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Cited by 110Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario

Open access
Russo, Alessandro, Franchina, Tindara, Ricciardi, Giuseppina, Battaglia, Alessandra, Picciotto, Maria, Adamo, Vincenzo·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20061431PMC PMC6470640
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Abstract

Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

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Written from the paper’s full text.

TL;DR

Uncommon EGFR mutations account for approximately 10% of EGFR-mutated NSCLC and show highly heterogeneous sensitivity to EGFR TKIs, with some variants favoring second-generation TKIs and exon 20 insertions generally resistant to first-/second-generation agents. This review synthesizes current evidence and emerging options, concluding that each rare variant should be analyzed and treated separately.

Key findings

  • Uncommon EGFR mutations represent ~10% of all EGFR-mutated NSCLC; exon 18 mutations account for ~3–4% of EGFR mutations, exon 20 insertions include over 64 unique variants and up to ~10% of EGFR mutants, complex mutations are reported in 4–14% of EGFR mutations, and de novo T790M is observed in ~3% of EGFR-mutated patients with standard methods.
  • Exon 18 mutations: first-line EGFR TKI versus chemotherapy showed median PFS 14.6 vs. 5.8 months; G719X had ORR 14–53% with first-generation TKIs but 75–78% with afatinib/neratinib. E709X complex mutations in TKI-pretreated patients had ORR 50%, DCR 100%, and time-to-treatment failure exceeding 12 months with afatinib in the ACUC data.
  • Exon 20 insertions: first-/second-generation EGFR TKIs produced ORR 0–11% and median PFS 2–3 months; platinum-doublet chemotherapy produced ORR 58–63% and PFS six months. Poziotinib showed 43% confirmed ORR and median PFS 5.5 months; TAK-788 showed 39% ORR and 94% DCR; luminespib showed 17% ORR, 38% DCR, and median PFS 2.8 months.
  • Uncommon exon 21 mutations had shorter median PFS (4.5 vs. 10.4 months, p = 0.003) and OS (12.2 vs. 16.9 months, p = 0.04) than L858R; L861Q accounts for ~1–2% of EGFR mutations and afatinib is supported as preferable. S768I with afatinib had ORR 100% and median PFS 14.7 months in combined LUX-Lung 2/3/6 data, while G719X + S768I had ORR ~50% and median PFS 8–10 months with first-generation TKIs; de novo T790M had ORR 14–33% and median PFS 1.94–2.9 months with first-/second-generation TKIs.

Methods

  • Narrative review; no primary patient cohort or experimental data are reported.
  • Evidence base includes published preclinical studies, clinical trials, retrospective analyses, case series, case reports, and ongoing trials, organized by mutation class and emerging therapeutic strategies.
  • Main analysis is a qualitative synthesis of sensitivity to EGFR TKIs and investigational agents; no systematic review, meta-analysis, or formal quality assessment is described.

Limitations

  • Stated: most pivotal first-line EGFR TKI studies excluded patients with rare and/or complex variants; data are scant and come mostly from small retrospective studies, case series, or case reports, with no firmly established standard of care for the vast majority of uncommon mutations.
  • Stated: the role of osimertinib in mutations besides exon 19 deletions and/or L858R is largely unknown, and many emerging agents have only preliminary or ongoing trial data.
  • Evident: as a narrative review, it lacks a systematic search strategy, formal risk-of-bias assessment, and quantitative pooling; findings may be affected by publication bias and small sample sizes.

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Integrity signals

Registry

Crossref · 10.3390/ijms20061431

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Uncommon EGFR mutations account for approximately 10% of all EGFR-mutated NSCLC patients.

    “Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients.”
    • Also stated in: § 1. Introduction · plain
      “that accounts for approximately 10% of all EGFR mutations in both Caucasian and Asian patients”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [20] Pilotto, 2018, Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study, Clin. Lung Cancer source

      Not checked in the free run.

    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

      Not checked in the free run.

    • cites [22] Keam, 2013, Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer, Int. J. Clin. Oncol. source

      Not checked in the free run.

  • Premisecitation

    The sensitivity of uncommon EGFR mutations to first- and second-generation EGFR TKIs is widely heterogeneous.

