EGFR

  • Epidermal growth factor receptor (EGFR)
  • Gene location: chromosome 7 (7p11)

EGFR Biology

  • EGFR was first described in 1973 and was later acknowledged as the first of 4 human epidermal tyrosine kinase receptors (HER1-4).1
  • EGFR is present in various organs and plays a crucial role in regulating cell proliferation, survival, and differentiation, both during development and in maintaining normal physiological functions.1
  • Dysregulation of EGFR occurs in a number of ways and in NSCLC the most important are activating EGFR mutations and increased protein expression.1

Etiology and Epidemiology

  • EGFR mutations occur in about 32% of all NSCLCs, with prevalence differing based on geographic region and ethnicity. The highest rates are observed in Asians (~49%), while the lowest are found in Europeans (~12%). EGFR mutations are also more common in females (~43%) and in smokers (~49%).2,3
  • Common EGFR mutations, including exon 19 deletions and the exon 21 L858R point mutation, account for 85% to 90% of all EGFR mutations in NSCLC. These mutations are strong predictors of a positive clinical response to EGFR tyrosine kinase inhibitors (EGFRi).4-6
  • They enable first-generation EGFRi to outcompete adenosine triphosphate (ATP) binding to the mutated receptor, preventing its activation and leading a higher response rate and extended progression-free survival.5,6
  • However, the EGFR T790M mutation increases ATP affinity, leading to the activation of the receptor despite the presence of inhibitors.6
  • Second-generation EGFRi were developed to bind irreversibly to EGFR and overcome resistance. Their efficacy has been limited by poor selectivity and toxicities.5,6
  • Third-generation EGFRi, such as osimertinib, have shown greater selectivity for EGFR T790M mutations vs the wild-type EGFR, leading to their successful use in treating patients with NSCLC with EGFR T790M mutations.5,6
  • Uncommon EGFR mutations, including those within exons 18 to 25, comprise the remaining 10% to 15% of EGFR mutations in NSCLC; these are associated with poorer responses to EGFRi.6,7 These mutations (including exon 18 deletions and substitutions in EGFR E709 and EGFR G719X, exon 19 insertions, exon 20 insertions, the EGFR S768I and exon 21 L861Q substitutions, EGFR kinase domain duplications, and complex mutations) exhibit varying sensitivities to EGFRi compared with common mutations.6

EGFR Testing

When to Test:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.8
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis.8
  • In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.8

Available Testing Methods:

  • Next-generation sequencing (NGS), real-time polymerase chain reaction (PCR), and Sanger sequencing (ideally paired with tumor enrichment) are the most commonly deployed methodologies for examining alterations in EGFR.8

Guideline Recommendations for Testing:

  • To optimize tissue use and minimize waste, the National Comprehensive Cancer Network advises broad molecular profiling through a validated test.
  • In patients with advanced or metastatic NSCLC, testing should include, at a minimum, the following biomarkers: ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, METex14, NTRK, RET, ROS1, and PD-L1.
  • Liquid biopsy may also be considered in conjunction with tissue NGS testing. For patients with early-stage NSCLC, testing should assess PD-L1 status, EGFR mutations, and ALK rearrangements.8

EGFR Targeted Therapies

Available Agents:

  • The FDA has approved 5 EGFR TKIs in patients with EGFR-mutant NSCLC.9-19
  • Erlotinib was the first EGFR TKI to receive approval, with an initial indication for use in metastatic NSCLC with EGFR mutations that was later modified to include only patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations.9,10
  • Subsequent approvals include afatinib (2013),11 gefitinib (2015),12 osimertinib (2015),13 and dacotinib (2018).14
  • FDA-approved indications for these EGFR TKIs are summarized in the table below.15-19
FDA Approved EGFR Targeted Therapies for NSCLC

FDA Approved EGFR Targeted Therapies for NSCLC

Learn more about Afatinib >

Learn more about Dacomitinib >

Learn more about Erlotinib >

Learn more about Gefitinib >

Learn more about Osimertinib >

References

  1. Vincent MD, Kuruvilla MS, et al. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol. 2012 19(Suppl 1):S33-44. doi:10.3747/co.19.1149
  2. Melosky B, Kambartel K, Häntschel M, et al. Worldwide prevalence of epidermal growth factor receptor mutations in non-small cell lung cancer: a meta-analysis. Mol Diagn Ther. 2022;26(1):7-18. doi: 10.1007/s40291-021-00563-1.
  3. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. doi: 10.18632/oncotarget.12587.
  4. Sharma M, Basu DA, Nathany S, Amrith BP, Batra U. A narrative review of the role of common EGFR mutations in pathogenesis and treatment of non-small cell lung carcinoma. Cancer Res Stat Treat. 2022;5(3):507-518. doi:10.4103/ crst.crst_222_22
  5. Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016;1(3):e000060. doi:10.1136/esmoopen-2016-000060
  6. 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
  7. John T, Taylor A, Wang H, Eichinger C, Freeman C, Ahn MJ. Uncommon EGFR mutations in non-small-cell lung cancer: a systematic literature review of prevalence and clinical outcomes. Cancer Epidemiol. 2022;76:102080. doi:10.1016/j.canep.2021.102080
  8. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2024. Accessed April 23. 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  9. FDA approves first personalized medicine for EGFR mutation-positive metastatic non-small cell lung cancer in the United States. Press Release. Genentech, Inc.; May 14, 2013. Accessed April 23. 2024. https://www.gene.com/media/news-features/tarceva-approval-nsclc
  10. Erlotinib (Tarceva). US FDA. Updated October 18, 2016. Accessed April 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/erlotinib-tarceva
  11. FDA broadens afatinib indication to previously untreated, metastatic NSCLC with other non-resistance EGFR mutations. US FDA. January 16, 2018. Accessed May 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-broadens-afatinib-indication-previously-untreated-metastatic-nsclc-other-non-resistant-egfr#:~:text=resistant%20EGFR%20mutations-,FDA%20broadens%20afatinib%20indication%20to%20previously%20untreated%2C%20metastatic%20NSCLC,other%20non%2Dresistant%20EGFR%20mutations&text=On%20January%2012%2C%202018%2C%20the,Boehringer%20Ingelheim%20Pharmaceutical%2C%20Inc.)
  12. Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res. 2016;22(6):1307-1312. doi: 10.1158/1078-0432.CCR-15-2266.
  13. Osimertinib (Tagrisso). US FDA. Updated July 28, 2017. Accessed April 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso
  14. FDA. FDA approves dacomitinib for metastatic non-small cell lung cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dacomitinib-metastatic-non-small-cell-lung-cancer-0
  15. Tagrisso (Osimertinib). Prescribing information. AstraZeneca Pharmaceuticals; 2024. Accessed December 2, 2024. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/52503580-1192-44f7-a05e-5743159ed19b/52503580-1192-44f7-a05e-5743159ed19b_viewable_rendition__v.pdf
  16. Gilotrif (Afatinib). Prescribing information. Boehringer Ingelheim. 2022. Accessed December 2, 2024. https://content.boehringer-ingelheim.com/DAM/07c11f94-358a-439d-b0c8-af1e011f04c4/gilotrif-us-pi.pdf
  17. Tarceva (Erlotinib). Prescribing information. Genentech; 2016. https://www.gene.com/download/pdf/tarceva_prescribing.pdf
  18. Iressa (Gefitinib). Prescribing information. AstraZeneca; 2023. Accessed December 5, 2024. https://medicalinformation.astrazeneca-us.com/home/prescribing-information/iressa.html
  19. Vizimpro (Dacomitinib). Prescribing information. Pfizer Inc.; 2020. Accessed December 5, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=11019