HER2-Targeted Therapies for Non-Small Cell Lung Cancer

If you have non-small cell lung cancer (NSCLC), your care team may test your tumor for changes in a gene called HER2. When certain changes are found, HER2-targeted therapies become an option. Three targeted therapies now have US Food and Drug Administration (FDA) approval for HER2-mutant NSCLC.^1-3

What does HER2-positive lung cancer mean?

HER2 is a protein that helps cells grow, and the HER2 gene carries the instructions for growth. In lung cancer, the change that matters most for treatment with a HER2-targeted therapy is a HER2 mutation. It leaves the HER2 protein switched on all the time, and that constant signal tells cancer cells to keep growing.⁴

About 3 out of every 100 people with NSCLC have this kind of mutation. It is more common in people who have never smoked, in women, and in people of Asian descent. These tumors are usually adenocarcinoma.^1,4

Why HER2 testing comes first

There is no way to know whether a HER2-targeted therapy fits you without a test, called biomarker testing. Panel testing, such as next-generation sequencing, is now standard care for advanced lung cancer and checks for HER2 and other gene changes at once.⁴

All 3 HER2-targeted therapies for NSCLC require an FDA-authorized test first. Some use tumor tissue, others a blood sample. Ask whether your tumor has had complete biomarker testing.^1-4

How do HER2-targeted therapies work?

These drugs work in 2 ways, depending on the specific medication:^2-4

• Antibody-drug conjugates (ADCs) – An antibody finds HER2 on the cancer cell surface, and a chemotherapy drug attached to it is carried inside the cell and kills it.
• Tyrosine kinase inhibitors (TKIs) – These pills block the HER2 signal on the cancer cell, which slows tumor growth.

Targeted therapy is not the same as immunotherapy or general chemotherapy. But an ADC that carries a chemotherapy drug can cause some of the same chemotherapy effects.⁴

Examples of HER2-targeted drugs

All 3 are approved for NSCLC that cannot be removed with surgery or has spread (metastatic), when an approved test confirms a HER2 mutation.^1-3,5

• Fam-trastuzumab deruxtecan (Enhertu®) – An ADC given by infusion. In August 2022, it became the first HER2-targeted drug approved for lung cancer, for people who have already been treated. Tumors shrank in 58 percent of people, and responses lasted a median of about 9 months.
• Zongertinib (Hernexeos®) – A TKI taken by mouth, approved in August 2025 for people who had already had treatment and in February 2026 for people starting treatment for the first time. Among 72 people taking it as first treatment, tumors shrank in 76 percent, and 64 percent of those responses lasted at least 6 months.
• Sevabertinib (Hyrnuo®) – A TKI taken by mouth, approved in November 2025 for people who have already been treated. Among 70 people who had not taken a HER2-targeted drug before, tumors shrank in 71 percent, with responses lasting a median of 9.2 months.

What are the possible side effects?

Side effects can vary depending on the specific drug you are taking.^1,3,6,7

• Fam-trastuzumab deruxtecan – Nausea, tiredness, constipation, hair loss, low appetite, vomiting, and low blood cell counts
• Zongertinib – Diarrhea, rash, liver problems, tiredness, nausea, muscle and joint pain, and upper respiratory infections. It can also affect how well the heart pumps.
• Sevabertinib – Diarrhea, rash, nail problems, mouth sores, and nausea. Diarrhea often starts in the first week. It can also cause eye and pancreas problems.

Fam-trastuzumab deruxtecan has a boxed warning, the strictest warning from the FDA. It has this warning because it can cause interstitial lung disease and pneumonitis, potentially resulting in swelling and scarring of lung tissue that is sometimes life-threatening, though most cases are mild and improve with treatment. ^1,4

All 3 drugs can cause lung inflammation. Tell your doctor right away about a new or worsening cough, fever, or trouble breathing.^1-3

These are not all the possible side effects of HER2-targeted therapies. Talk to your doctor about what to expect when taking HER2-targeted therapies. You also should call your doctor if you have any changes that concern you when taking HER2-targeted therapies.

Other things to know

Before beginning treatment for non-small cell lung cancer, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you take. This includes over-the-counter drugs.

All 3 approvals are accelerated approvals. The FDA may give accelerated approval to new drugs that treat a health condition that has few or no other treatments. Companies typically must run more studies to confirm the benefit; an approval can be narrowed or withdrawn if they do not.^1-3

Both TKIs interact with other drugs, and grapefruit (and grapefruit juice) should be avoided with sevabertinib.⁷

All 3 medications can harm an unborn baby, so ask about birth control considerations.^4,6,7

Talk with your doctor

Results and side effects are different for each person. Ask your care team whether your tumor has been tested for HER2, which option fits your situation, and what to watch for.