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Recent advances in trastuzumab and its antibody-drug conjugates-related liver injury
Liyi Chen1, Guo-H Li1, Chun-Y Li1
1National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Introduction:
Trastuzumab and its antibody-drug conjugates (ADCs) are pivotal in treating human epidermal growth factor receptor 2(HER2)-positive cancers. With the growing scope of clinical use, an increasing body of evidence from studies and case reports suggests that these agents can induce hepatotoxicity of varying severity.
Areas Covered:
This review synthesizes evidence from published clinical trials, preclinical studies, pharmacovigilance data, drug labeling information, meta-analyses and clinical guidelines to comprehensively evaluate the potential mechanisms, risk factors, potential predictive methods, and preventive strategies associated with liver injury induced by trastuzumab and its ADCs.
Expert Opinion:
Trastuzumab-related liver injury is uncommon but occurs more frequently with its antibody-drug conjugates, particularly trastuzumab emtansine (T-DM1), which can cause hepatopulmonary syndrome (HPS), nodular regenerative hyperplasia (NRH), and sinusoidal obstruction syndrome (SOS). Risk factors include dosage, treatment duration, and drug interactions. T-DM1 shows dose-dependent hepatotoxicity, while cytochrome P450 3A4 (CYP3A4) inhibitors may increase hepatic accumulation of trastuzumab deruxtecan (T-DXd). Trastuzumab mainly induces hepatocellular and cholestatic injury, whereas T-DM1 involves both HER2-dependent and independent pathways. Diagnosis relies on causality assessment, and most cases are reversible with liver function monitoring and timely dose adjustment.
Insights
Trastuzumab antibody-drug conjugates (ADCs) can cause liver injury in HER2-positive cancer patients. Early detection and dose adjustment are key for managing this rare but serious side effect.
Area of Science:
- Oncology
- Pharmacology
- Hepatology
Background:
- Trastuzumab and its antibody-drug conjugates (ADCs) are crucial for HER2-positive cancers.
- Increasing clinical use reveals potential for drug-induced liver injury (hepatotoxicity).
Purpose of the Study:
- To review mechanisms, risk factors, predictive methods, and prevention strategies for trastuzumab-ADC-induced liver injury.
- To synthesize evidence from diverse sources including clinical trials and pharmacovigilance data.
Main Methods:
- Comprehensive literature review.
- Synthesis of data from clinical trials, preclinical studies, pharmacovigilance, drug labels, meta-analyses, and guidelines.
Main Results:
- Hepatotoxicity is more frequent with ADCs, especially trastuzumab emtansine (T-DM1), causing HPS, NRH, and SOS.
- Risk factors include dosage, duration, and drug interactions; T-DM1 exhibits dose-dependent toxicity.
- Trastuzumab causes hepatocellular/cholestatic injury; T-DM1 involves HER2-dependent and independent pathways.
Conclusions:
- Trastuzumab-related liver injury is uncommon but requires monitoring, especially with ADCs.
- Diagnosis involves causality assessment; most cases are reversible with monitoring and dose adjustment.
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