Enhertu: FDA Clears New Pre- and Post-Surgery Uses in HER2-Positive Early Breast Cancer

Enhertu (fam-trastuzumab deruxtecan-nxki) is a prescription intravenous (IV) targeted cancer treatment called an antibody-drug conjugate. The FDA has approved it for two uses in adults with HER2-positive early-stage breast cancer. It can now be used before surgery (neoadjuvant care) along with other cancer treatments (a taxane plus trastuzumab and pertuzumab therapy often called THP) for patients with stage II or III HER2-positive breast cancer. It is also approved for use after surgery (adjuvant therapy) in patients who still have invasive cancer despite prior treatment with trastuzumab (with or without pertuzumab) and taxane-based therapies.

The FDA also cleared two lab tests – the PATHWAY anti‑HER‑2/neu (4B5) IHC and the VENTANA HER2 Dual ISH DNA Probe Cocktail – to help identify eligible patients.

Breast cancer remains one of the leading causes of cancer deaths worldwide, with more than 320,000 cases diagnosed each year. HER2 is a protein found on the surface of many cancer cells, promoting their growth and survival. Enhanced expression of the HER2 gene leads to overproduction of the HER2 protein, which is often linked to more aggressive breast cancer and poor outcomes. About 1 in 5 breast cancer cases are HER2-positive, and many patients face a higher risk of the disease returning even after treatment (recurrence).

Treatment usually happens in two stages: before surgery (neoadjuvant) and after surgery (adjuvant). The goal of early treatment is to completely remove cancer cells before surgery, which can improve long-term survival. But about half of the patients show a partial response to neoadjuvant therapy, increasing their risk of recurrence. In some cases, a poor response to adjuvant therapy may lead to invasive cancer or death.

Enhertu is a type of medicine that combines an HER2-targeting antibody with a cancer-fighting medicine, connected via a special linker. Once Enhertu attaches to the HER2 protein on tumor cells, it is taken inside, where the linker is removed, and the cancer-fighting medicine is released, triggering cancer cell death. Thus, Enhertu’s unique design helps deliver the treatment directly to the cancer cells while limiting damage to healthy cells. Pertuzumab and trastuzumab are lab-made antibodies that target the HER2 protein on cancer cells, blocking signals that help the cells grow and spread while also helping the immune system recognize and destroy them.

First approved in 2019, Enhertu is also approved for HER2-low and HER2-ultralow breast cancers and other HER2-positive solid tumors, including certain types of lung and stomach cancers.

This approval matters because it places Enhertu earlier in the treatment plan, when therapy goals include curing and lowering the chance of recurrence in those who still have the disease. This provides another choice alongside standard treatment for managing HER2-positive early breast cancer.

Why Was It Approved?

The FDA’s approval is based on results from two clinical studies that showed that Enhertu made for significant clinical improvement in both neoadjuvant and adjuvant settings in patients with HER2-positive, high-risk, early-stage breast cancer.

The effectiveness of Enhertu followed by THP was studied in a trial involving 927 patients with HER2-positive early-stage breast cancer. Patients were split into three groups to receive eight cycles of pre-surgery or neoadjuvant treatment: one group received four cycles of Enhertu followed by four cycles of THP, another received standard chemotherapy (doxorubicin and cyclophosphamide for four cycles followed by THP), and the third group received investigational therapy for all eight cycles. The main goal was to measure pathologic complete response (pCR), meaning no invasive cancer was found in the breast or lymph nodes after surgery. The pCR rate was 67.3% in the Enhertu-THP group, compared with 56.3% in the standard chemotherapy group, showing a statistically significant improvement.

Another trial evaluated Enhertu as an adjuvant treatment in 1,635 patients with HER2-positive breast cancer who still had residual disease after prior therapy. Patients received either Enhertu or trastuzumab emtansine (T-DM1) for up to 14 cycles. After three years, 92.4% of patients treated with Enhertu were alive without invasive disease recurrence, compared with 83.7% in the T-DM1 group. At the time of the invasive disease-free survival analysis, a total of 47 (2.9%) of patients had died across both study arms. No new safety issues were found with Enhertu in either of the clinical studies.

Common side effects of Enhertu followed by THP in HER2-positive early breast cancer include low hemoglobin and potassium levels and reduced white blood cell (neutrophil and lymphocyte) counts. Other frequent effects are nausea, diarrhea, vomiting, fatigue, hair loss, nerve damage (peripheral neuropathy), rash, mouth sores (stomatitis), constipation, muscle and joint pain, loss of appetite, and increased liver enzyme levels. Serious adverse reactions such as decreased platelet count, lung inflammation (interstitial lung disease or ILD) and pneumonitis, radiation pneumonitis, or pneumonia can happen and may be fatal. People treated with Enhertu may have a higher risk of developing left ventricular dysfunction, a condition in which the heart’s left ventricle doesn’t pump blood as well as it should.

What Do I Need to Know?

Your health care provider must confirm HER2-positive status to use Enhertu in early breast cancer care. Enhertu is given only by IV infusion. It is not given as a quick IV push or bolus. The first infusion usually takes about 90 minutes. If you tolerate it, later infusions may run about 30 minutes.

Before starting and prior to each dose of Enhertu, your health care provider will check your blood counts to watch for neutropenia and platelet levels. They will also assess your heart’s pumping function – left ventricular ejection fraction (LVEF) – at baseline and monitor it during the treatment, if required.

Your health care provider will stop Enhertu permanently if you get confirmed lung inflammation that is more than mild, your LVEF values are very low, or if you show symptoms that suggest heart failure.

Be sure to let your health care provider know about your medical history. Tell them about all the medicines, including prescription and over-the-counter medicines, vitamins, and herbal supplements, you take.

Enhertu can harm a fetus. Your health care provider will check your pregnancy status before treatment. Use effective birth control during treatment and for seven months after the last dose if you can become pregnant and for four months if your partner can become pregnant. Do not breastfeed during treatment, and follow the timing on the label after your last dose.

Call your health care provider right away if you notice a new or worsening cough, trouble breathing, or a fever, as these could be signs of ILD.