BC Cancer Protocol Summary for First-Line Treatment of ALK-

Positive Advanced Non-Small Cell Lung Cancer (NSCLC) with

Brigatinib
Protocol Code: LUAVBRI

Tumour Group: Lung

Contact Physician: Dr. Barb Melosky

ELIGIBILITY:
Patients must have:
 Stage IIIB or IV non-small cell lung cancer,
 Laboratory confirmed anaplastic lymphoma kinase (ALK)-positive tumour defined as
either IHC 3+, FISH positive, or positive by molecular testing (next-generation
sequencing), and
 No prior systemic therapy

Patients should have:

 ECOG performance status 0 to 2

Notes:
 Patients who are currently on first-line crizotinib (LUAVCRIZF) started prior to 1 Jun
2022 may switch to LUAVBRI if they have not experienced progression and meet
other eligibility criteria
 Patients are eligible to receive one of: brigatinib, alectinib, crizotinib or lorlatinib in
the first-line setting. Switching for intolerance is permitted. Switching after
progression is not funded
 Sequential ALK targeted therapy are not funded after first-line brigatinib

EXCLUSIONS:
Patients must not have:
 Progression during treatment on previous ALK-targeted tyrosine kinase inhibitor

CAUTION:
 Patients with low heart rate at baseline (< 60 bpm), history of syncope or arrhythmia,
sick sinus syndrome, sinoatrial block, atrioventricular block, ischemic heart disease,
or congestive heart failure
 Most pulmonary adverse reactions are observed within the first 7 days of treatment
initiation and usually within the first 24 to 48 hours; if possible, patients should start
treatment early in the week, preferably on a Monday.

BC Cancer Protocol Summary LUAVBRI Page 1 of 5

Activated: 1 Jun 2022 Revised: 1 Oct 2024 (Tests updated)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use
TESTS:
 Baseline: creatinine, alkaline phosphatase, ALT, total bilirubin, LDH, creatine
phosphokinase, lipase, fasting glucose, heart rate, blood pressure
 Baseline, if clinically indicated: ECG, CBC & Diff, sodium, potassium,
magnesium, CEA, C-reactive protein and albumin
 Cycles 1 to 3, every 2 weeks: alkaline phosphatase, ALT, total bilirubin, LDH
 Cycle 4 onward, prior to each visit: alkaline phosphatase, ALT, total bilirubin,
LDH, creatine phosphokinase, lipase, heart rate, blood pressure
 If clinically indicated: CBC & Diff, sodium, potassium, magnesium, CEA, fasting
glucose, creatinine; chest X-ray, ECG, CT chest

PREMEDICATIONS:
 no premedications needed

TREATMENT:

BC Cancer Administration
Drug Dose
Guideline

180 mg once daily

brigatinib PO
Starting dose = 90 mg PO once daily
for 7 days; if tolerated†, increase to
180 mg PO once daily thereafter

† Prescriber to assess patient

For treatment interruptions of 14 days or longer (for reasons other than adverse
reactions), resume treatment at the starting dose of 90 mg PO once daily for 7 days
before increasing to the previously tolerated dose

Dose reduction:
Dose level -1: 120 mg once daily
Dose level -2: 90 mg once daily
Dose level -3: 60 mg once daily
Permanently discontinue treatment if patients are unable to tolerate 60 mg PO once
daily dosing.

 Careful re-evaluation after initiation of therapy is essential as brigatinib should be

continued only if tumour regression continues or the disease is stable and cancer-
related symptoms have improved. Continued brigatinib for “psychological” palliation
in the face of progressive disease is inappropriate.
BC Cancer Protocol Summary LUAVBRI Page 2 of 5
Activated: 1 Jun 2022 Revised: 1 Oct 2024 (Tests updated)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use
DOSE MODICATIONS:
1. Hepatic Dysfunction:

Severe hepatic impairment

(Child-Pugh class C) Reduce one dose level

Withhold until recovery of ALT to ≤ 3.0

ALT elevation to > 5.0 x ULN with
x ULN or baseline, then resume at the
bilirubin ≤ 2 x ULN
next lower dose level

ALT elevation to > 3.0 x ULN and

concurrent bilirubin elevation to > 2
Permanently discontinue
x ULN in the absence of
cholestasis or hemolysis

2. Renal dysfunction: if severe renal impairment (CrCl < 30 mL/min), reduce starting
brigatinib dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to
60 mg).

3. Interstitial Lung Disease (ILD)/Pneumonitis: for development of grade 1 or 2

ILD/pneumonitis, withhold brigatinib until recovery to baseline; dose reduction may
be required once treatment resumes. Permanently discontinue brigatinib for
development of Grade 3 or 4 ILD/pneumonitis or for recurrence of ILD/pneumonitis.

4. Hypertension: for severe hypertension, brigatinib should be withheld until recovery

to Grade 1 or to baseline. Dose modification may be required when treatment
resumes.

5. Bradycardia: for symptomatic, non-life threatening bradycardia, withhold treatment

until asymptomatic or heart rate increases to > 60 bpm. Dose modification may be
required when treatment resumes.

6. Visual disturbances: withhold brigatinib in patients with new or worsening visual

symptoms of Grade 2 or greater severity. Dose reduction is recommended upon
recovery to Grade 1 or baseline. Permanently discontinue treatment for development
of Grade 4 visual disturbances.

