1. Mann, Janelle E. PharmD, BCOP

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What is brigatinib?

Brigatinib is a broad spectrum multikinase inhibitor with activity against anaplastic lymphoma kinase (ALK), ROS1, insulin-like growth factor-1 receptor (IGF-1R), FLT-3, and selected EGFR deletion and point mutations. It has shown anti-tumor activity against EML4-ALK mutant forms in non-small cell lung cancer (NSCLC) cells.


How does brigatinib work?

Brigatinib works by inhibiting autophosphorylation of ALK and ALK-mediated phosphorylation of downstream signaling proteins STAT3, AKT, ERK1/2, and S6. It also has activity against cells expressing EML4-ALK and 17 mutant forms that are associated with ALK inhibitor resistance in NSCLC. Early data indicate ALK G1202R and ALK E1210K as possible mechanisms of clinical resistance to brigatinib.


What is this approved for?

Brigatinib is indicated for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approval was granted under an accelerated approval based on tumor response rate and duration of response.


What is the basis for this approval?

Brigatinib was evaluated in a randomized, multicenter, phase II trial for patients with metastatic ALK-positive NSCLC after progression on crizotinib. Two hundred and twenty two patients were randomized to brigatnib 90 mg daily or 180 mg daily (with a 7-day 90 mg daily lead-in) and followed for a median of 8 months. The objective response rate (ORR) was 48 percent and 53 percent, respectively. Patients with measurable brain metastases at baseline had an intracranial ORR of 42 percent and 67 percent, respectively. The median duration of response in both arms was 13.8 months (J Clin Oncol 2017;35:2490-2498).


How do you administer this drug?

The recommended dosing regimen for brigatinib is 90 mg by mouth daily for the first 7 days then, if tolerated, increase to 180 mg by mouth once daily and continue until disease progression or toxicity. Doses may be administered with or without food.


Are there any premedications needed for brigatinib?

Standard premedication is not indicated; however, given the toxicity profile, use of antiemetics for breakthrough nausea/vomiting may be warranted.


What are the common side effects associated with brigatinib (> or =10%)?

The following were common side effects of brigatinib at the approved dosing strategy (all grades):


* Nausea (40%)


* Diarrhea (38%)


* Fatigue (30%)


* Cough (34%)


* Headache (27%)


* Increased amylase/lipase (27%/21%)


* Increased creatinine phosphokinase (27%)


* Increased blood glucose (43%)



What are the uncommon side effects associated with brigatinib (less than 10%)?

Brigatinib at the approved dosing strategy is associated with following toxicities:


* Hypertension (6%)


* Bradycardia (7.6%)


* Pneumonia (5%)


* Interstitial lung disease/pneumonitis (9.1%)


* Visual disturbances (7.3%)



Are there any important drug interactions I should be aware of?

Briagtinib is a major substrate of CYP3A4; therefore, concomitant use with CYP3A strong inducers or inhibitors should be avoided. If concomitant use with CYP3A strong cannot be avoided, reduce the brigatinib dose by approximately 50 percent.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no necessary dose adjustments in the setting of pre-existing renal or hepatic insufficiency. Safety has not been evaluated in patients with moderate or severe hepatic impairment or severe renal impairment.


Practical tips


* If treatment is interrupted for greater than 14 days due to reasons other than toxicity, resume brigatinib at 90 mg daily for 7 days before increasing to the previously tolerated dose.


* Early onset pulmonary adverse effects have been observed and may be associated with older age and shorter interval (< 7 days) between last dose of crizotinib therapy and start of brigatinib.


What should my patients know about brigatinib?

Women of childbearing potential should be on non-hormonal contraception during treatment and for at least 4 months after the final dose of brigatinib. Males should use effective contraceptive treatment during treatment and for at least 3 months after discontinuation of brigatinib.


What else should I know about brigatinib?


* Brigatinib was approved under accelerated approval based on tumor response rate and duration of response. Confirmatory trials are needed for verification and description of clinical benefit in order for continued FDA approval.


* Monitoring for new or worsening respiratory symptoms, hypertension, bradycardia, visual symptoms, and elevations in amylase, lipase, glucose, and creatinine phosphokinase is recommended based on the observed toxicity profile.


What useful links are available regarding brigatinib?






Any ongoing clinical trials related to brigatinib?

Clinical trials with brigatinib are being conducted in NSCLC, including those involving upfront therapy for ALK-positive disease against crizotinib, as well as following treatment with second-generation ALK inhibitors. More information is available about the clinical trials at


JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.

Janelle E. Mann, Pha... - Click to enlarge in new windowJanelle E. Mann, PharmD, BCOP. Janelle E. Mann, PharmD, BCOP
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