Bringing the first agent to market for the indication, on August 5, 2022, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu®) for patients with unresectable or metastatic HER2-low breast cancer based on results from the DESTINY-Breast04 trial that demonstrated improved progression-free and overall survival. FDA also gave fam-trastuzumab deruxtecan its fourth approval on August 11, 2022, for unresectable or metastatic HER2-activating non-small cell lung cancer (NSCLC).
HER2-directed antibody and topoisomerase inhibitor conjugate.
Mechanism of Action
A small-molecule topoisomerase I inhibitor, DXd, attaches to the HER2-directed antibody via a cleavable linker. After binding to HER2 on a tumor cell, fam-trastuzumab deruxtecan is internalized and undergoes intracellular linker cleavage by lysosomal enzymes, causing DNA damage and cellular death.
Approved to treat adult patients with:
- Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2–based regimen in either the neoadjuvant, adjuvant, or metastatic setting and developed disease recurrence within six months of completing therapy
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH–) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence within six months of completing adjuvant chemotherapy
- Unresectable or metastatic NSCLC with HER2-activating variant (ERBB2) who have received prior systemic therapy
- Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
For breast cancer and NSCLC, administer 5.4 mg/kg every three weeks. For gastric cancer, give 6.4 mg/kg every three weeks.
Give as an IV infusion; do not administer as a push or bolus infusion. Administer the first infusion over 90 minutes and subsequent doses over 30 minutes if the previous infusions were well tolerated. Use a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer with other medications. Do not administer with sodium chloride.
More than 20% of patients with breast cancer or NSCLC in the agent’s clinical trials reported nausea, vomiting, fatigue, alopecia, constipation, musculoskeletal pain, decreased appetite, diarrhea, and respiratory infection. Laboratory abnormalities included decreased white blood cell count, hemoglobin, neutrophil count, lymphocyte count, platelet count, and hypokalemia and increased AST, ALT, and ALP. More than 20% of patients with gastric cancers in the agent’s clinical trials experienced nausea, vomiting, decreased appetite, fatigue, diarrhea, constipation, pyrexia, and alopecia with labs showing decreased hemoglobin, white blood cell count, neutrophil count, lymphocyte count, platelet count, and hypokalemia; and increased AST, ALT, ALP, and bilirubin.
Warnings and Precautions
The prescribing indications warn of neutropenia and left ventricular dysfunction (LVEF) and contain a black box warning for interstitial lung disease, pneumonitis, and embryo-fetal toxicity.
Fam-trastuzumab deruxtecan is moderately emetogenic (including delayed nausea and vomiting), and guidelines recommend premedication with antiemetics. Verify pregnancy status in patients of reproductive potential prior to starting treatment. Complete blood counts should be assessed prior to initiating therapy, prior to each dose, and as indicated. Assess LVEF prior to initiating therapy and at regular intervals throughout treatment as indicated. See the package insert for dose reduction indications and schedules.
Do not administer fam-trastuzumab deruxtecan with sodium chloride solution.
Female patients of reproductive potential should use effective contraception during treatment and for seven months after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment and for four months after the last dose. Fam-trastuzumab deruxtecan may impair male reproductive function and fertility; discuss fertility preservation with patients prior to starting therapy. Avoid breastfeeding during treatment and for seven months after the last dose. Use ONS’s patient education reference sheet with your patients.
Special Population Considerations
Safety and efficacy have not been established in pediatric patients. No overall differences were noted in safety or efficacy in clinical trials in patients 65 years or older compared to younger patients.
Fam-trastuzumab deruxtecan is a hazardous drug; use appropriate handling and disposal procedures.
Visit enhertu4u.com/patient.html or call 833-364-3788.