Clinical Practices and Institutional Protocols on Prophylaxis, Monitoring, and Management of Selected Adverse Events Associated with Trastuzumab Deruxtecan

Abstract

The treatment of metastatic breast cancer (mBC) has evolved significantly in the past several years with the approval of new targeted agents. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate with a topoisomerase I inhibitor payload, is a new addition to the class of therapies that target the human epidermal growth factor 2 (HER2) receptor. T-DXd was approved in the US in December 2019 for patients with HER2-positive metastatic or unresectable breast cancer who have received 2 or more prior anti-HER2–based regimens in the metastatic setting. In the DESTINY-Breast01 phase II trial (NCT03248492), T-DXd demonstrated high rates of durable responses in heavily pretreated patients with HER2-positive mBC, with a confirmed objective response rate of 62%, median duration of response of 18.2 months, and median progression-free survival of 19.4 months. In addition to efficacy, successful implementation of any new anticancer therapy includes learning how to prevent, monitor, and manage treatment-related adverse events. As T-DXd becomes more widely used, information can be gained from real-world clinical practices, institutional approaches, and the collaboration of multidisciplinary oncology teams who treat patients with T-DXd. This article reviews practical insights and management of nausea and vomiting, neutropenia, interstitial lung disease, risk of cardiotoxicity, and other adverse events associated with T-DXd administration from the perspective of health care providers who have experience utilizing T-DXd.

Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy

“…Use of systemic corticosteroids while withholding the active drug or initiating dose reductions (Table 4) may improve the situation, but permanent discontinuation might be warranted in more advanced cases. 10,11,15,18,25,26…”

“…Prompt management should be implied upon clinical suspicion with use of diagnostic imaging and comanagement with a pulmonologist. Use of systemic corticosteroids while withholding the active drug or initiating dose reductions (Table 4) may improve the situation, but permanent discontinuation might be warranted in more advanced cases 10,11,15,18,25,26 …”

“…Dose reductions (Table 4, Table 5, and Table 8), treatment interruption, or cessation may be needed. 25…”

“…Multidisciplinary management of patients with a team including a specialized cardiologist may be beneficial. 25,50…”

Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2‐Positive or HER2‐Low Metastatic/Unresectable Breast Cancer

“…In telemetered male cynomolgus monkeys treated with single intravenous doses of T‐DXd, no effects on the cardiovascular, respiratory, or central nervous systems were observed at dose levels up to 78.8 mg/kg 23 . Furthermore, clinically significant effects of T‐DXd on LVEF reduction or heart failure have been infrequently reported to date 2–4,6,24–26 . Nonetheless, the current International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use E14 guidelines still recommend the evaluation of effect of non‐antiarrhythmic drugs in development on QT intervals and QTc 27 .…”