Alunbrig
- Generic Name: brigatinib tablets
- Brand Name: Alunbrig
- Drug Class: Antineoplastics, Anaplastic Lymphoma Kinase Inhibitors
Patient Information
No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.
Description
Brigatinib is a kinase inhibitor. The chemical name for brigatinib is 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine. The molecular formula is C29H39ClN7O2P which corresponds to a formula weight of 584.10 g/mol. Brigatinib has no chiral centers. The chemical structure is shown below:
 |
Brigatinib is an off-white to beige/tan solid. The pKas were determined to be: 1.73 ± 0.02 (base), 3.65 ± 0.01 (base), 4.72 ± 0.01 (base), and 8.04 ± 0.01 (base).
ALUNBRIG is supplied for oral use as film-coated tablets containing 30 mg or 90 mg of brigatinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate, and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.
Indications
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].
Dosage And Administration
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].
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 Dosage Reductions
| Dosage | Dosage Reduction | ||
| First | Second | Third | |
| 90 mg once daily | 60 mg once daily | permanently discontinue | N/A* |
| 180 mg once daily | 120 mg once daily | 90 mg once daily | 60 mg once daily |
| * Not applicable | |||
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* | Dosage Modifications |
| Interstitial Lung Disease (ILD) /Pneumonitis [see WARNINGS AND PRECAUTIONS] | Grade 1 |
|
| Grade 2 |
|
|
| Grade 3 or 4 | Permanently discontinue ALUNBRIG for ILD/pneumonitis. | |
| Hypertension [see WARNINGS AND PRECAUTIONS] | 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) |
|
| Grade 4 hypertension (life-threatening consequences, urgent intervention indicated) |
|
|
| Bradycardia (HR less than 60 bpm) [see WARNINGS AND PRECAUTIONS] | Symptomatic bradycardia |
|
| Bradycardia with life-threatening consequences, urgent intervention indicated |
|
|
| Visual Disturbance [see WARNINGS AND PRECAUTIONS] | 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 | Grade 3 or 4 CPK elevation (greater than 5 × ULN) with Grade 2 or higher muscle pain or weakness |
|
| Lipase/Amylase Elevation [see WARNINGS AND PRECAUTIONS] | Grade 3 lipase or amylase elevation (greater than 2 × ULN) |
|
| 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). | |
| Hyperglycemia [see WARNINGS AND PRECAUTIONS] | 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 |
|
| Grade 4 |
|
|
| bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal * Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4). |
||
Dosage Modifications For Strong Or Moderate CYP3A Inhibitors
Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approxiimately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). 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
Avoid coadministration of moderate CYP3A inducers during treatment with ALUNBRIG [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. 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.
After discontinuation of a moderate CYP3A inducer, resume the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.
Dosage Modifications For Patients With Severe Hepatic Impairment
Reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh C) [see Use In Specific Populations, CLINICAL PHARMACOLOGY].
Dosage Modifications For Patients With Severe Renal lmpairment
Reduce the ALUNBRIG once daily dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min by Cockcroft-Gault] [see Use In Specific Populations, CLINICAL PHARMACOLOGY].
How Supplied
Dosage Forms And Strengths
- 180 mg: oval, white to off-white film-coated tablets with “U13” debossed on one side and plain on the other side
- 90 mg: oval, white to off-white film-coated tablets with “U7” debossed on one side and plain on the other side
- 30 mg: round, white to off-white film-coated tablets with “U3” debossed on one side and plain on the other side
Storage And Handling
180 mg tablets: oval, white to off-white film-coated tablets with “U13” debossed on one side and plain on the other side; available in:
| Bottle of 23 tablets | NDC 63020-180-23 |
| Bottle of 30 tablets | NDC 63020-180-30 |
90 mg tablets: oval, white to off-white film-coated tablets with “U7” debossed on one side and plain on the other side; available in:
| Bottle of 7 tablets | NDC 63020-090-07 |
| Bottle of 30 tablets | NDC 63020-090-30 |
30 mg tablets: round, white to off-white film-coated tablets with “U3” debossed on one side and plain on the other side; available in:
| Bottle of 30 tablets | NDC 63020-113-30 |
90 mg / 7 count tablets (NDC 63020-090-07) and 180 mg / 23 count tablets (NDC 63020-180-23) are also available in a single carton as a one-month initiation pack:
| One carton containing one bottle of 90 mg tablets (7 count) and one bottle of 180 mg tablets (23 count) | NDC 63020-198-30 |
Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) (see USP).
