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

• HER2+ breast cancer
• HER2+ gastric cancer

Diseases for which it is used

• HER2+ colorectal cancer
• HER2-mutant NSCLC

History of changes in FDA indication

HER2+ breast cancer

• 2019-12-20: 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)
  • 2022-05-04: Regular approval 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)
  • 2022-05-04: Regular approval 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)
• 2022-08-05: 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)
• 2022-08-05: 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

• 2021-01-15: 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

• 2022-08-11: 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)

HER2+ solid tumors

• 2024-04-05: Granted accelerated approval for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. (Based on DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02)

History of changes in EMA indication

HER2+ breast cancer

• 2021-01-18: Initial conditional authorization
• Uncertain date: Enhertu as monotherapy is conditionally indicated for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received one or more prior anti HER2 based regimens.
• 2023-02-16: Enhertu as monotherapy is conditionally indicated for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting.
• 2023-02-16: Enhertu as monotherapy is conditionally indicated for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

HER2+ gastric cancer

• 2023-02-16: Enhertu as monotherapy is conditionally indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

HER2-mutant NSCLC

• Future date (positive CHMP opinion): Enhertu as monotherapy is indicated for the treatment of adult patients with advanced NSCLC whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.

History of changes in Health Canada indication

• 2021-04-15: Initial notice of compliance with conditions for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1).

History of changes in PMDA indication

Breast cancer

• 2020-03-25: Conditional new approval for the treatment of unresectable or recurrent HER2-positive breast cancer in patients who have previously been treated with chemotherapy (for use only if refractory or intolerant to standard therapies).
• 2020-03-25: Newly indicated for the treatment of unresectable or recurrent HER2positive breast cancer in patients who have previously been treated with chemotherapy (for use only if refractory or intolerant to standard therapies).
• 2022-11-24: New indication for the treatment of unresectable or recurrent HER2-positive breast cancer in patients who have previously been treated with chemotherapy.

Gastric cancer

• 2020-09-25: New indication and a new dosage for the treatment of unresectable advanced or recurrent HER2-positive gastric cancer that has progressed after cancer chemotherapy.

Patient Drug Information

• Fam-trastuzumab deruxtecan (Enhertu) Package Insert

Also known as

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