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.6,7

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.8
  • 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, NRG1, and PD-L1.8
  • 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
Targetable Biomarkers in NSCLC

Targetable Biomarkers in NSCLC

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
  • Amivantamab, a bispecific monoclonal antibody targeting both EGFR and MET, was granted FDA approval in 2024 for the treatment of advanced EGFR-mutant NSCLC, applicable in both first- and second-line settings.15,16
  • In the first-line setting, amivantamab is approved in combination with the third-generation TKI lazertinib, based on data from the MARIPOSA trial (NCT04487080).17
  • In the second-line setting, it is approved in combination with carboplatin and pemetrexed, as supported by findings from the MARIPOSA2 trial (NCT04988295).18
  • FDA-approved indications for EGFR-targeted therapies are summarized in the table below.19-24
FDA Approved EGFR Targeted Therapies for NSCLC

FDA Approved EGFR Targeted Therapies for NSCLC

Afatinib21

  • FDA Approved Indication:
    • First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.
    • Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy.
  • Mechanism of Action:
    • Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
    • Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC.
    • Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods.
    • The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions.
    • Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients.
  • Drug Information:
  • Patient Resources:

Amivantamab25

  • FDA Approved Indication:
    • In combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
    • In combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.
  • Mechanism of Action:
    • Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.
    • In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or degradation of EGFR and MET.
    • The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
    • Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.
  • Drug Information:
    • Learn more about Amivantamab >
  • Patient Resources:

Dacomitinib24

  • FDA Approved Indication:
    • First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.
  • Mechanism of Action:
    • Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation).
    • Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR.
    • Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications.
  • Drug Information:
  • Patient Resources:

Erlotinib22

  • FDA Approved Indication:
    • Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
    • Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.
    • First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. (
  • Mechanism of Action:
    • The mechanism of clinical antitumor action of erlotinib is not fully characterized.
    • Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR).
  • Drug Information:

Gefitinib23

  • FDA Approved Indication:
    • First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
  • Mechanism of Action:
    • The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation.
    • Some EGFR activating mutations (exon 19 deletion or exon 21 point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
    • Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation.
    • Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR.
  • Drug Information:

Osimertinib20

  • FDA Approved Indication:
    • Adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
    • The treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
    • The first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
    • In combination with pemetrexed and platinum-based chemotherapy, the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
    • The treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.
  • Mechanism of Action:
    • Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletions) at approximately 9-fold lower concentrations than wild-type.
  • Drug Information:
  • Patient Resources:

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.
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  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. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. Updated August 20, 2024. US FDA. Accessed April 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
  16. FDA approves amivantamab-vmjw with carboplatin and pemetrexed for non-small cell lung cancer with EGFR exon 19 deletions or L858R mutations. US FDA. Updated September 19, 2024. Accessed Aprul 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexed-non-small-cell-lung-cancer-egfr-exon-19
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  18. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024 Jan;35(1):77-90. doi: 10.1016/j.annonc.2023.10.117
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