American Journal of Therapeutics 23, e572–e574 (2016)

Acute Pancreatitis Associated With Ado-Trastuzumab Emtansine Mahvish Muzaffar, MD,1* Jingquan Jia, MD,2 Darla Liles, MD,1 Musharraf Naveed, MD,1 and Anita Kumari, MD1

Ado-trastuzumab emtansine (T-DM1) is a novel antibody–drug conjugate with current FDA recommendation for second-line treatment of HER-2-positive metastatic breast cancer. It is a human epidermal growth factor receptor (HER-2)-targeted antibody–drug conjugate composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). Adotrastuzumab emtansine improved both progression-free and overall survival as reported in EMILIA trial. With ongoing clinical trials in adjuvant and first-line setting for HER-2-positive early and metastatic breast cancer, it is prudent to recognize, report, and treat any adverse events related to T-DM1. We report a case of acute pancreatitis in a 54-year-old woman with metastatic breast cancer after she received her first dose of ado-trastuzumab emtansine. To the best of our knowledge, this is the first reported case of acute pancreatitis with probable association with ado-trastuzumab emtansine. Keywords: T-DM1, ado-trastuzumab emtansine, pancreatitis, metastatic breast cancer

INTRODUCTION Ado-trastuzumab emtansine (T-DM1) is a novel antibody–drug agent that consists of trastuzumab conjugated to emtansine through a thioether linker.1 Trastuzumab is a humanized monoclonal antibody that binds to the extracellular region of the HER-2 receptor on tumor cell surface and on internalization and induces cytotoxicity.2 Emtansine represents a maytansinoid derivative that leads to cancer cell death by inhibiting microtubule assembly.3 Trastuzumab emtansine has been shown to significantly prolong progression-free and overall survival with less toxicity than lapatinib plus capcetabine in patients with HER-2-positive metastatic breast cancer and was recently approved as

Departments of 1Hematology/Oncology and 2Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC. The authors have no conflicts of interest to declare. *Address for correspondence: Assistant Professor, Division of Hematology/Oncology, 600 Moye Blvd, BSOM, Greenville, NC 27834. E-mail: [email protected]

a second-line therapy for HER-2-positive metastatic breast cancer.4 In this study, the common side effects with T-DM1 include nausea, vomiting, fatigue, thrombocytopenia, and elevated aspartate transaminase and alanine transaminase. Here, we report a case of acute pancreatitis in a patient with HER-2-positive metastatic breast cancer after receiving first cycle of T-DM1.

CASE REPORT We report a case of a 54-year-old white woman who was initially diagnosed with stage II left breast carcinoma estrogen and progesterone receptor positive, HER-2 unknown in 1998. She underwent mastectomy followed by 4 cycles of adjuvant Adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks followed by tamoxifen for 5 years. In 2003, she developed metastatic disease in bones; biopsy of bone lesion was estrogen and progesterone weakly positive and HER-2 positive by immunohistochemistry (3+) metastatic disease. She was treated with Navelbine/trastuzumab and bisphosphonates followed by letrozole with

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Pancreatitis Ado-Trastuzumab Emtansine

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emergency department revealed inflammation and in duration surrounding the pancreas raising the possibility of pancreatitis with mild diffuse pancreatic swelling along with small ascites, no gallstones (Figure 1). The laboratory values at admission included increased lipase of 2962 and leukocytosis (Table 1). No history of alcohol use, herbs, or other new medications was reported. Naranjo algorithm—adverse drug reaction probability scale revealed probable relationship with score of 6. The patient was treated conservatively and responded to bowel rest, hydration, and pain control followed by gradual introduction of feeds from clear to regular diet over a period of 1 week. At the time of discharge, her symptoms as well as abnormal laboratory values had improved.

DISCUSSION

FIGURE 1. Computed tomography scan of the abdomen showing induration of retroperitoneal fat plane around pancreas suggesting pancreatitis.

trastuzumab till 2010. Her disease progressed in 2010, and treatment was switched to lapatinib/trastuzumab/ capcetabine. In 2014, while patient was on trastuzumab and capcetabine imaging revealed progression of disease. The patient was started on ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg every 3 weeks, and she received first dose on 21st of the month uneventfully. The patient presented to the emergency department 3 days later on 24th of the month with a 2-day history of abdominal pain, nausea, vomiting, and fatigue. Computed tomography scan of abdomen performed in the

The anticancer drug landscape has undergone paradigm shift. Antibody–drug conjugate (ADC) is 1 such novel group with multiple effective agents already approved by FDA. Ado-trastuzumab emtansine (Kadcyla) is 1 such ADC that optimizes delivery of chemotherapy with an anti-HER-2 monoclonal antibody thus significantly minimizing the systemic side effects of cytotoxic agent. It was approved for metastatic breast HER-2 positive breast cancer in second-line setting after phase III trial EMILIA reported improvement in both PFS and OS.4 Postmarketing pharmacovigilance can be of significant importance in recognizing and treating adverse event. We report a case of acute pancreatitis after patient received first dose of ado-trastuzumab emtansine (TDM-1). The causal relationship between adotrastuzumab and acute pancreatitis in this case is probable (6) as per Naranjo algorithm.

Table 1. Relevant laboratory parameters at baseline (on the day to start T-DM1 infusion), on admission, and at discharge.

WBC (k/mL), ref range: 4.5–11 Hb (g/dL), ref range: 12–16 Platelet (k/mL), ref range: 150–440 Glucose (mg/dL), ref range: 70–126 Bilirubin, total (mg/dL), ref range: 0.3–1.2 Lipase (U/L), ref range: 0–75 AST, ref range: 14–36 U/L ALT, ref range: 13–69 U/L ALP, ref range: 38–126 U/L

Day of drug administration

Day of admission

Discharge from hospital

7.2 9.5 163 102 0.4 NA 32 16 152

19.9 12.1 86 109 0.7 2962 92 32 167

10.7 7.7 75 97 0.3 314 49 17 128

ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase.

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American Journal of Therapeutics (2016) 23(2)

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The cytotoxic component of TDM-1 emtansine belongs to maytansinoid family and interacts with tubulin and microtubules thus inhibiting tubulin assembly into microtubules. It has been reported to share its binding site with Vinca alkaloids on tubulin and is more potent than Vinca alkaloids.5 Antineoplastic agent–induced pancreatitis is rare. Vinca alkaloids have been reported to cause autophagy and degeneration in pancreatic acinar cell, and there are multiple reports of acute pancreatitis associated with these drugs. Emtansine can be the implicating factor causing pancreatic injury in this case, but this adverse event does not seem to be a common occurrence.6 The most common adverse events reported in clinical trials with ado-trastuzumab emtansine have been hepatotoxicity, thrombocytopenia, and cardiac, among other side effects. Other maytansine analogs, such as monomethyl auristatin E is part of ADC brentuximab vedotin used in lymphomas and has been associated with pancreatitis, in some cases fatal.7,8 Phase III trials are ongoing to establish role of adotrastuzumab in early stage HER-2-positive breast cancer along with first-line setting for metastatic breast cancer, thus making it pertinent to report any new side effect with possible association. Extensive review of literature did not result in any reported cases of acute pancreatitis associated with ado-trastuzumab emtansine. In the context of temporal relationship after drug administration along with no other evident cause of acute pancreatitis, there is probable association between the drug and adverse event reported. Postmarketing surveillance is

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essential to determine the true risk profile of a drug. Recognizing and reporting potentially new side effects will improve safety and patient care.

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Acute Pancreatitis Associated With Ado-Trastuzumab Emtansine.

Ado-trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate with current FDA recommendation for second-line treatment of HER-2-positive metas...
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