The epidermal growth factor receptor (EGFR) is a protein on cell surfaces that regulates growth and division. The EGFR protein is produced based on instructions from the EGFR gene. “EGFR Exon 20” refers to specific genetic alterations, known as insertion mutations, within the 20th exon of the EGFR gene. These mutations involve the addition of genetic material into this region. While over 100 different changes can occur in the EGFR gene, exon 20 insertions are a distinct type of mutation.
Significance in Cancer
EGFR exon 20 insertion mutations are “driver mutations” in certain cancers, particularly non-small cell lung cancer (NSCLC). They are the third most common EGFR mutation in NSCLC, making up about 1% to 10% of all NSCLC cases. These insertions add amino acids within the EGFR protein’s kinase domain, causing structural changes. This alteration permanently activates the receptor, mimicking continuous growth factor signals and driving uncontrolled cell growth. This persistent activation of the EGFR pathway drives tumor development. Patients with EGFR exon 20 insertion mutations often share characteristics with those who have more common EGFR mutations, such as being non-smokers, female, and having lung adenocarcinoma. However, these specific mutations are resistant to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs), drugs typically used to block cancer growth in other EGFR-mutated cancers. This inherent resistance makes them a challenging subtype to treat.
Identifying the Mutation
Detecting EGFR exon 20 insertion mutations involves precise genetic testing. These tests are usually performed on tumor tissue obtained through biopsies, where a sample of cells is taken from the tumor using a needle or bronchoscope. If a tissue biopsy is not feasible or sufficient, a liquid biopsy (blood test) can be used to look for biomarkers. Next-generation sequencing (NGS) is the preferred method for detection. NGS can identify a wide range of EGFR exon 20 insertion variants, with over 100 unique types identified. While Polymerase chain reaction (PCR)-based assays are also used, they may miss a significant proportion of these mutations. Accurate identification is important for guiding treatment decisions, as not all EGFR tests can find exon 20 insertions.
Targeted Therapies
Treatment approaches for EGFR exon 20 insertion mutations have advanced, offering specific targeted therapies. Unlike more common EGFR mutations, exon 20 insertion tumors do not respond well to earlier generations of EGFR TKIs, such as gefitinib and erlotinib, due to structural changes that restrict drug access to the protein’s binding pocket. This distinct resistance profile necessitated the development of new drugs. Several targeted therapies are approved or in development for these specific mutations. Amivantamab (Rybrevant) is an antibody-based therapy that targets both EGFR and MET proteins, involved in cancer cell growth. It received accelerated approval in May 2021 for patients whose disease progressed after platinum-based chemotherapy. Amivantamab works through multiple mechanisms, including blocking ligands and degrading receptors. Mobocertinib (Exkivity) was an oral TKI specifically designed for EGFR exon 20 insertion mutations, approved in September 2021 as the first oral therapy for this patient group. However, mobocertinib was later withdrawn from the market. Sunvozertinib (Zegfrovy) is a newer oral, irreversible EGFR TKI that received accelerated FDA approval for metastatic NSCLC with EGFR exon 20 insertion mutations after platinum-based chemotherapy. It works by irreversibly binding to the tyrosine kinase domain of the EGFR receptor, blocking signaling pathways that promote cell proliferation and survival.
Living with the Mutation
Managing an EGFR exon 20 insertion mutation diagnosis involves continuous monitoring and a collaborative approach to care. Patients undergo ongoing surveillance to track the cancer’s response to therapy and detect progression, allowing for timely adjustments to the treatment plan. Managing potential side effects from targeted therapies is another aspect of living with this mutation. Common side effects can include skin rash and diarrhea, while more serious but less frequent side effects might involve lung or heart issues. A multidisciplinary care team, including oncologists, nurses, and other specialists, works together to address these challenges and support the patient’s well-being. Patient support resources, such as advocacy groups and educational materials, can also provide valuable assistance throughout the treatment journey.