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Cited by 241Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsHER2/EGFR in Cancer Research

Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC

Open access
Riess, Jonathan W., Gandara, David R., Frampton, Garrett M., Madison, Russell, Peled, Nir, Bufill, Jose A., Dy, Grace K., Ou, Sai-Hong Ignatius +9 more·2018·Journal of Thoracic Oncology
DOI 10.1016/j.jtho.2018.06.019PMC PMC6764748
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Abstract

Introduction EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.Methods Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes.Results Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded.Conclusions In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.

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Crossref · 10.1016/j.jtho.2018.06.019

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    6% (15/263) of EGFR exon 20 insertion cases harbored EGFR A763_Y764insFQEA.

    “6% (15/263) harbored EGFR A763_Y764insFQEA”
    Quote in the paperNot a substantial claim
  • Findingown data

    Co-occurring alterations did not substantially differ between EGFR exon 20 insertion cases and canonical EGFR mutations (exon 19 deletion and L858R) that were negative for T790M.

    “Co-occurring alterations did not substantially differ between EGFRex20ins and canonical EGFR mutations (EGFR exon 19 deletion and EGFR L858R) that were negative for the most common acquired EGFR TKI resistance mutation, EGFR T790M”
    Quote in the paperSubstantial claim
  • Findingown data

    RB1 co-occurring alterations occurred in 11% of EGFR exon 20 insertion cases.

    “RB1 (11%)”
    • Also stated in: § Results · plain
      “RB1 (11%)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Comprehensive genomic profiling of 14,483 NSCLC cases identified 263 cases with EGFR exon 20 insertions, which was 1.8% of all NSCLC cases tested.

    “Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins”
    • Also stated in: § Results · plain
      “Comprehensive genomic profiling (CGP) performed on 14,483 NSCLC cases in the course of clinical care identified 2,251 cases with EGFR mutations, 263 of these cases were EGFRex20ins, representing 12% of all EGFR-mutant NSCLC and 1.8% of all NSCLC cases tested.”
    Quote in the paperSubstantial claim
  • Findingown data

    TP53 was the most common co-occurring genomic alteration in EGFR exon 20 insertion cases, occurring in 56%.

    “The most common co-occurring GA effected TP53 (56%)”
    • Also stated in: § Results · plain
      “The most common co-occurring alterations affected TP53 (56%)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    N771_P772>SVDNP was the second most common EGFR exon 20 insertion, occurring in 20% of cases.

    “N771_P772>SVDNP (20%)”
    • Also stated in: § Results · plain
      “N771_P772>SVDNP (20%)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    This study represents the largest series of EGFR exon 20 insertion NSCLC, with over 60 unique insertions detected.

    “This study represents the largest series of EGFRex20ins with over 60 unique EGFR exon 20 insertions detected.”
    • Also stated in: § Conclusion · plain
      “In the largest series of EGFRex20ins NSCLC”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    EGFR amplification in EGFR exon 20 insertion cases was comparable to other EGFR mutations in the dataset when T790M cases were excluded (exon 19 deletion 23%, L858R 25%) and higher than in EGFR-wild-type NSCLC.

    “EGFR amplification was detected in 22% of EGFRex20ins-positive NSCLCs, which is comparable to other EGFR mutations in our dataset when cases with co-occurring T790M are excluded (EGFR ex19del 23%, L858R 25%) and higher than EGFR-WT NSCLC”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tumor mutational burden in EGFR exon 20 insertion cases was comparable to that in EGFR exon 19 deletion and EGFR L858R cases and lower than in EGFR-wild-type NSCLC.

    “comparable with TMB in EGFR exon 19del and EGFR L858R and lower than EGFR-WT NSCLC”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    62% of EGFR exon 20 insertion patients were female.

    “62% of patients were female”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The median age for EGFR exon 20 insertion-positive cases was 63 years.

    “The median age for EGFRex20-positive cases was 63 years”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    EGFR exon 20 insertions occurred at approximately the same frequency as ROS1 gene fusions (~1%) and BRAF V600E mutations (~2%) in NSCLC in this dataset.

    “occur at approximately the same frequency as ROS1 gene fusions (~1% in our dataset; data not shown) and BRAF V600E mutations in NSCLC (~2% in our dataset; data not shown)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The EGFR A763_Y764insFQEA insertion comprised 6% of all EGFR exon 20 insertions in this series, representing less than 1% of all EGFR mutations.

    “The EGFR A763_Y764insFQEA insertion, for which sensitivity to first- and second-generation EGFR TKIs has been described, only comprised 6% of all EGFRex20ins in our series (thus representing less than 1% of all EGFR mutations).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Clinical and pathologic characteristics were available for all 263 patients with EGFR exon 20 insertions.

