Alunbrig Drug Information

Generic name: BRIGATINIB

Kinase Inhibitor [EPC]

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Uses of Alunbrig

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.

Dosage & Administration of Alunbrig

Patient Selection

Select patients for the treatment of metastatic NSCLC with ALUNBRIG based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

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.

Dosage Modifications for Adverse Reactions

ALUNBRIG dosage reductions for adverse reactions are summarized in Table 1. Table 1: Recommended ALUNBRIG 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 Interstitial Lung Disease (ILD) /Pneumonitis Hepatotoxicity (Elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) for Strong or Moderate CYP3A Inhibitors Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG. After discontinuation of a strong or moderate CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the CYP3A inhibitor.

Dosage Modifications for Moderate CYP3A Inducers

If coadministration of a moderate CYP3A inducer cannot be avoided, increase the ALUNBRIG once daily dose in 30 mg increments after 7 days of treatment with the current ALUNBRIG dose as tolerated, up to a maximum of twice the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

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

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.
Hypertension [see Warnings and Precautions (5.2) ]	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).
Visual Disturbance [see Warnings and Precautions (5.4) ]	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).
Other	Grade 4	Withhold ALUNBRIG until recovery to baseline and resume at next lower dose (Table 1). Recurrence: Permanently discontinue ALUNBRIG.

Side Effects of Alunbrig

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. The median relative dose intensity was 97% for ALUNBRIG.

Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis ( %), 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. 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 = % (All Grades Per CTCAE version 4.03 ) of Patients by Arm in ALTA 1L N = 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. The most common serious adverse reactions were pneumonia ( 0 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 frequent adverse reactions that led to discontinuation were ILD/pneumonitis % 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). Table 5 and Table 6 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

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
Adverse Reactions	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
Laboratory Abnormality	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

Table 5: Adverse Reactions in ≥10% (All Grades Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 ) 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 (%)
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 Includes abdominal distension, abdominal pain, and epigastric discomfort	17	0	10	0
General Disorders and Administration Site Conditions
Fatigue Includes asthenia and fatigue	29	1.8	36	0
Pyrexia	14	0	6.4	0.9
Respiratory, Thoracic and Mediastinal Disorders
Cough	18	0	34	0
Dyspnea Includes dyspnea and exertional dyspnea	27	2.8	21	1.8 Includes one Grade 5 event
ILD/Pneumonitis	3.7	1.8	9.1	2.7
Hypoxia	0.9	0	2.7	2.7
Nervous System Disorders
Headache Includes headache and sinus headache	28	0	27	0.9
Peripheral Neuropathy Includes peripheral sensory neuropathy and paresthesia	13	0.9	13	1.8
Skin and Subcutaneous Tissue Disorders
Rash Includes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash	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
Myalgia Includes musculoskeletal pain and myalgia	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 Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment	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 Per CTCAE version 4.0 ) 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 (%)
Chemistry
Increased aspartate aminotransferase	38	0.9	65	0
Hyperglycemia Elevated blood insulin was observed in both regimens	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

Warnings & Cautions for Alunbrig

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. 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. 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. Grade 3 bradycardia occurred in 1 patient (0.7%). 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 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.

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.

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.

Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. One patient (0.7%) had a serious adverse reaction of hepatocellular injury.

Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during first 3 months. 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 as described in Table 2. 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.

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 antihyperglycemic 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 as described in Table 1 or permanently discontinuing ALUNBRIG.

Photosensitivity In ALTA 1L, photosensitivity occurred in 3.7% of patients who received ALUNBRIG, with 0.7% Grade 3 to 4. Advise patients to limit sun exposure while taking brigatinib, 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 as described in Table 2.

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. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily), as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.

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.

Drug Interactions with Alunbrig

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. If coadministration of strong or moderate CYP3A inhibitors cannot be avoided, modify dose as recommended. 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.

Pregnancy Safety for Alunbrig

Pregnancy Risk Summary Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of ALUNBRIG in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily).

Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.

Pediatric Use of Alunbrig

Pediatric Use The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.

Clinical Studies of Alunbrig

TKI-naïve Advanced ALK-positive NSCLC (ALTA 1L Study) The efficacy of ALUNBRIG was demonstrated in a randomized (1:1), open-label, multicenter trial (ALTA 1L, NCT02737501) in adult patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. The study required patients to have an ALK rearrangement based on a local standard of care testing. Eligible patients were allowed to have up to 1 prior regimen of chemotherapy in the locally advanced or metastatic setting and were required to have an ECOG Performance Status of 0-2.

Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis were excluded. The major efficacy outcome measure was progression-free survival (PFS) as evaluated by a Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

Additional efficacy outcome measures included confirmed overall response rate (ORR), duration of response (DOR), intracranial ORR, and intracranial DOR as evaluated by BIRC, and overall survival (OS). Of the 275 enrolled patients, 239 had positive results using the companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit; central results were negative for 20 patients and unavailable for 16 patients. Crossover from the crizotinib arm to the ALUNBRIG arm was permitted following disease progression.

Randomization was stratified by CNS metastases (present vs absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no). CNS metastases were present in 35% (n = 96) of patients; 41 of those patients had measurable CNS lesions. ALTA 1L demonstrated a statistically significant improvement in PFS by BIRC.

Efficacy results from this study are described in Table 7 and Figure 1. Table 7: Efficacy Results by B by BIRC in ALTA 1L At the final analysis of overall survival, conducted approximately 3 years after the last patient enrolled, there were 92 deaths (33% of all patients) including 41 deaths on the ALUNBRIG arm and 51 deaths on the crizotinib arm; median OS was not reached on either arm. BIRC assessment of confirmed intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 41 patients with measurable CNS metastases (≥10 mm in longest diameter) at baseline are summarized in Table 8.

Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death. Table 8: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTA 1L Figure 1 ALK-positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib The efficacy of ALUNBRIG was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis ® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test.

Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC).

Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR. Randomization was stratified by CNS metastases (present vs absent) and best prior response to crizotinib (complete or partial response vs any other response/unevaluable). Sixty-four percent of patients had an objective response to prior crizotinib.

The median duration of follow-up was 8 months (range: 0.1 to 20.2). Efficacy results from ALTA are summarized in Table 9.

Table 7: Efficacy Results by BIRC Assessment in ALTA 1L
Efficacy Parameters	ALUNBRIG N = 137	Crizotinib N = 138
CI = Confidence Interval, NE = Not Estimable
Progression-Free Survival
Number of Events, n (%)	63 (46%)	87 (63%)
Median (months) (95% CI)	24.0 (18.5, NE)	11.0 (9.2, 12.9)
Hazard ratio (95% CI)	0.49 (0.35, 0.68)
p-value Stratified by presence of iCNS metastases at baseline and prior chemotherapy for locally advanced or metastatic disease for log-rank test and Cochran Mantel-Haenszel test, respectively	<.0001
Tumor Responses
Confirmed Overall Response Rate, % (95% CI)	74% (66, 81)	62% (53, 70)
p-value	0.0342
Complete Response, % (95% CI)	15% (9, 22)	9% (5, 15)
Partial Response, % (95% CI)	59% (50, 67)	53% (44, 61)
Duration of Response
Number of Confirmed responders	n=101	n=85
Median (months) (95% CI) Based on final analysis data for confirmed responders observed at interim analysis	33.1 (22.0, NE)	13.8 (10.4, 20.8)

Table 8: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTA 1L
Efficacy Parameter	ALUNBRIG (N = 18)	Crizotinib (N = 23)
CI = Confidence Interval; NE = Not Estimable
Confirmed Intracranial Overall Response Rate, (95% CI)	78% (52, 94)	26% (10, 48)
Complete Response, % (95% CI)	28% (10, 53)	0 (0, 15)
Partial Response, % (95% CI)	50% (26, 74)	26% (10, 48)
Duration of Intracranial Response
Number of Confirmed Responders	n = 14	n = 6
Intracranial Response Duration ≥24 months	64%	NE

Table 9: ALTA Efficacy Results
Efficacy Parameter	IRC Assessment		Investigator Assessment
Efficacy Parameter	90 mg once daily (N = 112)	90→180 mg once daily (N = 110)	90 mg once daily (N = 112)	90→180 mg once daily (N = 110)
CI = Confidence Interval; NE = Not Estimable
Overall Response Rate (95% CI)	48% (39,58)	53% (43,62)	45% (35,54)	54% (44,63)
Complete Response, n (%)	4 (3.6%)	5 (4.5%)	1 (0.9%)	4 (3.6%)
Partial Response, n (%)	50 (45%)	53 (48%)	49 (44%)	55 (50%)
Duration of Response, median in months (95% CI)	13.8 (7.4,NE)	13.8 (9.3,NE)	13.8 (5.6,13.8)	11.1 (9.2,13.8)

Table 10: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTA
Efficacy Parameter	IRC Assessment
Efficacy Parameter	90 mg once daily (N = 26)	90→180 mg once daily (N = 18)
CI = Confidence Interval
Intracranial Overall Response Rate, (95 % CI)	42% (23,63)	67% (41,87)
Complete Response, n (%)	2 (7.7%)	0
Partial Response, n (%)	9 (35%)	12 (67%)
Duration of Intracranial Response
Number of Responders	11	12
Intracranial Response Duration ≥6 months	7 (64%)	6 (50%)
Intracranial Response Duration ≥12 months	4 (36%)	3 (25%)

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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