HER2 Mutant Non-Small Cell Lung Cancer

HER2 mutant non-small cell lung cancer is a rare form of lung cancer caused by specific genetic changes in the HER2 protein. Though it affects only a small percentage of lung cancer patients, recent advances in targeted treatments are offering new hope for those diagnosed with this condition.

Table of contents

• What is HER2 mutant non-small cell lung cancer?
• Who is affected?
• Understanding the role of HER2
• The importance of biomarker testing
• Treatment options
• Clinical outlook

What is HER2 mutant non-small cell lung cancer?

HER2 mutant non-small cell lung cancer is a specific type of lung cancer characterized by changes, or mutations, in the HER2 gene. Non-small cell lung cancer, often called NSCLC, is the most common form of lung cancer, accounting for 80% to 85% of all lung cancer cases.^[13]

HER2 mutations are found in approximately 2% to 4% of people with NSCLC.^[3][13] While this makes it a relatively rare subtype, it represents thousands of patients who may benefit from specific treatments designed to target this genetic change. Research shows that HER2 alterations can be present in 7% to 27% of newly diagnosed NSCLC cases when considering all types of HER2 changes, including mutations, gene amplifications, and protein overexpression.^[2]

Who is affected?

HER2 mutant lung cancer tends to affect specific groups of people more than others. Research has found that people with this type of lung cancer are more likely to be female, younger in age, and have a history of light smoking or never smoking at all.^[2][13]

Studies examining real-world patient populations have found that the majority of HER2 mutant NSCLC patients are women, with some studies showing up to 73% female patients. Many patients are never-smokers or former smokers, and a significant proportion are of Asian descent.^[7][14]

The median age at diagnosis is typically in the mid-50s to mid-60s, though the disease can affect both younger and older adults.^[7][14] Most patients have the adenocarcinoma form of NSCLC, which starts in the cells that line the airways and produce mucus.^[14]

Understanding the role of HER2

HER2 stands for human epidermal growth factor receptor 2. It is a protein that naturally lives on the surface of cells. This protein is part of a larger family called the ERBB family of tyrosine kinase receptors, which play important roles in how cells grow and communicate.^[2]

In healthy cells, HER2 helps control normal cell growth. However, mutations in the HER2 gene can cause the HER2 protein to become activated all the time, even when it shouldn’t be. These mutations most commonly occur at the base of the HER2 protein inside the cell.^[3] When HER2 is constantly activated, it can promote abnormal cell activity and encourage cancer cells to grow and multiply.^[3]

The most common type of HER2 mutation in lung cancer is called an exon 20 mutation. An exon is a section of a gene that contains instructions for making proteins. The HER2 exon 20 mutation is now recognized as a well-validated biomarker, which is a biological characteristic that can be measured and used to guide treatment decisions.^[2]

The importance of biomarker testing

Identifying HER2 mutations requires special testing called biomarker testing or molecular testing. This type of testing looks for specific genetic changes in cancer cells that can help doctors choose the most effective treatment.^[7]

All patients with advanced NSCLC should receive comprehensive biomarker testing. This testing is considered standard care and should look for HER2 mutations along with other important genetic changes, such as those in the EGFR, ALK, and BRAF genes.^[7] Panel testing, such as next-generation sequencing, allows doctors to test for multiple genetic changes at once.^[7]

Two companion diagnostic tests have been approved specifically for detecting HER2 gene mutations. The Guardant360 CDx test uses a blood sample, while the Oncomine Dx Target Test uses a sample of tumor tissue.^[7] Before receiving certain HER2-targeted treatments, patients must have their cancer tested to confirm the presence of an activating HER2 mutation.^[3]

Treatment options

Treatment for HER2 mutant NSCLC has evolved significantly in recent years. Until 2022, there were no FDA-approved targeted therapies specifically for patients with HER2 mutations in lung cancer.^[7] This represented an important unmet clinical need, as research showed that HER2 alterations may also develop as a resistance mechanism in up to 10% of patients with EGFR-mutated NSCLC who are being treated with other targeted therapies.^[2]

In August 2022, the Food and Drug Administration granted accelerated approval for trastuzumab deruxtecan, also known as Enhertu, to treat adults with NSCLC that has a certain activating mutation in the HER2 gene.^[7] To be eligible for this treatment, patients must have cancer that cannot be removed by surgery or has spread to other parts of the body, and they must have already received one or more previous cancer treatments.^[7]

Trastuzumab deruxtecan belongs to a class of drugs called antibody-drug conjugates, or ADCs. These treatments work by chemically linking a cancer-fighting drug to an antibody that targets a specific protein on the cancer cell surface. The antibody delivers the drug directly to cancer cells, which can make treatment more effective while potentially reducing side effects on healthy cells.^[7]

The approval was based on results from a clinical trial called DESTINY-Lung02, which included 102 patients. In this study, tumors shrank in 58% of patients who received the treatment, including one person whose tumors disappeared completely. Among those whose tumors shrank, the treatment kept their cancer under control for a median of 9 months.^[7]

Researchers are also studying other types of HER2-targeted treatments, including novel tyrosine kinase inhibitors, or TKIs. These are drugs that work by blocking specific enzymes involved in cancer cell growth. Several TKIs targeting HER2 exon 20 mutations have shown promising results in clinical trials, including poziotinib, mobocertinib, pyrotinib, zongertinib, and sevabertinib.^[2][6][12]

Clinical outlook

The outlook for patients with HER2 mutant NSCLC varies depending on the stage of disease at diagnosis and how the cancer responds to treatment. Research has shown that individuals with HER2 mutations may have a poorer prognosis and a higher incidence of brain metastases compared to those with other types of NSCLC.^[13]

In studies of patients with advanced disease who received standard chemotherapy before HER2-targeted treatments were available, the median overall survival was approximately 10.7 months for stage IV patients.^[11] However, patients diagnosed at earlier stages who could receive surgery had much better outcomes, with all patients with stage I-III disease alive at 2 years in one study.^[14]

The development of targeted therapies specifically for HER2 mutations represents a significant advance. As one lung cancer specialist noted, the approval of trastuzumab deruxtecan is highly anticipated and exciting because, up until that point, there were no FDA-approved targeted therapies for HER2-mutant lung cancer.^[7]

Research continues to advance rapidly in this field. Scientists are working to better understand which specific HER2 alterations respond best to different treatments, particularly for HER2 amplification and overexpression. Future studies will focus on determining the best sequence of treatments and identifying optimal combination therapies based on more complete data from clinical trials and toxicity profiles.^[2]