Manufactured for: Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139-4234. Revised: May 2020
Side Effects
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]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Bradycardia [see WARNINGS AND PRECAUTIONS]
- Visual Disturbance [see WARNINGS AND PRECAUTIONS]
- Creatine Phosphokinase (CPK) Elevation [see WARNINGS AND PRECAUTIONS]
- Pancreatic Enzymes Elevation [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Hyperglycemia [see WARNINGS AND PRECAUTIONS]
- Photosensitivity [see WARNINGS AND PRECAUTIONS]
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]. 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].
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 |
||
| 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† | 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 | 22° | 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 Þ | 32 | 13 | 8 | 2.9 |
| General Disorders and Administration Site Conditions | ||||
| Fatigueβ | 32 | 1.5 | 40 | 2.2 |
| Edemaa | 18 | 0.7 | 48 | 0.7 |
| Pyrexia | 15 | 0.7 | 15 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Myalgiae | 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 | ||||
| Headacheð | 22 | 2.2 | 17 | 0 |
| Dizziness | 15 | 0.7 | 20 | 0.7 |
| Peripheral neuropathyø | 11 | 0.7 | 18 | 0 |
| Dysgeusia | 2.9 | 0 | 14 | 0 |
| Investigations | ||||
| Increased Blood cholesterolý | 13 | 0 | 0.7 | 0 |
| Cardiac Disorders | ||||
| Bradycardia£ | 12 | 0.7 | 23 | 0 |
| Infections and Infestations | ||||
| Pneumonia¥ | 15° | 5.1 | 6.6° | 2.9 |
| Upper respiratory tract infectionOE | 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 Disturbanceoe | 7.4 | 0 | 53 | 0.7 |
| * 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 hypertension and systolic hypertension β Includes asthenia and fatigue a Includes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face e Includes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia ð Includes headache and migraine ø Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy ý Includes blood cholesterol increased, hypercholesterolaemia £ Includes bradycardia, heart rate decreased, sinus bradycardia ¥ Includes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia OE Includes upper respiratory tract infection and viral upper respiratory tract infection oe Includes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters Ð Includes Grade 5 events |
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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** |
||
| 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† | 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 |
| * 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 |
||||
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 ALKpositive 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].
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 |
||
| 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† | 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 Neuropathy# | 13 | 0.9 | 13 | 1.8 |
| Skin and Subcutaneous Tissue Disorders | ||||
| RashÞ | 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 |
| Myalgiaβ | 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 Disturbancea | 7.3 | 0 | 10 | 0.9 |
| Infections | ||||
| Pneumonia | 4.6 | 2.8e | 10 | 5.5e |
| Psychiatric Disorders | ||||
| Insomnia | 11 | 0 | 7.3 | 0 |
| * 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 headache and sinus headache # Includes peripheral sensory neuropathy and paresthesia Þ Includes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash β Includes musculoskeletal pain and myalgia a Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment e Includes one Grade 5 event |
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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 |
||
| All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
| 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 |
| * Per CTCAE version 4.0 † Elevated blood insulin was observed in both regimens |
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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%).
Drug Interactions
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]. 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].
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]. 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].
Warnings
Included as part of the PRECAUTIONS section.
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 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, ADVERSE REACTIONS].
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, ADVERSE REACTIONS].
Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia [see WARNINGS AND PRECAUTIONS].
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].
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].
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, ADVERSE REACTIONS].
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, ADVERSE REACTIONS].
Pancreatic Enzymes Elevation
In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients. 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 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 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 90→180 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 90→180 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 as described in Table 2 [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
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. 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 90→180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90→180 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 90→180 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 90→180 mg group.
Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during 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 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 [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
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 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 [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
Photosensitivity
In ALTA 1L, photosensitivity occurred in 3.7% of patients who received ALUNBRIG, with 0.7% Grade 3 to 4.
In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group experienced photosensitivity and 0.9% of patients in the 90 mg→180 mg group. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90→180 mg group.
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 [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
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 [see Use In Specific Populations, CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Interstitial Lung Disease (ILD)/Pneumonitis
Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms [see WARNINGS AND PRECAUTIONS].
