Tarik Hadid, MD, MPH, is a thoracic oncologist at the Karmanos Cancer Institute in Detroit, Michigan, who treats people with mutated lung cancers. The information shared here represents his expertise in HER2-mutated NSCLC.
HER2-mutated non-small-cell lung cancer (NSCLC) is a rare type of lung cancer affecting 2% to 4% of people with lung cancer. The HER2 mutation is the driver behind the cancer cells’ uncontrolled growth.
To help you understand this type of cancer better, Tarik Hadid, MD, MPH, a thoracic oncologist at the Karmanos Cancer Institute in Detroit, Michigan, offers his clinical insights and expertise.
Can you explain what “HER2-mutated non-small-cell lung cancer” means in simple terms?
Lung cancer is divided into two major types, small-cell and non-small-cell. Among the non-small-cell type, there are numerous mutations that could be present in the cancer cells and drive cancer growth. One of those mutations can involve the HER2 gene. HER2 is a part of normal cell function. It maintains growth and repair of cells. HER2 in normal cells will balance the growth and division of the cell with the repair and survival of the cell. When HER2 is mutated, this balance is lost, which turns the cell from a normal controlled cell into a malignant or cancer cell with uncontrolled growth, which results in lung cancer.
A term we use more frequently than HER2 mutation now is HER2 alteration. HER2 mutation is a subset of HER2 alterations, which also include HER2 overexpression and HER2 amplification. HER2 overexpression means that the number of proteins produced by the HER2 gene is high in the cancer cells, but the gene itself is not mutated. HER2 amplification means that copy of the DNA in the cell is also increased, but the gene did not specifically mutate. The most tested and researched HER2 alteration is HER2 mutation, and that's the alteration for which we have an effective targeted treatment. HER2 overexpression and HER2 amplification are currently being researched extensively by multiple institutions.
Why is knowing your HER2 status important in NSCLC?
HER2 mutated cancer does not follow the same algorithm as most lung cancers. For example, it tends to happen more frequently in young nonsmoking women. It's a different population than the one in which we see most lung cancer. HER2 is a rare mutation. It occurs in only about 2% to 4% of all non-small-cell lung cancers. That's critical because you really must look for it to find it. If it's not tested, you will not know about it and you will lose effective treatment options. We encourage everyone with NSCLC to undergo genetic testing for multiple genes — HER2 being one of them — because this information impacts treatment in an enormous way. So even though it's rare, it is an important finding because of the treatment implications. Since the field of HER2 is relatively new, in lung cancer, seeking an opinion with an institution and a team with experience in HER2 is key, particularly institutions that are involved in HER2 research. This may give you access to teams with the most up-to-date knowledge in and treatment of HER2-mutated NSCLC.
What kinds of treatments are available for HER2-mutated NSCLC?
HER2 treatment is typically individualized based on the patient condition, cancer stage, and type of HER2 alteration. In general, first-line treatment is similar to how we treat most lung cancer, which typically involves immunotherapy with or without chemotherapy. Once the first treatment is no longer effective, second-line treatment typically involves targeted therapy, specifically drugs that target the HER2 gene. Trastuzumab deruxtecan is a treatment option for patients with HER2-mutated NSCLC. This drug is called an antibody drug conjugate, which I also call “smart chemo.” It’s chemotherapy connected to a special antibody that specifically targets the cells that have the HER2-mutated gene, which makes it a precise treatment. This drug preferentially and effectively targets the HER2-mutated cells and spares the normal cells, which minimize the side effects. Another effective drug that was just recently approved for treatment of HER2 lung cancer is called zongertinib. You take it orally, which is more convenient than other options, and in recently published studies, it’s been effective at shrinking tumors in over 70% of people with HER2-mutated NSCLC. In November 2025, the FDA gave accelerated approval to another oral drug, sevabertinib (Hyrnuo) for treatment of certain types of locally advanced NSCLC with a HER2 mutation. While these are the only options currently approved by the FDA, there are numerous trials and newer drugs being tested, both as second-line treatments and even in first-line treatments you could take immediately after diagnosis.
What are some ways people can be an active part of their own HER2-mutated NSCLC team?
Read about your disease, know about it, and have good background information about it, and be involved in your care. Ask your doctor what type of gene alteration you have. Ask about your treatment options and discuss why certain treatment choices are recommended over others. Choice of therapy can vary based on your condition, baseline organ functions, cancer stage, and other factors. For example, HER2 drugs can reversibly affect the heart function, so your doctor will need to test your heart function before starting those treatments and may not recommend some of these choices if your heart function is reduced. Ask about what clinical trials may be available for you and whether you can take part in them. Clinical trials are an excellent way to improve treatment and they also give you access to new drugs that are being developed or are in the process of being tested for HER2-mutated NSCLC. Provide your doctor with information about symptoms, priorities, preferences, and any concerns you may have. Read about HER2-targeted drugs, as these are additional options available to you given your HER2 mutation that are not useful for people without this mutation.