BC Cancer Protocol Summary LUAVBRI Page 3 of 5

Activated: 1 Jun 2022 Revised: 1 Oct 2024 (Tests updated)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use
7. Creatine phosphokinase:
Withhold brigatinib until recovery to
Grade ≤ 1 (≤ 2.5 x ULN) or baseline,
then resume at prior dose.
Grade 3 or 4 elevation (> 5 x ULN)
with Grade ≥ 2 muscle pain or Recurrence: withhold brigatinib until
weakness recovery to Grade ≤ 1 (≤ 2.5 x ULN) or
baseline, then resume at next lower
dose.

8. Pancreatic Enzymes Lipase/Amylase:

Withhold brigatinib until recovery to
Grade ≤ 1 (≤ 1.5 x ULN) or baseline, then
Grade 3 elevation (> 2 x ULN) resume at prior dose.

Recurrence: withhold brigatinib until

recovery to Grade ≤ 1 (≤ 1.5 x ULN) or
baseline, then resume at next lower dose.
Grade 4 elevation (> 5 x ULN) Withhold brigatinib until recovery to
Grade ≤ 1 (≤ 1.5 x ULN) or baseline, then
resume at next lower dose.

9. Hyperglycemia: if adequate hyperglycemic control cannot be achieved with optimal

medical management, withhold brigatinib. Upon recovery, resume treatment at the
next lower dose. Permanent treatment discontinuation may be required.

10. Drug interactions – CYP 3A4 inhibitors: brigatinib is a substrate of CYP 3A4. The
concomitant use of moderate or strong CYP 3A4 inhibitors should be avoided. If
concomitant use of moderate CYP 3A4 inhibitors cannot be avoided, reduce
brigatinib dose by one dose level. If concomitant use of strong CYP 3A4 inhibitors
cannot be avoided, reduce brigatinib dose by approximately 50%, from 180 mg to 90
mg, or from 90 mg to 60 mg. After discontinuation of the moderate or strong
inhibitor, brigatinib may resumed at the prior dose.

11. Drug interactions – CYP 3A4 inducers: brigatinib is a substrate of CYP 3A4. The
concomitant use of moderate or strong CYP 3A4 inducers should be avoided. If
concomitant use of moderate CYP 3A4 inducers cannot be avoided, brigatinib dose
increase is recommended. Increase dose in 30 mg increments after 7 days of
treatment at the current dose as tolerated, up to a maximum of twice the brigatinib
dose that was tolerated prior to initiating the inducer. After discontinuation of the
inducer, brigatinib may be resumed at the prior dose.

BC Cancer Protocol Summary LUAVBRI Page 4 of 5

Activated: 1 Jun 2022 Revised: 1 Oct 2024 (Tests updated)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use
PRECAUTIONS:
1. Respiratory: Pulmonary adverse reactions have been reported, including severe,
life-threatening, and fatal reactions and those with features consistent with
ILD/pneumonitis. The etiology of pulmonary reactions is not known. Increased age
and recent prior treatment with crizotinib (within 7 days) may be independent risk
factors. Most reactions are observed within the first 7 days of treatment initiation and
usually within the first 24-48 hours. Reactions have also been reported when
treatment was resumed following dose interruption. Therefore, monitoring for new or
worsening respiratory symptoms during these periods is important. Pneumonitis can
also occur later in treatment (median onset of 150 days). Any evidence of
pneumonitis should be promptly investigated.
2. Bradycardia: Bradycardia, sinus bradycardia, and prolongation of the PR interval
has occurred in patients treated with brigatinib. Heart rate and blood pressure
should be monitored regularly. Use caution in patients with a low heart rate at
baseline (< 60 bpm), a history of syncope or arrhythmia, sick sinus syndrome,
sinoatrial block, atrioventricular block, ischemic heart disease, or congestive heart
failure. Concomitant medications that decrease heart rate or prolong PR interval
should be avoided to the extent possible.
3. Hypertension: Hypertension, including grade 3 hypertension and hypertensive
retinopathy, have been reported. Ensure blood pressure is controlled prior to
treatment and monitor blood pressure regularly during treatment. Hypertension
should be treated according to standard guidelines to control blood pressure. Dose
interruption and/or reduction may be required for severe hypertension.
4. Musculoskelatal: Elevations in creatine phosphokinase have occurred in up to 75%
of patients and should be monitored regularly. Median time to onset is 27 days.
Patients should be advised to report any unexplained muscle pain, tenderness, or
weakness.
5. Visual Disturbances: Visual disturbances such as blurred vision, photophobia,
photopsia, diplopia, and reduced visual acuity may occur. Severe reactions such as
grade 3 macular edema and cataract have been reported. Obtain an ophthalmologic
evaluation in patients with new or worsening visual symptoms of grade 2 or greater
severity. Ability to drive or operate machinery may be compromised.
6. Photosensitivity: Photosensitivity to sunlight has been reported, although severe
reactions are not common. To prevent reactions, patients should avoid prolonged
sun exposure during treatment with brigatinib and for 5 days after the last dose. Use
of broad spectrum UVA/UVB sunscreen and lip protection with at least SPF 30 are
recommended.

Call Dr. Barb Melosky or tumour group delegate at (604) 877-6000 or 1-800-663-
3333 with any problems or questions regarding this treatment program.

References:
1. Takeda Canada Inc. Brigatinib (ALUNBRIG®) product monograph. Toronto, Ontario; 2 March 2021.
2. Cambridge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib for ALK-positive non-small cell
lung cancer. N Engl J Med 370: 21; 2018.

BC Cancer Protocol Summary LUAVBRI Page 5 of 5

Activated: 1 Jun 2022 Revised: 1 Oct 2024 (Tests updated)
Warning: The information contained in these documents are a statement of consensus of BC Cancer professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to
apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these documents is at
your own risk and is subject to BC Cancer's terms of use available at www.bccancer.bc.ca/terms-of-use