The warnings and precautions of Brigatinib

Introduction

ALUNBRIG (Brigatinib) is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. Owing to the resistance associated with the first-generation (crizotinib) and second-generation (alectinib and ceritinib) ALK inhibitors, brigatinib was developed to achieve potent activity against a broad range of ALK resistance mutations. In preclinical studies, brigatinib showed higher potency and the capability to overcome mechanisms of resistance associated with crizotinib[1].

Warnings and precautions[2]

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients.

Hypertension

In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; 13% of patients experienced Grade 3 hypertension. In ALTA, hypertension was reported in 11% of patients in the 90 mg group and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG.

Bradycardia

In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG; one patient (0.7 %) experienced Grade 3 bradycardia. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% in the 90→180 mg group. One patient (0.9%) in the 90 mg group experienced Grade 2 bradycardia. Monitor heart rate and blood pressure during treatment with ALUNBRIG.

Visual Disturbance

In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance, including blurred vision, photophobia, photopsia, and reduced visual acuity, were reported in 7.4% of patients receiving ALUNBRIG. In ALTA, adverse reactions leading to visual disturbance, including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group.

Creatine Phosphokinase (CPK) Elevation

In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients.

Pancreatic Enzyme Elevation

In ALTA 1L, amylase elevation occurred in 52% of patients, and Grade 3 or 4 amylase elevation occurred in 6.8% of patients who received ALUNBRIG. Lipase elevations occurred in 59% of patients, and Grade 3 or 4 lipase elevation occurred in 17%.

Hepatotoxicity

In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients, and Grade 3 or 4 AST elevations occurred in 4.5% of patients who received ALUNBRIG. Alanine aminotransferase (ALT) elevations occurred in 52% of patients, and Grade 3 or 4 ALT elevations occurred in 5.2%.

The others include Hyperglycemia, Photosensitivity, and Embryo-Fetal Toxicity. Hence, Assess fasting serum glucose before initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

References

[1] Neeraj Gupta. “Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.” Clinical Pharmacokinetics 62 8 (2023): 1063–1079.

[2] https://www.alunbrig.com/hcp

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