    “the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known”
    • Also stated in: § 1. Introduction · plain
      “the sensitivity of uncommon mutations to currently available EGFR TKIs is widely heterogeneous and less well known”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [20] Pilotto, 2018, Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study, Clin. Lung Cancer source

      Not checked in the free run.

    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

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    • cites [22] Keam, 2013, Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer, Int. J. Clin. Oncol. source

      Not checked in the free run.

  • Premisereasoning

    The sensitivity of uncommon EGFR mutations to first- and second-generation EGFR TKIs is less well known compared with classic mutations.

    “the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Wu, 2014, Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial, Lancet Oncol. source

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    • cites [7] Sequist, 2013, Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma WithEGFRMutations, J. Clin. Oncol. source

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    • cites [8] Maemondo, 2010, Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR, N. Engl. J. Med. source

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  • Premisecitation

    Patients with G719X mutations treated with first-generation EGFR TKIs have lower overall response rates (14-53%).

    “lower overall response rate (ORR) (14–53%) in patients harboring G719X mutations, treated with first-generation EGFR TKIs [12,21,35,36]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [12] Watanabe, 2014, Effectiveness of Gefitinib against Non–Small-Cell Lung Cancer with the Uncommon EGFR Mutations G719X and L861Q, J. Thoracic Oncol. source

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    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

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    • cites [35] Pas, 2011, Activity of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Patients with Non-small Cell Lung Cancer Harboring Rare Epidermal Growth Factor Receptor Mutations, J. Thoracic Oncol. source

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    • cites [36] Wu, 2011, Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non-Small Cell Lung Cancer, Clin. Cancer Res. source

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  • Premisecitation

    G719S is less sensitive to gefitinib than erlotinib.

    “G719S is less sensitive to gefitinib than erlotinib [34]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Kancha, 2009, Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy, Clin. Cancer Res. source

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  • May combine two claims. 33
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    Premisecitation

    Uncommon EGFR mutations define a small and highly heterogeneous subgroup of patients with EGFR mutations.

    “Patients with uncommon mutations define a small and highly heterogeneous subgroup of patients with EGFR mutations, with different sensitivity to first- and second-generation EGFR TKIs”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [20] Pilotto, 2018, Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study, Clin. Lung Cancer source

      Not checked in the free run.

    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

      Not checked in the free run.

    • cites [22] Keam, 2013, Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer, Int. J. Clin. Oncol. source

      Not checked in the free run.

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    Premisecitation

    G719X is the most frequently observed exon 18 mutation and the second most frequently observed uncommon mutation after exon 20 insertions.

    “G719X is the most frequently observed exon 18 mutation for incidence and the second most frequently observed uncommon mutation, after exon 20 insertions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

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

    Premisecitation

    Exon 19 insertions have a reported frequency of <0.5% of all EGFR mutations.

    “Exon 19 insertions are a relatively uncommon family of EGFR mutations with a reported frequency of <0.5% of all EGFR mutations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] He, 2011, EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma, Clin. Cancer Res. source

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    Premisecitation

    Exon 18 mutations include point mutations that in >80% of cases involve codons 719 or 709, and more rarely deletion-insertions.

    “include point mutations, which, in >80% of cases, involve the codons 719 (G719X and the most common variants, G719A, G719S, and G719C) or 709 (E709X), and more rarely, deletion–insertions [19,29,30].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [29] Konduri, 2016, EGFR Fusions as Novel Therapeutic Targets in Lung Cancer, Cancer Discov. source

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    • cites [30] Kobayashi, 2015, EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs, Clin. Cancer Res. source

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

    Premisecitation

    Exon 19 deletions are the most common EGFR mutations, accounting for approximately 45% of all EGFR mutations.

    “Exon 19 deletions are the most common EGFR mutations (approximately 45% of all EGFR mutations)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Russo, 2015, A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives, Oncotarget source

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    • cites [52] Costa, 2016, Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: Moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements, Transl. Lung Cancer Res. source

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    Premisecitation

    Patients with exon 20 insertions may experience a higher ORR (58-63%) and a longer PFS (six months) with platinum-doublet chemotherapy.

    “These patients may experience a higher overall response rate (ORR) (58–63%) and a longer PFS (six months) with platinum-doublet chemotherapy, as reported in small retrospective studies [70,71].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Naidoo, 2015, Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib, Cancer source

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    • cites [71] Oxnard, 2013, Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions, J. Thoracic Oncol. source

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    Premisecitation

    G719X mutations are oncogenic and sensitive to EGFR TKI, although they display different sensitivity profiles to these agents.

