Non-small-cell lung cancer (NSCLC) is the most common kind of lung cancer. Between 2% to 4% of cases happen because of an alteration (change) in your human epidermal growth factor receptor 2 (HER2) gene.
This gene controls HER2, a protein that’s found on cells throughout your body, including in your lungs. It tells cells when to grow and spread. But if your HER2 gene doesn’t work like it should, your cells can grow out of control, which can lead to cancer.
Researchers keep learning more about HER2 and the role it plays in NSCLC. Here are some recent advances to know about and how they could affect your diagnosis and treatment.
Better, Faster Testing for HER2 NSCLC
HER2 mutations in lung cancer can now be found using a technique called next generation sequencing (NGS). A tiny amount of cancer cells are removed through a sample of your blood or tissue. Then, the genes are studied at a lab to spot specific changes.
That can include:
- HER2 mutations, mistakes in the gene sequence (order) that cause out-of-control cell growth
- HER2 amplifications, when your body makes too much HER2 protein
- HER2 overexpression, which means there’s too much HER2 protein on your cells
Knowing these issues helps doctors choose treatments that are most likely to work. But researchers are still looking for ways to get this key genetic information faster.
“Even though NGS testing has revolutionized the treatment of lung cancer, the procedure still comes with a significant lag time of weeks and sometimes will fail if there isn’t a sufficient sample to complete the testing,” says Collin Vu, MD, a medical oncologist at MemorialCare Cancer Institute at Orange Coast Medical Center in Fountain Valley, California.
One solution could involve artificial intelligence (AI).
“AI models trained on standard biopsy slides could help spot the visual and cellular signs that predict whether a cancer cell has a certain mutation, even without gene sequencing,” Vu says.
So far there’s only been limited success in doing that, but “as more advanced AI models and more complete training data are utilized in the future, this may ultimately allow for faster decision making for the use of targeted agents than is possible with current standard technology,” says Vu.
That doesn’t mean that AI will take over for your doctor.
”Partnering with AI platforms may be a part of the near future, but they will not be replacing humans in the medical space,” says Isabel Preeshagul, DO, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.
Advances in HER2 NSCLC Treatments
Treatment for HER2-mutated NSCLC usually begins with the same standard chemotherapy with or without immunotherapy that’s used to treat lung cancers that don’t have the HER2 gene. That helps kill the cancer cells in your body. Then, your doctor can try a special treatment that only targets the HER2 gene.
There are different types of targeted therapy options. HER2-directed drugs that have been recently approved by the FDA include:
- Fam-trastuzumab deruxtecan (T-DXd or Enhertu), which has an antibody that attaches to the HER2 protein, as well as a chemotherapy drug that destroys it
- Sevabertinib (Hyrnuo) stops abnormal HER2 signals that drive tumor growth
- Zongertinib (Hernexeos) blocks HER kinase, an enzyme that promotes cell growth. That can stop cancer cells from spreading.
The available targeted treatments for HER2-mutated NSCLC “work well, in that they have a high chance that the tumor will respond, ranging between approximately 50% to 70%,” Vu says. “Regardless, challenges do remain even as newer treatments are being approved for this condition.”
For example, in other cancers, like breast cancer, that are linked to HER2, “therapies used to treat [them] can work for long periods of time, often for years,” Vu says. “In lung cancer, the currently available treatments can keep the disease in check for on average a year or less.”
Experts believe this may be because of the different types of HER2 abnormalities seen in lung cancer. Some gene changes could also keep medications from working well.
What’s on the Horizon?
“Ongoing research in the development of drugs for the treatment of HER2-mutated lung cancer is trying to discover better forms of the drugs currently in use,” Vu says.
For instance, sevabertinib, which was approved by the FDA in November 2025, is “more selective against the HER2 mutated gene than previous generations of similar drugs and is noted to have a higher chance of response, longer durations of effectiveness, and theoretically, less toxicity,” says Vu.
So how could researchers improve on that?
Some options include:
Next-generation antibody-drug conjugates (ADCs). Get ready to see more drugs like trastuzumab rezetacan that pair an antibody against the mutated HER2 gene with an attached chemotherapy molecule. These are the fastest growing class of cancer drugs because they work like “homing missiles,” delivering powerful medicine only where it needs to go inside your body.
New ways to use targeted drugs. Other studies are rethinking when and how these powerful newer therapies are used. “There are active clinical trials using these targeted drugs earlier in the treatment course or in combination with other therapies, like the use of targeted agents in other lung cancer types,” Vu says. “This will ultimately allow for earlier, more aggressive therapies and hopefully longer survival times.”
Expect to see even more options to treat HER2-mutated NSCLC in the years ahead.
“For lung cancer in general, there’s a great deal of exploring targeted therapy in the early-stage setting,” says Preeshagul. “I’m excited about what developments lay here.”
