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FDA Approves ALUNBRIG™ (Brigatinib)

May 03, 2017

FDA Approves ALUNBRIG™ (Brigatinib) for the Treatment of Patients with Anaplastic Lymphoma Kinase-Positive Metastatic Non-Small Cell Lung Cancer who have Progressed on or are Intolerant to Crizotinib

On April 28, 2017, the United States Food and Drug Administration (FDA) approved ALUNBRIG (brigatinib) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approved recommended dosing regimen is 90 mg orally once daily for the first 7 days; if tolerated, increase to 180 mg once daily, with or without food, until disease progression or unacceptable toxicity. Recommendations for safety monitoring and dose modifications of ALUNBRIG for the management of adverse reactions are described in the full prescribing information (link below). Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) of Prigatinib

  • MOA: Brigatinib is a tyrosine kinase inhibitor. In vitro inhibition was observed with ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations.
  • Dose Proportionality: Exhibited dose-proportional increases in systemic exposure over the dose range of 60 to 240 mg (i.e., 0.3 to 1.3 times the approved recommended dosage of 180 mg).
  • Accumulation: The mean accumulation ratio after once daily repeat dosing is 1.9 to 2.4.
  • Absorption: The median time to peak concentration ranged from 1 to 4 hours. A high-fat meal did not affect brigatinib absorption.
  • Plasma Protein Binding: 66% bound (not concentration-dependent) to human plasma proteins in vitro.
  • Elimination: Mean elimination half-life is 25 hours.
  • Metabolism: Primarily metabolized by CYP2C8, CYP3A4, N-demethylation, and conjugation. The active metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro and represents less than 10% of its steady-state AUC.
  • Excretion: A total of 65% of the recovered radio-labeled brigatinib dose was eliminated in the feces (with 41% as unchanged drug) and 25% was eliminated in the urine (with 86% as unchanged drug).

Drug Interaction Potential

  • Avoid concomitant use of strong CYP3A inhibitors during treatment with ALUNBRIG. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG dose by approximately 50% (i.e., from 180 mg to 90 mg or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, resume the ALUNBRIG dose that was taken prior to initiating the strong CYP3A inhibitor. Coadministration of the strong CYP3A inhibitor itraconazole increased brigatinib AUC by 101% and Cmax by 21%.
  • Avoid concomitant use of strong CYP3A inducers during treatment with ALUNBRIG. Coadministration of the strong CYP3A inducer rifampin decreased brigatinib AUC by 80% and Cmax by 60%.
  • Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

Use in Specific Populations

Age, race, sex, body weight, albumin concentration, mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 and up to 1.5 times ULN and any AST), and mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault [C-G]) have no clinically meaningful effect on the pharmacokinetics of brigatinib. The pharmacokinetics and safety of ALUNBRIG in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) and severe renal impairment (CLcr < 30 mL/min [C-G]) have not been studied.

Safety and Efficacy

Clinical effectiveness and safety of brigatinib were demonstrated at the approved recommended dosage in a two-arm (90 mg once daily [Arm A] versus 90 mg for the first 7 days, then 180 mg once daily [Arm B]), open-label, multicenter trial in adult patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib. A higher overall response rate (ORR) was observed in Arm B (53% [95% CI: 43%, 62%]) than Arm A (48% [95% CI: 39%, 58%]). A higher intracranial ORR was observed in patients with brain metastases at baseline in Arm B (67% [95% CI: 41%, 87%]) than Arm A (42% [95% CI: 23%, 63%]).

The most common adverse reactions (≥ 25%) with ALUNBRIG were nausea, diarrhea, fatigue, cough, and headache. The most common serious adverse reactions were pneumonia and ILD/pneumonitis. Dose reductions due to adverse reactions were higher in Arm B than Arm A (20% vs. 7.3%); treatment-emergent adverse events leading to brigatinib discontinuation is relatively low in both Arm A and Arm B (2.8-8.2%).


Full prescribing information is available at https://go.usa.gov/x5m6j.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

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Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This burst was prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.