    “Preclinical studies have shown that these mutations are oncogenic and are sensitive to EGFR TKI, although they display different sensitivity profiles to these agents.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Kancha, 2009, Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy, Clin. Cancer Res. source

      Not checked in the free run.

    • cites [30] Kobayashi, 2015, EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs, Clin. Cancer Res. source

      Not checked in the free run.

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    Premisecitation

    Exon 18 mutations are associated with male sex and smoking history.

    “an association with the male sex [18] and smoking history has been reported [19,31]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Mok, 2018, Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer and EGFR-Activating Mutations, J. Clin. Oncol. source

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    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

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    • cites [31] Frega, 2017, Clinical features and treatment outcome of non-small cell lung cancer (NSCLC) patients with uncommon or complex epidermal growth factor receptor (EGFR) mutations, Oncotarget source

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    Premisecitation

    In TKI-pretreated patients harboring complex E709X mutations, afatinib produced an ORR of 50%, a DCR of 100%, and a time-to-treatment failure exceeding 12 months.

    “reported, in TKI-pretreated patients harboring complex E709X mutations, an intriguing time-to-treatment failure exceeding 12 months, with an ORR of 50% and a disease control rate (DCR) of 100% [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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

    Premisecitation

    Exon 18 mutations collectively account for approximately 3-4% of all EGFR mutations.

    “Exon 18 mutations collectively account for approximately 3–4% of all EGFR mutations”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [29] Konduri, 2016, EGFR Fusions as Novel Therapeutic Targets in Lung Cancer, Cancer Discov. source

      Not checked in the free run.

    • cites [30] Kobayashi, 2015, EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs, Clin. Cancer Res. source

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    Premisecitation

    Exon 20 insertions are the third most common family of EGFR mutations, with over 64 unique variants and an estimated incidence of up to about 10% of all EGFR mutants in NSCLC.

    “After classic mutations, exon 20 insertions are the third most common family of EGFR mutations. These insertions encompass residues from 762 to 775 (spatially located after the C-helix of the EGFR kinase domain) and represent a highly heterogeneous family of EGFR mutations, with over 64 unique variants described to date, with an estimated incidence of up to about 10% of all EGFR mutants in NSCLC [”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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    • cites [67] Cardona, 2018, EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP), Lung Cancer source

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    Premisecitation

    Exon 19 deletions are not homogenously sensitive to EGFR TKIs; non-LRE deletions have a lower response to EGFR TKIs than LRE deletions.

    “this subgroup of EGFR mutations is not homogenously sensitive to the EGFR TKIs, since differential sensitivity has been reported between deletions encompassing the amino acids from codons L747 to E749 (LRE fragment) and non-LRE deletions, with a lower response to EGFR TKIs in the latter molecular subgroup [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Chung, 2012, Clinical Outcomes in Non-Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR, Clin. Cancer Res. source

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    Premisecitation

    Patients with G719X mutations treated with afatinib or neratinib have high ORRs (75-78%), comparable to those seen in patients with common mutations.

    “but high ORRs (75–78%) with afatinib [37] and neratinib [38], comparable to those seen in patients with common mutations”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. source

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    • cites [38] Sequist, 2010, Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non–Small-Cell Lung Cancer, J. Clin. Oncol. source

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  • May combine two claims.

    Premisecitation

    Patients harboring exon 20 insertions have an ORR of 0-11% and a median PFS of 2-3 months when treated with first- or second-generation EGFR TKIs.

    “Patients harboring exon 20 insertions are associated with an ORR of 0–11% and a median progression-free survival (PFS) of 2–3 months when treated with first- or second-generation EGFR TKIs [19,21,37,44,45,70]”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [19] Prim, 2013, Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network, Ann. Oncol.

      Not checked in the free run.

    • cites [21] Tu, 2017, A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer, Lung Cancer source

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    • cites [37] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. source

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    • cites [70] Naidoo, 2015, Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib, Cancer source

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    Premisecitation

    E709X mutations account for <0.5% of all EGFR mutations.

