Introduction

Margetuximab is a monoclonal antibody to HER2 used in combination with chemotherapy for treatment of adults with advanced, relapsed or refractory HER2-positive breast cancer. Margetuximab therapy is associated with transient serum aminotransferase elevations during therapy in as many as one-third of patients but has not been linked to instances of clinically apparent liver injury.

Background

Margetuximab (mar” je tux’ i mab) is a mouse-human chimeric, cytolytic monoclonal antibody to human epidermal growth factor receptor-2 (HER2) that is used to treat adults with relapsed or refractory HER2-positive cancer. HER2 is a cell surface receptor that is overexpressed in approximately 20% of breast cancers. Engagement of the receptor induces pathways that promote cell proliferation and growth. Margetuximab was found to be cytolytic to HER2 positive cancer cells in culture and resulted in objective response rates in a proportion of adults with relapsed or refractory advanced breast cancer. Margetuximab was granted accelerated approval in 2020 for patients with HER2 positive breast cancer after treatment with at least two previous anti-HER2 therapies such as trastuzumab, trastuzumab-emtansine, and pertuzumab or in combination with a tyrosine kinase inhibitor of HER2 such as lapatinib, tucatinib, or neratinib. Margetuximab is available in solution in single dose vials of 250 mg in 10 mL (25 mg/mL) under the brand name Margenza. The recommended dose is 15 mg/kg intravenously every 3 weeks, the first dose infused over 120 minutes and subsequent doses over 30 minutes. Premedication with acetaminophen, antihistamines, and corticosteroids is recommended to prevent serious infusion reactions. In prelicensure trials, adverse events were common and included infusion reactions, fatigue, nausea and vomiting, diarrhea, constipation, abdominal pain, fever, peripheral neuropathy, cough, decreased appetite, arthralgia, alopecia, and hand-foot syndrome. Laboratory abnormalities included decreases in hemoglobin, white blood cell counts, and platelets and increases in serum creatinine, ALT AST, alkaline phosphatase and lipase. These common adverse events and abnormalities were similar in frequency with trastuzumab as with margetuximab and chemotherapy. Severe adverse reactions included severe infusion related reactions, febrile neutropenia, left ventricular dysfunction, and embryo-fetal toxicity. Margetuximab should only be administered by health care personnel with experience, expertise, and facilities capable of managing the complications of cancer chemotherapy.

Hepatotoxicity

Margetuximab was compared to trastuzumab both combined with chemotherapy in a large, controlled trial involving 536 patients with advanced, relapsed or refractory HER2 positive breast cancer and previous therapy with at least two anti-HER2 directed regimens. The objective response rate was 22% with margetuximab vs 19% with trastuzumab, and both the frequency and pattern of adverse events were similar between the two regimens. The two groups had similar rates of total and severe adverse events. Furthermore, “there were no clinically meaningful differences between treatment groups in laboratory values over time or toxicity grade shifts for any hematology, chemistry, coagulation, or urinalysis parameter.” Serum ALT elevations arose in 32% vs 30% and were 5 times ULN in 2% vs 0.8%. There were no cases of clinically apparent liver injury with jaundice in either group, and no deaths from liver failure. Since its approval in 2020, there have been no published reports of clinically apparent liver injury attributable to margetuximab therapy, although clinical experience with its use has been limited.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The causes of the frequent liver test abnormalities during margetuximab therapy are not known but were likely due to the underlying metastatic cancer or to the other chemotherapeutic agents that were used with margetuximab.

Outcome and Management

The product label for margetuximab does not recommend monitoring of routine liver tests during therapy, and considerations of the severity of the underlying tumor and its poor prognosis generally outweigh concerns about serum aminotransferase elevations not accompanied by jaundice or symptoms of liver injury.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies