Introduction

Brigatinib is a tyrosine kinase receptor inhibitor and antineoplastic agent used in the therapy of selected forms of advanced non-small cell lung cancer. Brigatinib is associated with a moderate rate of transient elevations in serum aminotransferase levels during therapy but has yet to be linked to instances of clinically apparent acute liver injury.

Background

Brigatinib (bri ga' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against anaplastic lymphoma kinase (ALK) that is rearranged and mutated in some cancers including approximately 5% of non-small cell lung cancer (NSCLC). The mutated, rearranged ALK promotes unregulated cell growth and proliferation. Brigatinib has been found to inhibit mutated ALK in cell culture and in several clinical trials was found to induce objective responses in a proportion of patients with refractory, advanced NSCLC that are ALK-positive. Brigatinib was approved for use in the United States in 2017 in patients with ALK-positive, metastatic NSCLC who have progressed despite therapy with first generation ALK inhibitors (such as crizotinib). Brigatinib is available in tablets of 30, 90 and 180 mg under the brand name Alunbrig. The recommended dose is 90 to 180 mg daily, continued until disease progression or intolerable toxicity occurs. Side effects are common and can be dose limiting. Common adverse events include fatigue, nausea, diarrhea, headache and cough. Less common but potentially severe side effects include severe pulmonary toxicity, interstitial lung disease, myopathy, bradycardia and embryo-fetal toxicity.

Hepatotoxicity

In preregistration trials of brigatinib, ALT elevations occurred in up to 40% of patients but values above 5 times the upper limit of normal (ULN) were found in only 1% to 3%. Brigatinib therapy was also associated with frequent elevations in alkaline phosphatase (15% to 29%), but the serum enzyme elevations were usually mild-to-moderate in degree as well as asymptomatic and transient in nature. Clinically apparent liver injury with jaundice was not reported in the prelicensure studies of brigatinib and no reports have been published since its approval. In general, the ALK kinase inhibitors are associated with a high rate of serum enzymes elevations during therapy, but convincing cases of idiosyncratic, clinically apparent liver injury from their use have been rare. Most cases have been reported with crizotinib [approved in 2011] which is also the most frequently used of the kinase inhibitors with activity against ALK. Cases of liver injury with jaundice were reported to occur in trials of alectinib [2015] and ceritinib [2014], but details were not provided. Thus, acute liver injury with jaundice may occur with brigatinib but it must be rare if it occurs at all.

Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury).

Mechanism of Injury

Serum enzyme and bilirubin elevations are frequent during therapy with tyrosine kinase inhibitors, but their cause is unknown. The liver injury may be due to direct activity against essential intracellular kinases or to production of a toxic metabolite during metabolism of the kinase inhibitor. Brigatinib is metabolized in the liver predominantly by CYP 3A4 and is susceptible to drug-drug interactions with strong inhibitors or inducers of this microsomal enzyme.

Outcome and Management

Brigatinib has been shown to cause transient serum aminotransferase elevations but has not been linked to cases of clinically apparent liver injury, acute liver failure or chronic hepatitis. The product label recommends monitoring of serum glucose, CPK and pancreatic enzymes, but not specifically routine liver tests. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks or if symptoms or jaundice arise.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors