What Are EGFR Exon 20 Insertion Mutations?

A Genetic Subtype of Non-Small Cell Lung Cancer

If you have non-small cell lung cancer (NSCLC), you may have been told that your cancer is positive for EGFR (EGFR+). The EGFR (epidermal growth factor receptor) is a gene that can change, or mutate, in some people with NSCLC and cause a cancer to grow more rapidly. But not all EGFR mutations are the same, and one specific type is called an EGFR exon 20 insertion mutation.

People with this EGFR mutation don’t respond as well to therapies used to treat other kinds of EGFR changes in NSCLCs. Research and clinical trials in this area are active, however, and science is making progress with new therapies for people who have genetic changes like the EGFR exon 20 mutations.

Cancer patient in oncology unit

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What Are EGFR Mutations?

Cancers are partly caused by genetic changes in the unique DNA that a person carries. Usually, by the time a person develops cancer, the cells involved have accumulated multiple genetic mutations that alter their behavior.

Because of its role in regulating cell growth, an EGFR mutation may signal the production of more EGFR protein than normal because the mutation means it's no longer working properly. This can cause cells to grow and divide more rapidly and contribute to the cancer's spread.

EGFR is only one type of mutation that can be involved in the development of NSCLC, and not everyone has it or its subtypes. But if your healthcare provider says you are EGFR+, that means you have an EGFR mutation—and one of the subtype possibilities is the EGFR exon 20 insertion mutation.

Types of Genetic Mutation in NSCLC

An EGFR mutation is just one type of genetic change found in people with lung cancer. Other genes, including BRAF, KRAS, ROS1, or ALK, may be altered and influence NSCLC growth and spread. Genetic testing is now routine as part of precision treatment because targeted therapies, like Rybrevant (amivantamab-vmjw), can be matched to the specific genetic mutations found in people diagnosed with cancer.

What Is an EGFR Exon 20 Insertion Mutation? 

The exon 20 insertion mutation is a specific type of mutation in the EGFR gene. In this type, a bit of genetic material is inserted accidentally into a specific region of the gene called the exon 20.

The exon 20 insertion mutation occurs in up to 4% of people diagnosed with NSCLC overall. In the subset of those who have mutations in EGFR, about 4 to 12% have this type of mutation. This makes it the third most common type of EGFR mutation.

The exon 20 insertion mutation is less common even among people who have EGFR mutations, but it's also linked to less favorable outcomes. That's partly because targeted therapies used to treat other EGFR mutations, including the three generations of ever-evolving medications called tyrosine kinase inhibitors, are not effective in people who have an exon 20 insertion mutation.


If you are diagnosed with NSCLC, your healthcare provider will almost certainly recommend testing for EGFR mutations. This is especially important for those with the adenocarcinoma type of NSCLC.

Genetic testing is usually based on a tissue sample taken from the affected lung during a lung biopsy. It is possible to test for EGFR genetic material by using a blood sample, and a technique called next-generation sequencing makes these tests, called liquid biopsies, useful for more than one gene at a time. But the lung biopsy remains the most definitive way to test for genetics.

Once they have a sample, lab technicians will take a microscopic look at the DNA of the cancer cells and see if there is an EGFR mutation. They also analyze the specific type of mutation in EGFR, which is how they can determine if there is an exon 20 insertion mutation.

But don't be surprised if they look for other mutations too. Often, when a person is getting tested for EGFR, they will be tested for other important genetic alterations that may be linked to their cancer, such as KRAS and ALK.

The findings of the genetic tests will help determine your best treatment options. Your health care team may be able to deliver targeted therapies specifically designed for your cancer and genetic type, such as Rybrevant, which targets the exon 20 insertion mutation.


Unfortunately, NSCLC is most often diagnosed after the disease is fairly advanced. If this is the case, treatment doesn’t usually completely cure the disease. The goal is to limit cancer spread and decrease symptoms.

Historically, chemotherapy was the recommended treatment for most people with NSCLC. For example, a platinum-based chemotherapy (such as cisplatin or carboplatin) might be used to reduce cancer growth and prolong life.

Beginning in the early 2000s, though, the development of new targeted therapies helped researchers to discover that some of these EGFR inhibitors worked as well or better for people with cancer linked to EGFR mutations.

Tyrosine Kinase Inhibitors for Certain EGFR Mutations

EGFR inhibitors are also referred to as tyrosine kinase inhibitors (TKIs), for the general type of enzyme that they block. These therapies can help turn off the overactive EGFR and slow cancer growth in the majority of people with EGFR mutations that respond to TKIs. They include:

  • Gilotrif (afatinib)
  • Iressa (gefitinib)
  • Tagrisso (osimertinib)
  • Tarceva (erlotinib)
  • Vizimpro (dacomitinib)

Still, the EGFR inhibitors didn't work when treating people with the exon 20 insertion mutation, and there was no option for this mutation until the FDA approved Rybrevant (amivantamab-vmjw) in May 2021. It is the first targeted therapy available for people with this type of EGFR mutation.

The exon 20 insertion mutation isn’t the only less common type of mutation in EGFR, and some of these other mutations also fail to respond to EGFR inhibitors. Other targeted therapies are being developed to specifically target rare EGFR mutations like the exon 20 insertion mutation.

Treatment When Positive for the EGFR Exon 20 Insertion Mutation

Because the EGFR inhibitors don't work for people with the exon 20 insertion mutation, chemotherapy usually remained the first-line treatment for people with advanced disease.

A targeted therapy drug offers a promising alternative. If your disease is less advanced, surgery and/or radiation therapy may be options too. Some types of immunotherapy may work for some people, although they've been less effective in people with EGFR mutations overall. Additionally, you and your healthcare provider may combine one or more of these therapies, depending on the situation.

Clinical Trials

Scientists are actively working to find therapies to treat people with the EGFR exon 20 insertion mutation more effectively. The hope for the future is that more targeted therapies will be found to treat people with this and other mutations.

A number of clinical trials are investigating potential treatments that might be effective. Some of these are agents or combinations of agents approved for other types of NSCLC. Others are brand-new therapies.

Clinical trials are designed to advance the medicine, but those advances in cancer care also mean that, more than ever, the trials have the potential to benefit individuals with specific cancer types.

So talk to your oncologist. Learn about clinical trials, and tap into resources to help you find information about NSCLC and any available trials that may be a more precise match for you.


People with the exon 20 insertion mutation in EGFR tend not to live as long as people who have other types of EGFR mutations that respond to the TKI drugs. But a lot will depend on your cancer stage and the other specifics of your medical situation. Your oncologist can give you an idea of what you might expect and what treatment possibilities may be available. 

A Word From Verywell

New treatment possibilities are a hopeful sign, especially when none existed before. So even if there’s a lot to learn about this type of lung cancer, try to keep the same sense of optimism that new therapies represent.

It's important to become a good partner and advocate for your own care. That said, the complexity of the information may seem intimidating and the diagnosis may feel overwhelming. Let your loved ones know when you feel you need support, and let them help you work through the changes and challenges you will encounter on this journey.

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Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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By Ruth Jessen Hickman, MD
Ruth Jessen Hickman, MD, is a freelance medical and health writer and published book author.