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A - Regimen Name

BRIG Regimen
brigatinib


Disease Site
Lung - Non-Small Cell

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of adult patients with crizotinib-refractory advanced (ALK)-positive non–small cell lung cancer (NSCLC).

 

 
B - Drug Regimen

ALK-positive status must be based on a validated ALK assay, prior to starting treatment with brigatinib.

Blood pressure should be controlled prior to initiating brigatinib therapy.

brigatinib
90 mg PO Daily on Days 1-7
(This drug is not currently publicly funded for this regimen and intent)

Then,

brigatinib
180 mg PO Daily
(This drug is not currently publicly funded for this regimen and intent)

(Available as 30mg, 90mg and 180mg tablets)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and may be considered.

If therapy is interrupted for ≥14 days due to reasons other than toxicity, resume treatment at 90 mg once daily for 7 days before escalating dose to the previously tolerated dose.

See the interactions section for dosing recommendations when administered with CYP3A4 inhibitors.

Dosage with toxicity

 

Dose Levels

Dose Level Brigatinib Dose (mg/day) Brigatinib Dose (mg/day)
0 90 (first 7 days) 180
-1 60 120
-2 Discontinue 90
-3  N/A 60
-4 N/A Discontinue

Note:

  • Once the dose is reduced for toxicity, do not subsequently escalate the dose.
     

Toxicity Severity Action 
Interstitial Lung Disease (ILD) /Pneumonitis Grade 1

Hold until recovery to baseline; resume at same dose.

(if WITHIN first 7 days: Do not escalate to 180 mg).

If recurs, discontinue.

Grade 2

Hold until recovery to baseline; resume at 1 dose level ↓.

(if WITHIN first 7 days: Do not escalate to 180 mg).

If recurs, discontinue.

≥ Grade 3 Discontinue.
Hypertension Grade 3

Hold until recovery to ≤ grade 1; resume at same dose.

If recurs, hold until recovery to ≤ grade 1; resume at 1 dose level ↓ or discontinue.

Grade 4

Hold until recovery to ≤ grade 1; resume at 1 dose level ↓ or discontinue.

If recurs, discontinue.

Bradycardia (HR < 60 bpm) Symptomatic

Hold until recovery to asymptomatic or resting heart rate ≥ 60 bpm; 

If contributing medication identified and discontinued (or dose-adjusted), resume at same dose.

If no contributing medication identified (or cannot be discontinued or dose-adjusted); resume at 1 dose level ↓.

Life-threatening (urgent intervention indicated)

Hold until recovery to asymptomatic or resting heart rate ≥ 60 bpm; 

If contributing medication identified and discontinued (or dose-adjusted), resume at 1 dose level ↓

If no contributing medication identified; discontinue.

If recurs, discontinue.

Visual Disturbance Grade 2-3 Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.
Grade 4 Discontinue.
Creatine Phosphokinase (CPK) Elevation Grade 3 

Hold until recovery to ≤ grade 1 or baseline; resume at same dose.

Recurrent Grade 3 or grade 4 Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.
Lipase/Amylase Elevation Grade 3  Hold until recovery to ≤ grade 1 or baseline; resume at same dose.
Recurrent Grade 3 or grade 4 Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.
Hyperglycemia ≥ Grade 3 Hold until adequate hyperglycemic control; resume at 1 dose level ↓ or discontinue.
Elevation of
hepatic enzymes
≥ Grade 3 AST/ALT with bilirubin ≤2 × ULN Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.
≥ Grade 2 AST/ALT with bilirubin >2 × ULN in the absence of cholestasis or hemolysis Discontinue.
Other Toxicities Grade 3

Hold until recovery to baseline; resume at same dose.

If recurs; hold until recovery to baseline; resume at 1 dose level ↓ or discontinue.

Grade 4

Hold until recovery to baseline; resume at 1 dose level ↓.

If recurs; hold until recovery to baseline; resume at 1 dose level ↓ or discontinue.



Hepatic Impairment

Hepatic Impairment Brigatinib Dose
Mild No dose adjustment required
Moderate or severe Not recommended (has not been studied)

Renal Impairment

Renal Impairment Brigatinib Dose
Mild or moderate No dose adjustment required
Severe (CrCl <30 mL/min) Not recommended (has not been studied)

Dosage in the Elderly

No dosage adjustment is required.  Increased age was associated with an increased risk of early pulmonary adverse reactions. There are no available data on patients over 85 years of age.

 

Dosage based on Gender and Ethnicity 

No dose adjustment required. Population pharmacokinetic analyses showed that gender and race had no clinically meaningful effect on the pharmacokinetics of brigatinib.

 


 
F - Adverse Effects

Refer to brigatinib drug monograph(s) for additional details of adverse effects.


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • ↑ LFTs
  • ↑CPK (maybe severe)
  • Myelosuppression (mild)
  • Nausea, vomiting
  • ↑ Amylase / lipase 
  • Diarrhea
  • Fatigue
  • Cough, dyspnea
  • Headache
  • Rash, dry skin, pruritus
  • Hypertension (maybe severe)
  • Musculoskeletal pain
  • Anorexia
  • Constipation
  • Peripheral neuropathy
  • Visual disorders
  • Abdominal pain
  • Dizziness
  • Creatinine increased
  • Edema
  • Interstitial lung disease
  • Bradycardia
  • QT interval prolonged
  • Hyperglycemia
  • Abnormal electrolytes
 
G - Interactions

Refer to brigatinib drug monograph(s) for additional details.


  • Avoid co-administration with strong CYP3A4 inhibitors. If combination cannot be avoided, reduce brigatinib dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of strong CYP3A inhibitor, resume brigatinib at dose that was tolerated prior to the initiation of the strong CYP3A inhibitor. Monitor therapy with co-administration of moderate CYP3A4 inhibitors.

  • Avoid co-administration with strong / moderate CYP3A4 inducers.

  • Caution must be exercised with co-administration of CYP3A4 substrates and substrates of pregnane X receptor (PXR) inducible enzymes and transporters, P-gp, BCRP, OCT1, MATE1, and MATE2K.  Drugs with narrow therapeutic indices should be monitored closely for toxicity/efficacy.

  • Avoid to the extent possible co-administration with agents that decrease heart rate.  If concomitant use cannot be avoided, monitor heart rate more frequently.

 
H - Drug Administration and Special Precautions

Refer to brigatinib drug monograph(s) for additional details.


Administration

  • Administer with or without food.

  • Swallow tablets whole; do not crush or chew.

  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
  • If a dose is missed or vomited, do not administer an additional dose; take the next dose at the regularly scheduled time.

  • Store at 20°C to 25°C


Contraindications

  • Patients who have a hypersensitivity to this drug or any of its components.

 

Other Warnings/Precautions

  • Patients with bradycardia (< 60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, congestive heart failure or on medications leading to bradycardia.

  • Patients with a history of ILD or drug-induced pneumonitis were excluded from clinical trial.

  • Brigatinib contains lactose; consider use in patients with lactose intolerance, hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption

  • Caution with driving or using machinery as visual disturbances, dizziness, and fatigue may occur with treatment.

 

Pregnancy and Lactation

  • Brigatinib is not recommended for use in pregnancy.  Effective non-hormonal contraception should be used during treatment and for at least 4 months in females (and for at least 3 months in males) following the final dose.

  • Breastfeeding is not recommended during treatment and for 1 week after the last dose.

  • Based on animal data, fertility in males may be reduced.

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • Heart rate and blood pressure; Baseline, after 2 weeks and at least monthly during treatment. Heart rate should be monitored more frequently in patients, if co-administration with medications known to cause bradycardia cannot be avoided.

  • Lipase, amylase, CPK, fasting serum glucose; Baseline, regularly and as clinically indicated

  • Clinical toxicity assessment for fatigue, visual disturbances, pulmonary, dermatological, GI and musculoskeletal effects; At one week (pulmonary) and at each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription; drug administered by patient or caregiver


 
K - References

Brigatinib drug monograph, Cancer Care Ontario.

Kim D, Tiseo M, Ahn M, et al. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 2017; 35:2490-2498.

May 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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