    “Clinical and pathologic characteristics were available for all of the 263 patients with EGFRex20ins as summarized in Table 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Poziotinib demonstrated a confirmed response rate of 64% in EGFR exon 20 insertion NSCLC in a phase 2 trial, albeit in a limited number of patients.

    “a confirmed response rate of 64% in EGFRex20ins NSCLC was noted in a phase 2 trial, albeit in a limited number of patients”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Robichaux, 2018, Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tumor mutational burden measured by comprehensive genomic profiling is comparable to measurements by whole exome sequencing and is typically higher in smoking-associated lung cancer.

    “TMB measured by comprehensive genomic profiling is comparable to measurements by whole exome sequencing and is typically higher in smoking associated lung cancer due to tobacco carcinogenesis”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Chalmers, 2017, Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden, Genome Med source

      Not checked in the free run.

    • cites [29] Alexandrov, 2016, Mutational signatures associated with tobacco smoking in human cancer, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Approval for this study, including a waiver of informed consent and a HIPAA waiver of authorization, was obtained from the Western Institutional Review Board.

    “Approval for this study, including a waiver of informed consent and a Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (Protocol No. 20152817).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with EGFR-mutant NSCLC appear to derive less clinical benefit from PD-1/PD-L1 blockade and in a recent meta-analysis do not have an overall survival benefit compared with chemotherapy.

    “patients with EGFR-mutant NSCLC appear to derive less clinical benefit from PD-1/PD-L1 blockade and in a recent meta-analysis do not have an overall survival benefit compared to chemotherapy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Lee, 2017, Checkpoint inhibitors in metastatic EGFR-mutated non–small cell lung cancer-a meta-analysis, J Thorac Oncol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EGFR exon 19 deletions and EGFR exon 21 L858R are exquisitely sensitive to approved EGFR TKIs such as erlotinib, gefitinib, and afatinib.

    “EGFR exon 19 deletions and EGFR exon 21 L858R represent the vast majority of EGFR activating mutations, and are exquisitely sensitive to approved EGFR TKIs such as erlotinib, gefitinib, and afatinib”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Mok, 2009, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N Engl J Med source

      Not checked in the free run.

    • cites [2] Rosell, 2012, Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial, Lancet Oncol source

      Not checked in the free run.

    • cites [3] Sequist, 2013, Phase III Study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J Clin Oncol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    EGFR T790M was excluded from the comparison of co-occurring alterations to control as much as possible for additional genomic aberrations resulting from acquired EGFR TKI resistance.

    “Since EGFR T790M is the most common acquired resistance mutation to first and second generation EGFR TKIs, these were excluded for this comparison to control as best as possible for additional genomic aberrations resulting from acquired EGFR TKI resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EGFR exon 20 insertions have previously been reported to comprise approximately 4-10% of all EGFR-mutant lung cancers.

    “These alterations have previously been reported to comprise approximately 4-10% of all EGFR mutant lung cancers”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [5] Jia, 2016, EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor, Cancer Res source

      Not checked in the free run.

    • cites [6] Oxnard, 2013, Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions, J Thorac Oncol source

      Not checked in the free run.

    • cites [7] Arcila, 2013, EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics, Mol Cancer Ther source

      Not checked in the free run.

    • cites [8] Riess, 2017, Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions, J Clin Oncol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The dataset represents patients selected by their physician to be tested, which may not represent a random cross-section of NSCLC.

    “this dataset represents patients that were selected specifically by their physician to be tested for analysis, which may not represent a random cross-section of NSCLC”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Other features such as tumor mutational burden appear to be associated with clinical benefit from PD-1/PD-L1 antibodies.

    “other features such as TMB appear to also be associated with clinical benefit to PD-1 / PD-L1 antibodies”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Rizvi, 2015, Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science source

      Not checked in the free run.

    • cites [28] Carbone, 2017, First-line nivolumab in stage IV or recurrent non–small-cell lung cancer, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Treatment outcomes were available for 11 of the 263 patients with EGFR exon 20 insertion-positive NSCLC.

    “Of the 263 patients with EGFRex20ins-positive NSCLC, treatment outcomes were available for 11 patients.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The diverse array of exon 20 insertions and the challenges associated with identifying them may lead to underestimation of their true frequency.

    “The diverse array of exon 20 insertions and the challenges associated with identifying them may lead to underestimation of their true frequency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several next-generation EGFR TKIs have demonstrated pre-clinical activity against EGFR exon 20 insertions and are in clinical development.

    “Several next-generation EGFR TKIs (some with pan-HER activity) have demonstrated pre-clinical activity against EGFRex20ins and are in clinical development”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Jia, 2016, EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor, Cancer Res source

      Not checked in the free run.

    • cites [10] Floc'h, 2018, Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions, Mol Cancer Ther source

      Not checked in the free run.

