Trastuzumab deruxtecan (Enhertu)

General information

Class/mechanism from the NCI Drug Dictionary: An antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (ERBB2; EGFR2; HER2) conjugated to a derivative of the camptothecin analog exatecan (DXd; DX-8951 derivative), a DNA topoisomerase 1 (topoisomerase I; Top1) inhibitor, with potential antineoplastic activity. Upon administration of anti-HER2 ADC conjugate DS-8201a, the antibody moiety targets and binds to HER2 on tumor cells. Upon antibody/antigen binding and internalization, the DX-8951 derivative moiety binds to and inhibits Top1-DNA complexes, which results in an inhibition of DNA replication, cell cycle arrest and tumor cell apoptosis. HER2, a tyrosine kinase receptor, is overexpressed by many cancer cell types. In addition, DS-8201a induces antibody-dependent cell-mediated cytotoxicity (ADCC) and causes a bystander killing effect, thereby killing neighboring HER2-expressing tumor cells.
Route: IV

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, MedScape,UpToDate (courtesy of Lexicomp), or the prescribing information.

Diseases for which it is established (work in progress)

• HER2+ breast cancer
• HER2+ gastric cancer
• HER2-mutant NSCLC

Diseases for which it is used

• HER2+ colorectal cancer

History of changes in FDA indication

HER2+ breast cancer

• 12/20/2019: Granted accelerated approval for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. (Based on DESTINY-Breast01)
• 5/4/2022: Approved for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen in the metastatic setting. (Converted to full approval; Based on DESTINY-Breast03)
• 5/4/2022: Approved for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. (Converted to full approval; Based on DESTINY-Breast03)
• 8/5/2022: Approved for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH‑) breast cancer who have received a prior chemotherapy in the metastatic setting. (Based on DESTINY-Breast04)
• 8/5/2022: Approved for adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH‑) breast cancer who have developed disease recurrence during or within six months of completing adjuvant chemotherapy. (Based on DESTINY-Breast04)

HER2+ gastric cancer

• 1/15/2021: Approved for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. (Based on DESTINY-Gastric01)

HER2-mutant NSCLC

• 8/11/2022: Granted accelerated approval for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. (Based on DESTINY-Lung02)

History of changes in EMA indication

• 1/18/2021: Initial conditional authorization

Patient Drug Information

• Fam-trastuzumab deruxtecan (Enhertu) Package Insert

Also known as

• Code name: DS-8201a
• Generic name: fam-trastuzumab deruxtecan-nxki
• Brand name: Enhertu