EGFR

Epidermal growth factor receptor (EGFR)

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 Dysregulation of EGFR occurs in a number of ways and in NSCLC the most important are activating EGFR mutations and increased protein expression.1 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).2-4 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.3,4 However, the EGFR T790M mutation increases ATP affinity, leading to the activation of the receptor despite the presence of inhibitors.4 Second-generation EGFRi were developed to bind irreversibly to EGFR and overcome resistance. Their efficacy has been limited by poor selectivity and toxicities. 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.3,4 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.4,5 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.4

EGFR Testing

Molecular testing for EGFR mutations should be performed when adjuvant tyrosine kinase inhibitor (TKI) therapy is a consideration for stage IB-IIIA and stage IIIB NSCLC.6 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.6

EGFR Targeted Therapies

The FDA has approved 5 EGFR TKIs in patients with EGFR-mutant NSCLC. 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.7,8 Subsequent approvals include afatinib (2013),9 gefitinib (2015),10 osimertinib (2015),11 and dacotinib (2018).12 FDA-approved indications for these EGFR TKIs are summarized in the table below.

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. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Erlotinib (Tarceva). US FDA. Updated October 18, 2016. Accessed April 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/erlotinib-tarceva
  9. 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.)
  10. 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.
  11. Osimertinib (Tagrisso). US FDA. Updated July 28, 2017. Accessed April 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso
  12. 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
  13. Tagrisso (Osimertinib). Package insert. AstraZeneca; 2024.
  14. Gilotrif (Afatinib)/ Package insert. Boehringer Ingelheim; 2022.
  15. Tarceva (Erlotinib). Package insert. Genetech; 2016.
  16. Iressa (Gefitinib) Package insert. AstraZeneca; 2023.
  17. Vizimpro (Dacomitinib). Package insert. Pfizer; 2020.