• Assess respiratory function (lung sounds, dyspnea, oxygen saturation) periodically during therapy.
• Monitor for signs and symptoms of interstitial lung disease (ILD) or pneumonitis (difficulty breathing, shortness or breath, cough with or without mucus, fever) periodically during therapy. Grade 1:If new pulmonary symptoms occur during first 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose; do not escalate to 180 mg if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after first 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib. Grade 2:If new pulmonary symptoms occur during first 7 days of therapy, hold brigatinib until recovery to baseline, then resume at same dose; do not escalate to 180 mg if ILD/pneumonitis is suspected. If new pulmonary symptoms occur after first 7 days of therapy, hold brigatinib until recovery to baseline. If ILD/pneumonitis is suspected, resume at next lower dose; if not, resume at same dose. If ILD/pneumonitis recurs, permanently discontinue brigatinib. Grade 3 or 4:Permanently discontinue brigatinib for ILD/pneumonitis.
• Monitor BP prior to therapy, after 2 wk, and monthly during therapy. Control BP prior to therapy. Monitor blood pressure after 2 wk and at least monthly during therapy. If Grade 3 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) occurs, hold brigatinib until hypertension ≤Grade 1 (SBP <140 mm Hg and DBP <90 mm Hg), then resume brigatinib at next lower dose. If recurrence of Grade 3: withhold therapy until recovery to ≤Grade 1, and resume at next lower dose or permanently discontinue treatment. If Grade 4 hypertension (life-threatening consequences, urgent intervention indicated) occurs, hold brigatinib until ≤Grade 1, and resume at next lower dose or permanently discontinue. Grade 4 recurrence: permanently discontinue brigatinib.
• Monitor for bradycardia (HR <60 bpm) periodically during therapy, especially if concurrent medications decrease HR. If symptomatic bradycardia (dizziness, lightheadedness, fainting) occurs, hold brigatinib until asymptomatic bradycardia or resting heart rate of ≥60 bpm. If concomitant medication known to cause bradycardia is identified and discontinued or dose reduced, resume at same dose once asymptomatic or resting heart rate of ≥60 bpm. If no concomitant medication known to cause bradycardia, or if contributing concomitant medications are not discontinued or dose reduced, resume brigatinib at next lower dose upon recovery to asymptomatic bradycardia or to resting heart rate of ≥60 bpm. If bradycardia with life-threatening consequences or urgent intervention needed, permanently discontinue brigatinib if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or dose reduced, resume therapy at next lower dose when recovered to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm, with frequent monitoring. Grade 4 recurrence: permanently discontinue therapy.
• Treat hypertension before starting therapy. Monitor BP after 2 wks and at least monthly during therapy. If Grade 3 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) occurs, hold brigatinib until hypertension ≤Grade 1 (SBP <140 mmHg and DBP <90 mmHg), then resume therapy at same dose. If hypertension recurs, hold brigatinib until ≤Grade 1; resume at next lower dose or permanently discontinue therapy. If Grade 4 hypertension (life-threatening) occurs, hold brigatinib until ≤Grade 1; resume at next lower dose or permanently discontinue therapy. If Grade 4 hypertension recurs, permanently discontinue brigatinib.
• Monitor for visual changes (blurred vision, diplopia, reduced visual acuity) periodically during therapy. If Grade 2 or 3 visual disturbance occurs, hold doses until recovery to Grade 1 or baseline, then resume at next lower dose. If Grade 4 visual disturbance occurs, discontinue brigatinib permanently.

Lab Test Considerations:

• Verify negative pregnancy before starting therapy.Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.Monitor CK levels periodically during therapy. If Grade 3 CK ↑ (>5× upper limit of normal [ULN]) occurs, hold therapy until ≤Grade 1 (≤2.5× ULN) or to baseline, then resume at same dose. If Grade 4 CK ↑ (>10× ULN) or recurrence of Grade 3 ↑ occurs, hold brigatinib until ≤Grade 1 (≤2.5× ULN) or to baseline, then resume therapy at next lower dose.
  • Monitor serum lipase and amylase periodically during therapy. If Grade 3 lipase or amylase ↑ (>2× ULN) occurs, hold brigatinib until ≤Grade 1 (≤1.5× ULN) or baseline, then resume brigatinib at same dose. If Grade 4 lipase or amylase ↑ (>5× ULN) or recurrence of Grade 3 ↑ occurs, hold brigatinib until ≤Grade 1 (≤ 1.5× ULN) or baseline, then resume therapy at next lower dose.
  • Monitor fasting serum glucose prior to starting and periodically during therapy. May cause new or worsening hyperglycemia. Use antihyperglycemic medications as needed. If Grade 3 (>250 mg/dL) or Grade 4 hyperglycemia occurs, hold brigatinib until adequate hyperglycemic control is achieved and resume at next lower dose or discontinue brigatinib.
  • Monitor AST, ALT, and total bilirubin during therapy, especially during first 3 mo. If Grade 3 or 4 elevation (>5× ULN) of either ALT or AST with bilirubin ≤2× ULN, hold brigatinib until recovery to ≤ Grade 1 (≤ 3x ULN) or to baseline, then resume at next lower dose. If Grade 2 to 4 elevation (>3× ULN) of ALT or AST with concurrent total bilirubin elevation >2× ULN in the absence of cholestasis or hemolysis, permanently discontinue brigatinib.