    “E709X mutations may occur as single or, in a third of the cases, as complex mutations and account for <0.5% of all EGFR mutations [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Costa, 2016, Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: Moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements, Transl. Lung Cancer Res. source

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    Premisecitation

    Exon 19 insertions are associated with in vitro and in vivo sensitivity to first-/second-generation EGFR TKIs, although ORR may be slightly lower (about 40-50%) than with classic mutations.

    “These insertions exhibit structural similarities with exon 19 deletions and have been associated with in vitro and in vivo sensitivity to first-/second-generation EGFR TKIs [60], although the ORR may be slightly lower (about 40–50%) than reported with classic mutations [61,62]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [60] He, 2011, EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma, Clin. Cancer Res. source

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    • cites [61] Lin, 2017, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-sensitive Exon 19 Insertion and Exon 20 Insertion in Patients With Advanced Non–Small-cell Lung Cancer, Clin. Lung Cancer source

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    • cites [62] Kobayashi, 2016, Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy, Cancer Sci. source

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    Premisecitation

    E709K transfected cells have greater IC90s (>25-fold) with erlotinib, gefitinib, and osimertinib than cells with exon 19 deletions, but no IC90 differences with afatinib or neratinib.

    “having greater IC90s (>25-fold) with erlotinib, gefitinib, and osimertinib in cells transfected with E709K than those with exon 19 deletions, but no IC90s differences with afatinib or neratinib [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Kobayashi, 2015, EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs, Clin. Cancer Res. source

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    Premisecitation

    Patients with complex mutations containing exon 19 deletions or exon 21 L858R point mutations are associated with a more favorable outcome than those containing rare mutations only, with the best objective rates seen in double exon 19 deletions/L858R.

    “clinical evidence suggesting that patients with complex mutations containing exon 19 deletions or exon 21 L858R point mutations are associated with a more favorable outcome than those containing rare mutations only [22,43,47,91], with the best objective rates seen in double exon 19 deletions/L858R [45].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [22] Keam, 2013, Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer, Int. J. Clin. Oncol. source

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    • cites [43] Baek, 2015, Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea, Lung Cancer source

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    • cites [47] Peng, 2014, Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations, Sci. Rep. source

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    • cites [45] Xu, 2016, EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China, Lung Cancer source

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    Premisecitation

    Uncommon exon 21 mutations are collectively associated with lower sensitivity to EGFR TKIs compared with classic L858R, with shorter median PFS (4.5 vs 10.4 months, p=0.003) and OS (12.2 vs 16.9 months, p=0.04).

    “These uncommon exon 21 mutations are collectively associated with lower sensitivity to the EGFR TKIs, compared with the classic L858R mutation, with a shorter median PFS (4.5 months vs. 10.4 months, p = 0.003) and overall survival (OS, 12.2 months vs. 16.9 months, p = 0.04) [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    L861Q is the second most frequent exon 21 mutation after L858R, accounts for approximately 1-2% of all EGFR mutations, and has oncogenic activity similar to L858R.

    “The second most frequent exon 21 mutation after L858R is the point mutation L861Q that accounts for approximately 1–2% of all EGFR mutations [42,84] and has oncogenic activity similar to the L858R mutation [85].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Zhang, 2017, Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations, Chin. J. Cancer Res. source

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    Premisecitation

    Preliminary phase II data in 50 heavily pretreated EGFR exon 20 mutated NSCLCs showed a 43% confirmed ORR and a median PFS of 5.5 months.

    “Preliminary data of a phase II study in 50 heavily pretreated EGFR exon 20 mutated NSCLCs have been recently reported, showing an intriguing activity in this rare subgroup of patients, with a 43% confirmed ORR and a median PFS of 5.5 months (CI 95%, 5.2-NA) [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Heymach, 2018, OA02.06 A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC), J. Thoracic Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The G719X + S768I compound mutation (about 1% of all EGFR mutations) is sensitive to first-generation EGFR TKIs but to a lesser extent than classic mutations, with ORR approximately 50% and median PFS of 8-10 months.

    “One of the most frequent compound mutations is the G719X + S768I (about 1% of all EGFR mutations) [37,84], which has been shown to be sensitive to the first-generation EGFR TKIs, but to a lesser extent than classic mutations (ORR approximately 50% and median PFS of 8–10 months) [12,33,46].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [37] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. source

      Not checked in the free run.

    • cites [84] Arrieta, 2015, The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer, Lung Cancer source

      Not checked in the free run.

    • cites [12] Watanabe, 2014, Effectiveness of Gefitinib against Non–Small-Cell Lung Cancer with the Uncommon EGFR Mutations G719X and L861Q, J. Thoracic Oncol. source

      Not checked in the free run.

    • cites [33] Passaro, 2018, Activity of EGFR TKIs in Caucasian Patients With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations, Clin. Lung Cancer source

      Not checked in the free run.

    • cites [46] Kobayashi, 2013, Compound EGFR Mutations and Response to EGFR Tyrosine Kinase Inhibitors, J. Thoracic Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using highly sensitive detection methods, low-level pretreatment T790M mutations can be detected in up to 65% of cases and are constantly associated with shorter PFS.

    “Using highly sensitive detection methods, low-level pretreatment T790M mutations can be detected in a significant fraction of patients (up to 65% of cases) and are constantly associated with shorter PFS [93,94,95].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [93] Costa, 2014, The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial, Clin. Cancer Res. source

      Not checked in the free run.

    • cites [94] Maheswaran, 2008, Detection of Mutations inEGFRin Circulating Lung-Cancer Cells, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [95] Su, 2012, Pretreatment Epidermal Growth Factor Receptor (EGFR) T790M Mutation Predicts Shorter EGFR Tyrosine Kinase Inhibitor Response Duration in Patients With Non–Small-Cell Lung Cancer, J. Clin. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S768I is associated with variable responses to EGFR TKIs but collectively seems less sensitive than common mutations to first-generation agents.

    “it has been associated with variable responses to EGFR TKIs, but collectively seems less sensible than common mutations to first generation agents [82,83].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [82] Russo, 2017, Rapid Acquisition of T790M Mutation after Treatment with Afatinib in an NSCLC Patient Harboring EGFR Exon 20 S768I Mutation, J. Thoracic Oncol. source

      Not checked in the free run.

    • cites [83] Hellmann, 2014, Clinical and in vivo Evidence that EGFR S768I Mutant Lung Adenocarcinomas Are Sensitive to Erlotinib, J. Thoracic Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase II study of luminespib in EGFR exon 20 insertions reported a 17% ORR, a 38% DCR, and a 2.8 month median PFS.

    “A phase II study in EGFR exon 20 insertions reported a modest activity in this molecularly defined subgroup, with a 17% ORR, a 38% DCR, and a 2.8 month median PFS [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Piotrowska, 2018, Activity of the Hsp90 Inhibitor Luminespib Among Non-Small Cell Lung Cancers Harboring EGFR Exon 20 Insertions, Ann. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other rarer exon 21 mutations have generally low sensitivity (L861R, L862V, V851X, A859X) or uncertain sensitivity (E866K, H825L, P848L, H870Y/R, and G836S).

    “Other rarer mutations may be identified in the exon 21, but their sensitivity is generally low (L861R, L862V, V851X, A859X) or uncertain (E866K, H825L, P848L, H870Y/R, and G836S) [35,49,54,63]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [35] Pas, 2011, Activity of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Patients with Non-small Cell Lung Cancer Harboring Rare Epidermal Growth Factor Receptor Mutations, J. Thoracic Oncol. source

      Not checked in the free run.

    • cites [49] Galli, 2018, Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review, Lung Cancer source

      Not checked in the free run.

    • cites [54] Massarelli, 2013, Uncommon Epidermal Growth Factor Receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance, Lung Cancer source

      Not checked in the free run.

    • cites [63] Klughammer, 2016, Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Whose Tumors Harbor Uncommon EGFR Mutations, J. Thoracic Oncol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Increased doses of osimertinib may be more useful than commonly used doses in patients with exon 20 insertions.

    “suggesting that increased doses may be more useful than commonly used doses in this setting.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Hirano, 2015, In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L861Q is less sensitive to erlotinib (IC50 92-103 nM) or gefitinib (IC50 170 nM) compared with L858R (IC50 4.5-6 nM), but shows more similar sensitivity to afatinib and osimertinib (IC50 0.5 and 9 nM, respectively) than L858R (IC50 0.2 and 2.5 nM, respectively).