Hypertension
Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension [see WARNINGS AND PRECAUTIONS].
Bradycardia
Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications [see WARNINGS AND PRECAUTIONS].
Visual Disturbance
Advise patients to inform their healthcare provider of any new or worsening vision symptoms [see WARNINGS AND PRECAUTIONS].
Creatine Phosphokinase (CPK) Elevation
Inform patients of the signs and symptoms of creatine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms [see WARNINGS AND PRECAUTIONS].
Pancreatic Enzymes Elevation
Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment [see WARNINGS AND PRECAUTIONS].
Hepatotoxicity
Inform patients of the signs and symptoms of hepatotoxicity, and the need to monitor for aspartate aminotransferase (AST), alanine animotransferase (ALT) and total bilirubin elevations during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms [see WARNINGS AND PRECAUTIONS].
Hyperglycemia
Inform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment with ALUNBRIG [see WARNINGS AND PRECAUTIONS].
Photosensitivity
Inform patients of the signs and symptoms of photosensitivity. Advise patients to limit sun exposure while taking ALUNBRIG and for at least 5 days after the final dose. Advise patients to wear a hat, protective clothing, and to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to protect against sunburn [see WARNINGS AND PRECAUTIONS].
Females And Males Of Reproductive Potential
Embryo-Fetal Toxicity
Advise females and males of reproductive potential that ALUNBRIG can cause fetal harm [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
- Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose [see Use In Specific Populations].
- 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 [see Use In Specific Populations].
Lactation
Advise females not to breastfeed during treatment with ALUNBRIG and for at least 1 week following the final dose [see Use In Specific Populations].
Infertility
Advise males of reproductive potential of the potential for reduced fertility from ALUNBRIG [see Use In Specific Populations, Nonclinical Toxicology].
Drug Interactions
Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking ALUNBRIG [see DRUG INTERACTIONS].
Dosing And Administration
Instruct patients to start with 90 mg of ALUNBRIG once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take ALUNBRIG with or without food [see DOSAGE AND ADMINISTRATION].
Missed Dose
Advise patients that if a dose of ALUNBRIG is missed or if the patient vomits after taking a dose of ALUNBRIG, not to take an extra dose, but to take the next dose at the regular time [see DOSAGE AND ADMINISTRATION].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been performed with brigatinib.
Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.
Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2 month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.
Use In Specific Populations
Pregnancy
Risk Summary
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. 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 2% to 4% and 15% to 20%, 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.
Lactation
Risk Summary
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 for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.
Females And Males Of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG [see Use In Specific Populations].
Contraception
ALUNBRIG can cause fetal harm [see Use In Specific Populations].
Females
Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months after the final dose.
Males
Because of the potential for genotoxicity, 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 [see Nonclinical Toxicology].
Infertility
Based on findings in male reproductive organs in animals, ALUNBRIG may cause reduced fertility in males [see Nonclinical Toxicology].
Pediatric Use
The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.
Geriatric Use
Of the 359 patients enrolled in the ALTA 1L ALUNBRIG arm and in ALTA, 26.7% were 65 and older and 7.5% were 75 and older. No overall differences in safety or effectiveness were observed between patients ≥65 years and younger patients.
Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). Reduce the dose of ALUNBRIG for patients with severe hepatic impairment (Child-Pugh C) [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Renal Impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min by Cockcroft-Gault]. Reduce the dose of ALUNBRIG for patients with severe renal impairment (CLcr 15 to 29 mL/min) [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Overdose
No information provided.
Contraindications
None.
Clinical Pharmacology
Mechanism Of Action
Brigatinib is a tyrosine kinase inhibitor (TKI) with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK½, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At clinically achievable concentrations (≤500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.
Pharmacodynamics
Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
Cardiac Electrophysiology
The QT interval prolongation potential of ALUNBRIG was assessed in 123 patients following once daily ALUNBRIG doses of 30 mg (0.16 times the recommended dose of 180 mg) to 240 mg (1.3 times the recommended dose of 180 mg). ALUNBRIG did not prolong the QT interval to a clinically relevant extent.
Pharmacokinetics
The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at ALUNBRIG doses of 90 mg and 180 mg once daily was 552 (49%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (45%) ng•h/mL and 20276 (62%) ng•h/mL. After a single dose and multiple dosing of ALUNBRIG, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the recommended dose of 180 mg) to 240 mg (1.3 times the recommended dose of 180 mg) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
Absorption
Following administration of single oral doses of ALUNBRIG of 30 mg to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect Of Food
Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.
