Trastuzumab emtansine (TE) is a human epidermal growth factor receptor 2 (HER2)–targeted antibody and microtubule inhibitor conjugate that is indicated for the treatment of patients with HER2-positive metastatic breast cancer (BC) who previously received trastuzumab and a taxane or as adjuvant treatment of patients with HER2-positive early BC who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment. The drug conjugate monoclonal antibody is associated with enhanced activity compared with trastuzumab and has demonstrated synergistic activity against malignant cells.

Despite its beneficial effects in BC, TE’s labeling carries a boxed warning for the risk of hepatotoxicity, liver failure, and death, as well as for cardiac toxicity and embryo-fetal toxicity. Additionally, recent evidence has emerged that indicates that with prolonged use, TE may be associated with hepatobiliary disorders.

Using the FDA Adverse Event Reporting System (FAERS) dataset, which is publicly released in the form of quarterly data extraction files, researchers collected data from January 1, 2013, to December 31, 2022, to assess the postmarketing risk of hepatobiliary disorders associated with TE. FAERS data are organized into seven tables. For the intent of this study, researchers utilized the information from the Demographic and Indication tables.

Multiple Demographic table records can correspond to one case report since the table accounts for the inclusion of follow-up reports that may include updated information. Hepatobiliary disorders in which TE was the primary suspected drug were explored further. Adverse events were assessed based on the MedDRA (Medical Dictionary for Regulatory Activities) classification. In addition to MedDRA terms, the investigators included adverse drug event preferred terms that were relevant to hepatic injury and were already being monitored as indicators of hepatoxicity based on the drug’s boxed warning. The authors accounted for confounders and performed a disproportionality analysis using a case/noncase method.

From the Demographic table, the investigators identified 11,837,088 case reports. These included 3,387 case reports with TE as the primary suspected drug and 11,833,701 case reports with other as the primary suspected drug for hepatobiliary disorders. From the Indications table, 11,633,752 case reports were identified, of which 174,848 had a BC indication recorded without data errors. A subgroup analysis revealed that 2,591 with a BC indication recorded TE as the primary suspected drug and 172,239 case reports in which BC was the indication found that other drugs were the primary suspected drug for the conditions in question. In the entire dataset, TE-related and other drug-related numbers of cases reported were 3,387 and 11,833,701, respectively. The median age of the TE population was 57 years, and the median age for the total cohort was 61 years.

Based on a disproportionality analysis for the entire dataset, hepatobiliary disorders (i.e., the system organ class) were reported 5.66 times more frequently with TE than with other drugs. In the disproportionality analysis using cases with BC indication records, the risk of hepatobiliary disorders reported with TE was 3.28 times higher than that reported with other drugs. Potential safety signals identified for both disproportionality analyses included increased alanine aminotransferase, hepatic cirrhosis, abnormal hepatic function, liver disorder, portal hypertension, hepatomegaly, nodular regenerative hyperplasia, increased hepatic enzyme, hepatotoxicity, increased liver function test, drug-induced liver injury, abnormal liver function test, hepatitis, hyperbilirubinemia, cholecystitis, venoocclusive liver disease, cholestasis, hepatic fibrosis, noncirrhotic portal hypertension, hepatic cytolysis, and hepatic pain.

Potential safety signals that were found for the entire dataset, but not when a BC diagnosis was factored in included hepatic failure, liver injury, jaundice, hepatic steatosis, and hypertransaminasemia. Both hepatocellular injury and acute hepatic failure did not demonstrate a potential safety signal in either disproportionality analysis. The median reported onset time of hepatobiliary disorders associated with TE was 41 days, 322.5 days for prolonged and chronic hepatobiliary disorders, and 301.5 days for suspected prolonged and chronic hepatobiliary disorders.

These findings stress the importance of increased clinical pharmacovigilance when TE is prescribed for long-term use. The temporal pattern observed alerts pharmacists to the time period that BC patients receiving TE may be most vulnerable to hepatobiliary disorders. Further, these observations can help pharmacists determine the risk versus benefit of treatment with TE so that they can assist in optimizing BC patients’ therapeutic regimens.

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