EGFR exon 20

  • Epidermal growth factor receptor (EGFR) exon 20
  • Gene location: chromosome 7 (7p11)

EGFR exon 20 Biology

  • 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.1
  • 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

When to Test:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.1
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis.1
  • In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.1

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.1
  • Because some EGFRex20 mutations may be sensitive to first- and third-generation inhibitors, the specific sequence of EGFRex20 insertion mutations remains important.1
  • Targeted PCR-based approaches for detection of EGFR variants may under-detect EGFRex20ins events; therefore, NGS-based strategies are preferred.1

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.
  • Testing for c-MET and HER2 overexpression via IHC in patients with advanced or metastatic NSCLC is also recommended along side broad panel NGS testing.
  • For patients with early-stage NSCLC, testing should assess PD-L1 status, EGFR mutations, and ALK rearrangements.1

EGFR exon 20 Targeted Therapy

Approved Agents:

  • 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

Amivantamab5

  • 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.
    • In combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.
    • As a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
  • 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:
  • Patient Resources:

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/
  5. RYBREVANT (amivantimab). Prescribing information. Janssen Biotech, Inc.;2024. Accessed October 2, 2024. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RYBREVANT-pi.pdf