    “Preclinical data suggest that this mutation is sensitive to various EGFR TKI, although it is less sensitive to erlotinib (IC50 92–103 nM) or gefitinib (IC50 170 nM), compared with L858R (IC50 4.5–6 nM), but shows more similar sensitivity to afatinib and osimertinib (IC50 0.5 and 9 nM, respectively) than L858R (IC50 0.2 and 2.5 nM, respectively) [34,85].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Kancha, 2009, Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy, Clin. Cancer Res. source

      Not checked in the free run.

    • cites [85] Banno, 2016, Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommonepidermal growth factor receptormutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?, Cancer Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Complex mutations with coexistence of both common and resistance mutations are generally associated with lower efficacy than single common mutation, whereas those containing common mutations and sensitive rare mutations are associated with similar efficacy to single common mutations.

    “complex mutations with a coexistence of both common and resistance mutations are generally associated with lower efficacy than usually observed with single common mutation, whereas those containing common mutations and sensitive rare mutations are associated with similar efficacy to single common mutations [90,91].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Tam, 2009, Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations, Mol. Cancer Ther. source

      Not checked in the free run.

    • cites [91] Shen, 2017, Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations, Lung Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    De novo T790M mutations are observed in approximately 3% of all EGFR-mutated NSCLC patients with standard methods and are associated with reduced sensitivity to first- or second-generation EGFR TKIs, with an ORR of 14-33% and a median PFS of 1.94-2.9 months.

    “De novo T790M mutations constitute a small subgroup of EGFR mutations, which are observed in approximately 3% of all EGFR-mutated NSCLC patients with standard methods [92], and are generally associated with reduced sensitivity to first- or second-generation EGFR TKIs, with an ORR of 14–33% and a median PFS of 1.94–2.9 months [37,45,91].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [92] Wei, 2017, Characterization of common and rare mutations in EGFR and associated clinicopathological features in a large population of Chinese patients with lung cancer, Pathol. Res. Pract. source

      Not checked in the free run.

    • cites [37] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. source

      Not checked in the free run.

    • cites [45] Xu, 2016, EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China, Lung Cancer source

      Not checked in the free run.

    • cites [91] Shen, 2017, Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations, Lung Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S768I occurs in approximately 1-2% of EGFR mutated NSCLCs and has demonstrated transforming capacity in vitro.

    “This point mutation occurs in approximately 1–2% of EGFR mutated NSCLCs, demonstrated transforming capacity in vitro”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Russo, 2017, Rapid Acquisition of T790M Mutation after Treatment with Afatinib in an NSCLC Patient Harboring EGFR Exon 20 S768I Mutation, J. Thoracic Oncol. source

      Not checked in the free run.

    • cites [83] Hellmann, 2014, Clinical and in vivo Evidence that EGFR S768I Mutant Lung Adenocarcinomas Are Sensitive to Erlotinib, J. Thoracic Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S768I mutations exhibit higher sensitivity to afatinib in preclinical models compared with first-/third-generation EGFR TKIs, with an ORR of 100% and a median PFS of 14.7 months in the combined analysis of the LUX-Lung 2, 3, and 6 trials.

    “Similarly, S768I mutations exhibit differential sensitivity to EGFR TKIs, with a higher sensitivity to afatinib in preclinical models compared with first-/third-generation EGFR TKIs [85], with an ORR of 100% and a median PFS of 14.7 months in the combined analysis of the LUX-Lung 2, 3, and 6 trials [37].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Banno, 2016, Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommonepidermal growth factor receptormutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?, Cancer Sci. source

      Not checked in the free run.

    • cites [37] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR-mutated NSCLCs are associated with an uninflamed phenotype and weak immunogenicity, exhibiting lower PD-L1 expression/CD8+ TILs in the tumor microenvironment.

    “A possible explanation for this phenomenon is that EGFR-mutated NSCLCs are associated with an uninflamed phenotype and weak immunogenicity, exhibiting lower PD-L1 expression/CD8+ TILs in the tumor microenvironment [101,102].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [101] Dong, 2017, EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer, OncoImmunology source

      Not checked in the free run.

    • cites [102] Liu, 2018, Clinical relevance of PD-L1 expression and CD8 T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer, Lung Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The sensitivity of uncommon EGFR mutations to different classes of EGFR TKIs may significantly vary, with some having increased sensitivity to second-generation EGFR TKIs (exon 18 mutations and S768I) and others unresponsive to first-/second-generation EGFR TKIs but sensitive to mutant-selective EGFR inhibitors such as osimertinib and poziotinib (exon 20 insertions).

