Mechanism of Action

See how ENHERTU delivers the cytotoxic agent to HER2+ cells3,4

ENHERTU® (fam-trastuzumab deruxtecan-nxki) is a specifically engineered, HER2-directed antibody-drug conjugate, or ADC, indicated for the treatment of adult patients in two tumor types:

  • Unresectable or metastatic HER2-positive breast cancer after two or more prior anti-HER2-based regimens in the metastatic setting. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • And locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regimen.

ENHERTU has Boxed WARNINGS for interstitial lung disease, or ILD, and embryo-fetal toxicity.

Interstitial lung disease and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Please see the Important Safety Information included at the end of this video.

Refer to the full Prescribing Information for more information.

Built upon the foundation established by earlier anti-HER2 treatments, ENHERTU is a HER2-directed ADC that provides targeted delivery of a cytotoxic agent.

ENHERTU is composed of a HER2-directed monoclonal antibody and a potent topoisomerase I inhibitor payload attached by a tumor-selective cleavable linker.

The monoclonal antibody consists of the same amino acid sequence as trastuzumab and targets HER2-expressing tumors.

The highly potent topoisomerase I inhibitor payload is an exatecan derivative, known as DXd, and has a short systemic half-life.

ENHERTU has a homogeneous and high drug-to-antibody ratio of approximately 8 molecules of cytotoxic agent per antibody.

The linker-payload is stable in plasma. The tumor-selective cleavable linker helps ensure ENHERTU remains stable in plasma.

ENHERTU delivers the cytotoxic agent to HER2-positive cells.

ENHERTU binds to HER2-receptors expressed on tumor cells to form an ENHERTU-HER2 complex, which is internalized.

After internalization, the linker is selectively cleaved by lysosomal enzymes that are upregulated in tumor cells, releasing the payload inside the cancer cells.

The topoisomerase I inhibitor payload enters the nucleus, causing DNA damage and cell death.

In addition, the released payload is membrane-permeable. It is able to move out of the HER2-expressing cell and act on surrounding cells of variable HER2 expression, known as the bystander antitumor effect.

ENHERTU is a specifically engineered HER2-directed ADC for adult patients with metastatic breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting; and for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

ENHERTU is a specifically engineered HER2-directed antibody-drug
conjugate (ADC)3,4

HER2-targeted antibody-drug conjugate

HER2-directed mAb3

  • Provides targeted
    delivery of cytotoxic
    agent3,4
  • Consists of the same
    amino acid sequence
    as trastuzumab5
HER2-targeted antibody-drug conjugate

Topoisomerase I inhibitor payload3,4,a

  • Highly potent payload is an exatecan derivative, known as DXd, with a short systemic half-life3,5
  • Upon release, membrane-permeable payload causes DNA damage and cell death, resulting in destruction of HER2+ tumor cells and surrounding cells of variable HER2 expression, known as the bystander antitumor effect3,5,6

Tumor-selective cleavable linker3-5,a

  • Attaches payload to the antibody3
  • Linker-payload is stable in plasma4,5
  • Linker selectively cleaved by enzymes that are upregulated in tumor cells3,5

ENHERTU has a homogeneous and high
drug-to-antibody ratio of ~8 molecules of
cytotoxic agent per antibody3-5,a

aBased on in vitro and in vivo non-clinical studies. The clinical relevance of these features is under investigation.

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DNA, deoxyribonucleic acid; HER2, human epidermal growth factor receptor 2; mAb, monoclonal antibody.