EGFR exon 20
Epidermal growth factor receptor (EGFR) exon 20
EGFR exon 20 Mutation
EGFR exon 20 mutations are generally a heterogeneous group, some of which are responsive to targeted therapy, requiring a detailed knowledge of the specific alteration.1 Most alterations are a diverse group of in-frame insertion (ex20ins) mutations. More than 60 unique variants of EGFRex20ins have been identified, representing up to 12% of all EGFR mutations in NSCLC and 0.1% to 4% of all mutations in NSCLC.2 As such, EGFRex20ins are the third most common EGFR-activating mutation, following exon 19 deletion and L858R.2 EGFRex20ins mutations induce structural changes that lead to activation of the kinase domain.3 However, these mutations often show resistance to first- and second-generation EGFR tyrosine kinase inhibitors (EGFRi).3
EGFR exon 20 Testing
Because some EGFRex20 mutations may be sensitive to first- and third-generation inhibitors, the specific sequence of EGFRex20 insertion mutations remains important. Targeted PCR-based approaches for detection of EGFR variants may under-detect EGFRex20ins events; therefore, NGS-based strategies are preferred.1
EGFR exon 20 Targeted Therapy
Effective treatment targeted to EGFRex20ins in NSCLC has been elusive. The most commonly represented EGFRex20 insertions/duplications in clinical studies evaluating specific targets have been insASV, insSVD, and insNPH, although a wide spectrum of other alterations were included. No evidence currently exists that the specific alteration type impacts the likelihood of responsiveness to this class of targeted therapy.1 Presently, amivantamab, a monoclonal antibody, is the only FDA-approved treatment for EGFRex20ins NSCLC on the market. In 2021, mobocertinib, an EGFRi, was granted accelerated approval by the FDA but was voluntarily withdrawn by the manufacturer in October 2023 as the confirmatory trial did not meet its primary end point.4 In November 2022, the FDA issued a complete response letter to the manufacturer of poziotinib, another EGFRi. Clinical trials have revealed differences in EGFRi sensitivity for distinct types of exon 20 insertions, demonstrating the heterogeneity of these mutations.3 The structural changes caused by EGFRex20ins result in a relatively small drug binding pocket which has prevented first generation EGFRi binding.3 Success of next generation EGFRi with EGFRex20ins will depend upon being able to fit into this binding pocket.2
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References
1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2024. Accessed May 17, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Reiss JW, Gandara DR, Frampton GM, Madison R, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations indentified by comprehensive genomic profiling of NSCLC. J Thorac Onc. 2018;13(10):1560-1568. doi:10.1016/j.tho.2018.06.019
3. Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020;61:167-179. doi:10.1016/j.semcancer.2019.09.015
4. Takeda provides update on EXKIVITY (mobocertinib). News release. Takeda. October 2, 2023. Accessed April 22, 2024. https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Provides-Update-on-EXKIVITY-mobocertinib/