    “However, the sensitivity of uncommon EGFR mutations to the different classes of EGFR TKIs may significantly vary, since some have increased sensitivity to second-generation EGFR TKIs (i.e., exon 18 mutations and S768I exon 20 point mutation), whereas others are unresponsive to first-/second-generation EGFR TKIs, but sensitive to mutant-selective EGFR inhibitors, such as osimertinib and poziotinib”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The highly heterogeneous nature of uncommon EGFR mutations suggests that each rare variant should be analyzed separately in clinical studies and that clinical recommendations should be made on a case-by-case basis.

    “The highly heterogeneous nature of these mutations, encompassing the complete spectrum of sensitivity to EGFR TKIs, suggests that each of these rare variants should be analyzed separately in clinical studies and that clinical recommendations should be made on a case-by-case basis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    EGFR-mutated NSCLCs have a lower TMB (median mutational load: 60) compared with other NSCLCs (TP53 mutated: 325; KRAS mutated: 179; STK11 mutated: 132), with no relative differences between canonical exon 19 del/L858R mutations and exon 20 insertions.

    “EGFR-mutated NSCLCs have a lower TMB (median mutational load: 60) compared with other NSCLCs (TP53 mutated: 325; KRAS mutated: 179; STK11 mutated: 132) [104], with no relative differences between canonical exon 19 del/L858R mutations and exon 20 insertions [66].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] Dong, 2016, Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma, Clin. Cancer Res. source

      Not checked in the free run.

    • cites [66] Riess, 2018, Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC, J. Thoracic Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Carboplatin/paclitaxel/bevacizumab/atezolizumab may represent a therapeutic option in EGFR-mutated NSCLCs and might be an attractive approach for patients with common mutations after failure of first-line EGFR targeting therapy with first-/second-generation EGFR TKIs and who do not acquire the secondary T790M mutation.

    “These data suggest that carboplatin/paclitaxel/bevacizumab/atezolizumab may represent a therapeutic option in EGFR-mutated NSCLCs and might be an attractive approach for patients with common mutations after failure of first-line EGFR targeting therapy with first-/second-generation EGFR TKIs and who do not acquire the secondary T790M mutation.”
    Quote in the paperSubstantial claim
37 of 37

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?

  • EGFR mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC).

    “Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1–3.”

    From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [1]

  • Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors, including osimertinib.

    “Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors1,3,7–10, including osimertinib12.”

    From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [1]

  • Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed.

    “Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed1,8,17.”

    From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [1]

  • The frequency and effects of atypical EGFR mutations on drug sensitivity are unknown.

    “Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10.”

    From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [1]

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.

  • Codon 790 is assigned to both exon 18 and exon 20

    Minor

    The introduction lists E790 substitutions as exon 18 mutations, but the paper later identifies a mutation at the same codon, T790M, as an exon 20 mutation.

  • Exon 18 deletion is named differently from the cited case

    Minor

    The text calls the deletion delE790_T710insD, whereas its cited case report names it delE709_T710insD. The differing starting codon changes the stated mutation.

2 of 2

Cites

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Authors
Russo, A., Franchina, T., Ricciardi, G., Battaglia, A., Picciotto, M., & Adamo, V.
Affiliations
University of Messina (IT)
Corresponding author
Adamo, Vincenzo
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-03-21
Volume
20
Issue
6
Pages
1431
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20061431
PMC
PMC6470640
OpenAlex
W2924631596
Cited by
110
References
110
Citations by year
2026: 6 · 2025: 9 · 2024: 18 · 2023: 16 · 2022: 26 · 2021: 19 · 2020: 11 · 2019: 5
FWCI
2.57
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
EGFR mutation, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, osimertinib, treatment sensitivity, exon 19 deletion, L858R mutation, chemoimmunotherapy, targeted therapy
MeSH terms
Carcinoma, Non-Small-Cell Lung, Combined Modality Therapy, Exons, Humans, Immunotherapy, Lung Neoplasms, Mutation, Biomarkers, Tumor, Mutagenesis, Insertional, Treatment Outcome, Sequence Deletion, Protein Kinase Inhibitors, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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