What is trastuzumab deruxtecan?
Trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (trastuzumab) bound to a topoisomerase I inhibitor (deruxtecan).
Trastuzumab deruxtecan binds HER2 on tumor cells and is internalized. Within the tumor cell, the tetrapeptide-based linker between trasutuzmab and deruxtecan is cleaved by lysosomal enzymes, allowing deruxtecan to inhibit topoisomerase I, thus causing DNA damage and apoptosis. Upon apoptosis, deruxtecan is able to affect cells regionally.
What is this approved for?
Trastuzumab deruxtecan is approved for treatment of unresectable or metastatic HER2-positive breast cancer. Trastuzumab deruxtecan was approved based on results from the DESTINY-Breast01 phase II study (N Engl J Med 2020;382:610-621). This two-part, open-label, single-group, multicenter study evaluated use of trastuzumab deruxtecan dosed at 5.4 mg/kg IV every 3 weeks in adult patients (N=184) with unresectable or metastatic HER2-positive breast cancer and good performance status. Patients had a median of 6 previous treatment regimens (range 2-27), with all patients having been through at least trastuzumab and trastuzumab emtansine.
Overall response rate was 60.9 percent by independent central review, with 6 percent achieving complete response and 54.9 percent achieving partial response. The median time to response was short at 1.6 months and corresponded to the time until the first imaging after baseline. The median duration of response was 14.8 months, median progression-free survival was 16.4 months, and overall survival was 93.9 percent at 6 months and 86.2 percent at 12 months. Median overall survival had not been reached at the time of publishing.
Among the 184 patients receiving at least one dose of trastuzuamb deruxtecan 5.4 mg/kg, 99.5 percent had at least one adverse event (AE), with 57.1 percent being grade 3 or higher severity. The most common grade 3 or higher AEs were cytopenias, which can be expected in patients having been through multiple lines of chemotherapy, nausea, fatigue, and febrile neutropenia. Dose interruptions, reductions, and discontinuations occurred in 35.3 percent, 23.4 percent, and 15.2 percent of patients respectively secondary to AEs.
How do you administer this drug?
Trastuzumab deruxtecan is given as 5.4 mg/kg IV once over 90 minutes every 3 weeks until disease progression or unacceptable toxicity. If the initial infusion is well-tolerated, you may administer further doses over 30 minutes.
Are there any premedications needed for trastuzumab deruxtecan?
No premedications are required for trastuzumab deruxtecan. Evaluation of common adverse effects does demonstrate a moderate risk of chemotherapy-induced nausea/vomiting. Consider addition of appropriate antiemetics for prevention of nausea/vomiting.
What are the common side effects associated with trastuzumab deruxtecan (> or =10%)?
The most common adverse effects include nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, thrombocytopenia, abdominal pain, headache, upper respiratory tract infection, stomatitis, dyspnea, epistaxis, dyspepsia, hypokalemia, dizziness, skin rash, and transaminitis.
What are the uncommon side effects associated with trastuzumab deruxtecan (less than 10%)?
Additional side effects include cellulitis (>1%), intestinal obstruction (>1%), febrile neutropenia (2%), interstitial pulmonary disease (9%), pneumonia (>1%), infusion-related reaction (3%), and decreased left ventricular ejection fraction (<1%).
Are there any important drug interactions I should be aware of?
There are no known drug-drug interactions, but caution should be used in patients with a systemic infection or patients undergoing anthracycline-based therapy due to potential for enhanced cardiotoxicity.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no recommended dose adjustments for renal or hepatic impairment, due to lack of patients of these populations in the primary literature.
What should my patients know about trastuzumab deruxtecan?
Important counseling points for patients include education on reduced blood cell counts, use of antiemetic agents for nausea and vomiting, signs of liver dysfunction, signs of interstitial lung disease and pneumonitis, and use of effective contraception during treatment due to risk of embryo-fetal toxicity.
What else should I know about trastuzumab deruxtecan?
There is a boxed warning for interstitial lung disease and pneumonitis, which occurred in 13.6 percent of patients on study. Most (10.9%) were grade 1-2; however, one patient had a grade 3 event, and four patients (2.2%) died due to interstitial lung disease. In the study, the median time to onset of interstitial lung disease was 193 days and median duration of 34 days.
There is an additional boxed warning for embryo-fetal toxicity. Patients of child-bearing age should be advised to use effective contraception during treatment.
What useful links are available regarding trastuzumab deruxtecan?
* FDA Approval Announcement: https://bit.ly/2TifjqJ
Any ongoing clinical trials related to trastuzumab deruxtecan?
Trastuzumab deruxtecan studies are targeting place in therapy by studying it in earlier stages of breast cancer, as well as in combination with other therapies like immunotherapy. There are also ongoing studies with other solid tumor types that are found to have HER2-expressing or HER2-mutated disease. More information is available about these clinical trials at https://clinicaltrials.gov.
CASSANDRA HACKER, PHARMD, is a PGY2 Oncology Resident at Barnes-Jewish Hospital, St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is the Manager of Clinical Pharmacy Services and practices as an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.