Enhertu is an antibody-drug conjugate, a type of targeted cancer therapy that delivers a potent cell-killing chemical directly inside cancer cells. It works by combining two tools into one: an antibody that seeks out a specific protein on cancer cells (HER2), and a toxic payload that destroys the cell from the inside once delivered. This targeted approach is what separates Enhertu from traditional chemotherapy, which circulates throughout the body and damages healthy cells along with cancerous ones.
The Three-Part Design
Enhertu (known generically as trastuzumab deruxtecan) is built from three connected components, each with a distinct job. The first is a monoclonal antibody, essentially a lab-engineered version of the immune proteins your body already makes. This particular antibody is designed to latch onto HER2, a protein found on the surface of certain cancer cells. It’s the same antibody backbone used in trastuzumab (Herceptin), a drug that has been treating HER2-positive breast cancer for decades.
The second component is the linker, a short chain of amino acids that connects the antibody to the drug payload. This linker is designed to stay stable while the drug circulates through your bloodstream, then break apart once it’s inside a cancer cell. That selective release is critical: it keeps the toxic payload from doing damage before it reaches its target.
The third piece is the payload itself, a small molecule that kills cells by blocking an enzyme called topoisomerase I, which cancer cells need to copy their DNA and divide. What makes Enhertu’s design unusual is how much payload it carries. Each antibody molecule is loaded with eight copies of the drug, a ratio significantly higher than older antibody-drug conjugates. That high drug-to-antibody ratio means more cell-killing power is delivered with each hit.
How It Gets Inside Cancer Cells
The process starts when the antibody portion of Enhertu binds to HER2 proteins on the surface of a cancer cell. Once attached, the cancer cell naturally pulls the entire complex inside through a process called internalization, essentially swallowing the drug. Inside the cell, enzymes break the linker apart, releasing the toxic payload directly where it can do the most damage. The freed drug then interferes with DNA replication, triggering the cell to die.
This sequence is why HER2 testing matters before treatment. The antibody needs HER2 on the cell surface to find its target. Without that protein acting as a landing pad, the drug has no way in.
The Bystander Effect
One of Enhertu’s most important features is something called the bystander effect. Tumors aren’t uniform. Even in a HER2-positive cancer, not every cell in the tumor expresses the same amount of HER2. Some neighboring cells may produce very little or none at all. Older targeted therapies could miss those cells entirely.
Enhertu’s payload is designed to cross cell membranes. Once released inside a HER2-positive cell, the freed drug can diffuse outward into surrounding tumor cells and kill them regardless of whether they express HER2. This ability to reach beyond the directly targeted cell helps Enhertu work against tumors that are mixed in their HER2 expression, a common challenge in cancer treatment.
Which Cancers It Treats
Enhertu is FDA-approved for several cancer types, all connected by HER2 involvement. In breast cancer, it covers a wide range of scenarios. It can be used as a first-line treatment for HER2-positive metastatic breast cancer (when combined with pertuzumab), or on its own after a prior HER2-targeted treatment has stopped working. It’s also approved for HER2-low breast cancer, defined as tumors with lower but still detectable levels of HER2, and even HER2-ultralow tumors that show faint membrane staining on testing. This expanded range is a direct result of the bystander effect and the drug’s high potency: it can work even when HER2 levels are far below what traditional HER2-targeted drugs require.
Beyond breast cancer, Enhertu is approved for HER2-positive gastric or gastroesophageal junction cancer after a prior trastuzumab-based treatment, for non-small cell lung cancer with specific HER2 mutations, and as a broader option for any HER2-positive (IHC 3+) solid tumor when no satisfactory alternative treatments exist.
How Effective It Has Been
The clinical results that built Enhertu’s reputation are striking. In the DESTINY-Breast03 trial, which compared Enhertu head-to-head against T-DM1 (an older antibody-drug conjugate) in HER2-positive metastatic breast cancer, patients on Enhertu went a median of 28.8 months before their cancer progressed. Patients on the older drug went 6.8 months. That’s roughly a fourfold difference in progression-free survival, a gap large enough to change the standard of care.
How Treatment Is Given
Enhertu is administered as an intravenous infusion once every three weeks. The standard dose for breast cancer is 5.4 mg per kilogram of body weight, so the exact amount varies by person. Treatment continues on this three-week cycle until the cancer progresses or side effects become unmanageable. The first infusion typically takes about 90 minutes, with subsequent infusions potentially shorter if well tolerated.
Lung Inflammation: The Key Risk
The most important side effect to understand with Enhertu is interstitial lung disease (ILD), a type of lung inflammation. Across pooled studies, roughly 12% of patients developed ILD. The large majority of cases, about 80%, were mild (grade 1 or 2), but severe and fatal cases have occurred. In the analyzed data, about 6% of ILD cases were fatal.
Dose matters here. Patients receiving a higher dose (6.4 mg/kg) developed ILD at more than twice the rate of those on the standard 5.4 mg/kg dose, which is one reason the lower dose became the recommended standard for breast cancer. Symptoms to be aware of include new or worsening cough, shortness of breath, and fever. Early detection makes a significant difference in outcomes, so any new respiratory symptoms during treatment should be reported to your care team promptly. If ILD is identified, treatment is typically paused or stopped depending on severity.