Trastuzumab Deruxetecan
Overview
Trastuzumab deruxtecan is an advanced antibody–drug conjugate (ADC) that combines the HER2-targeted monoclonal antibody trastuzumab with a potent topoisomerase I inhibitor payload. This structure allows it to bind HER2-expressing tumor cells, internalize, release the cytotoxic agent, and damage DNA to induce cancer cell death while maintaining tumor selectivity. Delivered via intravenous infusion, it has transformed treatment for HER2-positive and HER2-low cancers, including breast, gastric, lung, and other solid tumors. The ADC’s design enables a potent and more precise approach to oncology, offering improved response rates with a manageable safety profile.
Background and Date of Approval
Trastuzumab deruxtecan received accelerated FDA approval on December 20, 2019 for HER2-positive unresectable or metastatic breast cancer after prior anti-HER2 therapy. The European Union followed in early 2021, with early approval rooted in strong response and survival benefits demonstrated in clinical trials. Approval expanded in January 2021 for HER2-positive gastric or gastroesophageal junction adenocarcinoma. Recognizing emerging patient needs, in August 2022 the FDA approved the drug for HER2-low metastatic breast cancer, highlighting its efficacy in tumors with lower HER2 expression. A landmark tumor-agnostic approval followed in April 2024 for adults with unresectable or metastatic HER2-positive solid tumors across types, cementing trastuzumab deruxtecan's role as a versatile, HER2-targeted treatment.
Uses
Trastuzumab deruxtecan is indicated for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens. It is also approved for HER2-positive gastric or gastroesophageal junction adenocarcinoma after trastuzumab-based therapy. Crucially, it now serves as a first-line option for HER2-low metastatic breast cancer that progresses after endocrine treatment. The tumor-agnostic indication allows treatment of various HER2-positive solid tumors in heavily pretreated patients. These broadened uses offer hope where fewer effective options exist.
Administration
The standard dose of trastuzumab deruxtecan is 5.4 mg/kg administered intravenously every three weeks. In gastric cancer, a higher dose of 6.4 mg/kg may be used. Treatment continues until disease progression or unacceptable toxicity. Infusion typically lasts around 90 minutes, with close monitoring during administration and regular assessments of blood counts, liver and heart function. Dose reduction or temporary interruption is recommended if interstitial lung disease or serious toxicities develop.
Side Effects
Frequent adverse effects include nausea, fatigue, hair thinning, constipation, diminished appetite, dry eyes, headache, and abdominal discomfort. Newer data show consistent patterns across tumor types, with additional reports of peripheral neuropathy, diarrhea, and injection-site discomfort. These effects are generally manageable and resolve with supportive care and treatment adjustments.
Warnings
A key safety concern is interstitial lung disease (ILD) or pneumonitis, which can be life-threatening and requires immediate drug discontinuation and initiation of corticosteroid therapy if suspected. Cases of cardiotoxicity, such as diminished ejection fraction and cardiac dysfunction, have also been reported. Hematologic toxicities include neutropenia and thrombocytopenia, increasing infection and bleeding risk. Due to embryo-fetal toxicity, effective contraception is required during treatment and for several months afterward.
Precautions
Baseline pulmonary assessment and close monitoring for respiratory symptoms are critical. Patients should undergo serial blood counts and liver and cardiac function tests during treatment. Live vaccines should be avoided. While no major metabolic drug interactions are established, caution is advised with agents causing neutropenia or liver enzyme elevation. Patient education on symptom monitoring is essential for early detection of serious side effects.
Expert Tips
Discuss lung symptoms proactively with patients starting on trastuzumab deruxtecan, providing clear instructions for timely reporting. Regularly monitor blood counts and organ function, and coordinate with pulmonologists and cardiologists for managing toxicities. Consider prophylactic medications to manage nausea and support hydration. Use tumor boards to evaluate treatment continuation or transition following progression.