Headache^f	28	0	27	0.9
Peripheral neuropathy^g	13	0.9	13	1.8
Skin and Subcutaneous Tissue Disorders
Rash^h	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
Myalgiaⁱ	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 disturbance^j	7.3	0	10	0.9
Infections
Pneumonia	4.6	2.8^e	10	5.5^e
Psychiatric Disorders
Insomnia	11	0	7.3	0

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4.0).
^bIncludes abdominal distension, abdominal pain, and epigastric discomfort.
^cIncludes asthenia and fatigue.
^dIncludes dyspnea and exertional dyspnea.
^eIncludes one Grade 5 event.
^fIncludes headache and sinus headache.

^gIncludes peripheral sensory neuropathy and paresthesia.
^hIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash.
ⁱIncludes musculoskeletal pain and myalgia.
^jIncludes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment.

Laboratory Abnormalities With Incidence of ≥20% (All Grades)^a of Patients by Dose Group in ALTA (N=219)

Laboratory Abnormality	90 mg once daily (n=109)		90180 mg once daily (n=110)
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Chemistry
Increased aspartate aminotransferase	38	0.9	65	0
Hyperglycemia^b	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

^aPer NCI CTCAE v4.0.
^bElevated blood insulin was also observed in both regimens.

ILD/Pneumonitis

Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG
In ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90-mg arm and 9.1% of patients in the 90180-mg arm

Early in Treatment

In ALTA, 6.4% (14 of 219 treated patients) experienced reactions consistent with possible ILD within 9 days of initiation of ALUNBRIG (median onset was 2 days). None occurred after escalation to 180 mg, and 7 of the 14 patients were successfully re-treated with ALUNBRIG¹
2.7% of patients had Grade 3-4 events within the first 9 days of treatment

Recommendations for Management

Monitor for new or worsening respiratory symptoms (eg, dyspnea, cough, etc), particularly in the first week of initiating treatment with ALUNBRIG
Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia)
For Grade 1-2 adverse reactions, either resume ALUNBRIG with dose reduction as recommended 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

Indication

ALUNBRIG^® (brigatinib) is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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 Trial ALTA (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 early (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 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, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG 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 severity, resume ALUNBRIG at a reduced 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: Bradycardia can occur with ALUNBRIG. 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. 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. 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, 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, creatine phosphokinase (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 3‑4 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% 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. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: 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.

Hyperglycemia: 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 or permanently discontinuing ALUNBRIG.

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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal 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

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90180 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 90180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90180 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).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

Drug Interactions

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

Use in Specific Populations

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.
Females and Males of Reproductive Potential:
Contraception: Advise females of reproductive potential to use effective non-hormonal 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.
Infertility: ALUNBRIG may cause reduced fertility in males.
Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.
Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects directly to Takeda Oncology at 1-844-A1POINT (1-844-217-6468) or GlobalOncologyMedInfo@takeda.com.

Please see full Prescribing Information.

Reference: 1. Kim D-W, Tiseo M, Ahn M-J, et al. J Clin Oncol. 2017;35(22):2490-2498.

Safety

Safety and Tolerability Studied in 219 Treated ALK+ NSCLC Patients

Discontinuation Rates

Dose Modifications

Adverse Reactions in ≥10% (All Grades)^a or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Adverse Reactions

Laboratory Abnormalities With Incidence of ≥20% (All Grades)^a of Patients by Dose Group in ALTA (N=219)

Laboratory Abnormality

ILD/Pneumonitis

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Safety and Tolerability Studied in 219 Treated ALK+ NSCLC Patients

Discontinuation Rates

Dose Modifications

Adverse Reactions in ≥10% (All Grades)a or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Adverse Reactions

Laboratory Abnormalities With Incidence of ≥20% (All Grades)a of Patients by Dose Group in ALTA (N=219)

Laboratory Abnormality

ILD/Pneumonitis

Adverse Reactions in ≥10% (All Grades)^a or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Laboratory Abnormalities With Incidence of ≥20% (All Grades)^a of Patients by Dose Group in ALTA (N=219)