    • cites [11] Gonzalvez, 2016, AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, including exon 20 insertions, in preclinical models. In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, Louisiana, Cancer Res

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Testing was performed in a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited reference laboratory.

    “Testing was performed in a Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited reference laboratory (Foundation Medicine, Inc., Cambridge, MA).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Immune checkpoint inhibition with PD-1 and PD-L1 antibodies has revolutionized the treatment of NSCLC and improved survival outcomes for many lung cancer patients.

    “Immune checkpoint inhibition with PD-1 and PD-L1 antibodies has revolutionized the treatment of NSCLC and improved survival outcomes for many lung cancer patients”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Reck, 2016, Pembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The higher frequency of EGFR exon 20 insertions detected may reflect referral bias with enrichment for lung cancers from never-smoking patients.

    “This may reflect referral bias with enrichment for lung cancers from never smoking patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Small series have described activity of the addition of cetuximab to EGFR TKIs in EGFR exon 20 insertion NSCLC.

    “Small series have described activity of the addition of cetuximab to EGFR TKIs in EGFRex20ins NSCLC”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Tsigelny, 2015, Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer, Oncotarget source

      Not checked in the free run.

    • cites [24] Wheler, 2013, Revisiting clinical trials using EGFR inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center phase I population, Oncotarget source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Treatment with EGFR monoclonal antibodies based on EGFR amplification and overexpression has modestly improved clinical outcomes of squamous NSCLC, and cetuximab added to afatinib appears to increase response rates compared with afatinib alone in patients with EGFR exon 19 deletion or L858R.

    “Treatment with EGFR monoclonal antibodies based on EGFR amplification and overexpression has modestly improved clinical outcomes of squamous NSCLC, and cetuximab added to afatinib appears to increase response rates compared to afatinib alone in patients with EGFR exon 19 deletion or L858R”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Thatcher, 2015, Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial, Lancet Oncol source

      Not checked in the free run.

    • cites [22] Janjigian, 2014, Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations, Cancer Discov source

      Not checked in the free run.

26 of 26

  • The paper relies on this without support.

    The 14,483 NSCLC specimens tested by comprehensive genomic profiling are representative enough of the broader NSCLC population to estimate the frequency of EGFR exon 20 insertions.

    “this dataset represents patients that were selected specifically by their physician to be tested for analysis, which may not represent a random cross-section of NSCLC”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Comparator mutation is named inconsistently

    Minor

    The same comparison names the canonical comparator as EGFR L858R in Results but EGFR L585R in Discussion.

  • Sarcomatoid percentage is rounded incorrectly

    Minor

    Two of 263 cases is about 0.76%, which rounds to 0.8% at one decimal place, not the reported 0.7%.

    Reported 0.7 · recomputed 0.760456

2 of 2

Cites

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Research works printed but not linked: 1

  1. Gonzalvez, 2016, AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, including exon 20 insertions, in preclinical models. In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, Louisiana, Cancer Res, 76

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Authors
Riess, J. W., Gandara, D. R., Frampton, G. M., Madison, R., Peled, N., Bufill, J. A., Dy, G. K., Ou, S.-H. I., Stephens, P. J., McPherson, J. D., Lara, P. N., Burich, R. A., Ross, J. S., Miller, V. A., Ali, S. M., Mack, P. C., & Schrock, A. B.
Affiliations
  • UC Davis Comprehensive Cancer Center (US)
  • Foundation Medicine (United States) (US)
  • Ben-Gurion University of the Negev (IL)
  • Roswell Park Comprehensive Cancer Center (US)
  • University of California, Irvine (US)
Corresponding author
Riess, Jonathan W.
ORCID
Venue
Journal of Thoracic Oncology
Publisher
Elsevier BV
Published
2018-10
Volume
13
Issue
10
Pages
1560-1568
ISSN
1556-0864 (ISSN-L)
DOI
10.1016/j.jtho.2018.06.019
PMC
PMC6764748
OpenAlex
W2838798742
Cited by
240
References
31
Citations by year
2026: 21 · 2025: 29 · 2024: 29 · 2023: 50 · 2022: 46 · 2021: 34 · 2020: 18 · 2019: 12 · 2018: 1
FWCI
12.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thoracic Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (5 K12 CA 138464)
  • Bonnie J. Addario Lung Cancer Foundation
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
EGFR exon 20 insertion, non-small cell lung cancer, EGFR mutation, EGFR amplification, TP53, CDKN2A, CDKN2B, TTF-1, RB1, tumor mutational burden, EGFR tyrosine kinase inhibitors, treatment resistance, comprehensive genomic profiling, hybrid capture sequencing
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Gene Expression Profiling, Genomics, Tumor Burden, Young Adult, ErbB Receptors

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