Hernexeos: FDA Approves First-Line Use for Certain Advanced Non-Small-Cell Lung Cancers With HER2 Mutations

Hernexeos (zongertinib) is a prescription medicine known as a kinase inhibitor that is used for treating adults with advanced non-small-cell lung cancer (NSCLC) that cannot be removed surgically or has spread to other parts of the body (metastasized). The FDA has granted accelerated approval to Hernexeos as a first-choice targeted oral anticancer treatment for adults whose tumors have specific genetic changes known as tyrosine kinase domain (TKD) activating mutations in the human epidermal growth factor receptor 2 (HER2 [ERBB2]) gene, as confirmed by an FDA-authorized test.

Lung cancer is the leading cause of cancer-related deaths across the world, with the yearly number of new cases expected to climb past 3 million by 2040. NSCLC is the most common form of lung cancer. Because it is often found late, survival rates are low, with fewer than 1 in 10 people surviving five years after diagnosis; it also often impacts patients’ psychological and physical well-being. Although rare, about 4% of patients with NSCLC have mutations in their HER2 (ERBB2) gene, which stimulates unrestricted growth of cancer cells, preventing their natural death and helping them spread to other parts of the body.

Hernexeos belongs to a group of medicines called tyrosine kinase inhibitors that work by targeting HER2 and blocking the activity of the faulty HER2 protein. Its unique design ensures that it selectively binds to HER2 (ERBB2) in a lasting way without blocking the activity of normal epidermal growth factor receptor (EGFR). This distinctive design feature may help reduce some of the side effects that can come from blocking EGFR.

This approval is noteworthy because Hernexeos is the first oral targeted anticancer therapy that can be started as an initial treatment for advanced HER2‑mutant NSCLC. Your health care provider will use comprehensive biomarker testing, often with next‑generation sequencing, to look for the HER2 (ERBB2) TKD-activating mutations that make you eligible to get this treatment.

Why Was It Approved?

The FDA used the accelerated pathway for this approval because a clinical study showed that as a once-daily pill, Hernexeos was safe and effective in producing meaningful tumor shrinkage in previously untreated adults with inoperable or metastatic HER2‑mutant, non-squamous NSCLC. But continued approval of this medicine may depend on confirming that these benefits translate into clear clinical outcomes in a larger ongoing trial.

The study included 72 patients with advanced non-squamous NSCLC that could not be removed surgically or had spread to other parts of the body. All the people in the study had HER2 (ERBB2) TKD-activating mutations and had not received any prior treatment for their advanced cancer. The patients were given Hernexeos orally once daily until their illness worsened or the side effects became unbearably severe.

As a result, 76% of patients saw their cancer respond to the medicine, with 11% responding completely and 65% showing a partial response. Among those who responded to Hernexeos, the cancer remained under control for at least six months in 64% of the patients and for least 12 months in 44% of the patients.

The most common side effects were diarrhea, skin rashes, changes in liver‑related lab findings, tiredness, nausea, muscle or joint pain, upper airway infections like the common cold, and lab abnormalities including low blood potassium levels and decreased blood neutrophil (a type of white blood cell) counts. Serious side effects included severe liver injury, a decline in the pumping ability of the heart (left ventricular dysfunction), and lung inflammation called interstitial lung disease or pneumonitis.

What Do I Need to Know?

You need an FDA‑authorized test to confirm TKD-activating mutations in your cancer’s HER2 (ERBB2) gene before you start Hernexeos. Take the medicine by mouth once daily, with or without food. Swallow the tablets whole with water. Do not split, crush, or chew them. If you miss a dose, take it within 12 hours. But if more time has passed, skip it and take your next dose at the usual time.

The dose depends on your body weight. Treatment continues as long as it’s working and the side effects are manageable.

Your health care provider will check your heart function before starting your treatment and will also monitor it during treatment. They will also do blood tests to assess your liver function – every two weeks for the first 12 weeks, and then monthly, depending on your health status.

Tell your health care provider about all of your medical conditions and all the prescription and over-the-counter medicines, vitamins, and herbal supplements you take. Certain medicines that affect how your liver processes medicines (CYP3A inducers) can lower the amount of Hernexeos in your body and make it less effective. Other medicines (certain BCRP transporter medicines) are very sensitive to small changes in medicine levels, so taking them with Hernexeos may require close monitoring to help keep you safe.

Before starting Hernexeos, let your health care provider know about any liver or heart problems or lung or breathing problems, other than lung cancer, that you have and about other details of your medical history.

Be sure to tell your health care provider if you are pregnant, planning to become pregnant, or breastfeeding, as this medicine can harm a fetus. Use effective birth control and avoid breastfeeding during treatment and for two weeks after your last dose.

Contact your health care provider right away if you notice new or worse breathing problems, such as coughing, shortness of breath, or a fever; dark urine; yellowing of your skin or eyes; pain on the upper right side of your belly area; unusual bleeding or bruising; an irregular or pounding heartbeat; swelling of the legs, ankles, or feet; dizziness; or confusion, as these may be symptoms of serious side effects.