Distribution
Brigatinib is 91% bound to human plasma proteins and the binding is not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 307 L.
Elimination
Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 8.9 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism
Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) was the major circulating radioactive component.
Excretion
Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
Specific Populations
Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.
Patients With Hepatic Impairment
Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 37% higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. Unbound brigatinib systemic exposure (AUC0-INF) was similar between subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function [see DOSAGE AND ADMINISTRATION].
Patients with Renal Impairment
Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 86% higher in subjects with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min] compared to subjects with normal renal function.
Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to 89 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to 59 mL/min) and 270 subjects with normal renal function (CLcr ≥90 mL/min) [see DOSAGE AND ADMINISTRATION].
Drug Interaction Studies
Clinical Studies
Effect Of Strong And Moderate CYP3A Inhibitors On Brigatinib
Coadministration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of ALUNBRIG administered alone [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]. A moderate CYP3A inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Effect Of Strong CYP2C8 Inhibitors On Brigatinib
Coadministration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of ALUNBRIG decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of ALUNBRIG administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.
Effect Of Strong And Moderate CYP3A Inducers On Brigatinib
Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of ALUNBRIG decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of ALUNBRIG administered alone [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]. A moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Effect Of Brigatinib On CYP3A Substrates
Coadministration of 180 mg daily doses of ALUNBRIG with a single 3 mg oral dose of midazolam (a sensitive CYP3A substrate) decreased midazolam Cmax by 16% and AUC0-INF by 26%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib is considered a weak inducer of CYP3A.
In Vitro Studies
Effect Of Brigatinib On CYP Enzymes
Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.
Brigatinib did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.
Effect Of P-glycoprotein And BCRP Inhibitors On Brigatinib
Brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.
Effect Of Other Transporters On Brigatinib
Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).
Effect Of Brigatinib On Transporters
Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.
Clinical Studies
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).
A total of 275 patients were randomized to receive ALUNBRIG 180 mg orally once daily with a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib 250 mg orally twice daily (n = 138). 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).
Baseline demographic characteristics of the overall study population were: median age 59 years (range: 27 to 89, 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS 0 and 56% ECOG PS 1, and 58% never smokers. The disease characteristics of the overall study population were: 93% with Stage IV disease; 27% received chemotherapy in the locally advanced or metastatic setting; 14% had received CNS radiation; 31% had bone metastases; and 20% had liver metastases. 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 BIRC Assessment in ALTA 1L
| Efficacy Parameters | ALUNBRIG N = 137 |
Crizotinib N = 138 |
| 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* | <.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) † | 33.1 (22.0, NE) | 13.8 (10.4, 20.8) |
| CI = Confidence Interval, NE = Not Estimable * 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 † Based on final analysis data for confirmed responders observed at interim analysis |
||
Figure 1: Kaplan-Meier Plot of Progression-Free Survival 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
| Efficacy Parameter | ALUNBRIG (N = 18) |
Crizotinib (N = 23) |
| 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 |
| CI = Confidence Interval; NE = Not Estimable | ||
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. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. 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.
A total of 222 patients were randomized to receive ALUNBRIG either 90 mg once daily (90 mg arm; n = 112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90→180 mg arm; n = 110). Randomization was stratified by CNS metastases (present vs absent) and best prior response to crizotinib (complete or partial response vs any other response/unevaluable).
Baseline demographic characteristics of the overall study population were: median age 54 years (range: 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, CNS metastases in 69% (61% had received prior CNS radiation), bone metastases in 39%, and liver metastases in 26% of patients. 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 9: ALTA Efficacy Results
| Efficacy Parameter | IRC Assessment | Investigator Assessment | ||
| 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) |
|
| 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) |
| CI = Confidence Interval; NE = Not Estimable | ||||
IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable CNS metastases (≥10 mm in longest diameter) at baseline are summarized in Table 10. 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 10: Intracranial Overall Response in Patients with Measurable CNS Metastases in ALTA
| Efficacy Parameter | IRC Assessment | |
| 90 mg once daily (N = 26) |
90→180 mg once daily (N = 18) |
|
| 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%) |
| CI = Confidence Interval | ||