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Cited by 413Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

Open access
Kobayashi, Yoshihisa, Mitsudomi, Tetsuya·2016·Cancer Science
DOI 10.1111/cas.12996PMC PMC5021039
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Abstract

Somatic mutations in the epidermal growth factor receptor ( EGFR ) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR ‐tyrosine kinase inhibitors ( TKI ), gefitinib, erlotinib or afatinib showed high objective response rates ( ORR ) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR ‐ TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%–50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for ins FQEA ) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib ( EGF 816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.

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Written from the paper’s full text.

TL;DR

This review argues that EGFR mutations in lung cancer are heterogeneous and should be treated with mutation-specific TKI selection rather than as one sensitive group. It compiles frequency, in vitro, and clinical response data showing that uncommon mutations such as G719X, Del18, S768I, L861Q, Ins19, and Ins20 have distinct sensitivities to first-, second-, and third-generation EGFR-TKIs.

Key findings

  • Common mutations Del19 and L858R accounted for 44.8% and 39.8% of EGFR mutations in the authors’ survey; gefitinib, erlotinib, and afatinib showed ORR of approximately 60% and PFS of 9–13 months. Del19 may be more sensitive than L858R: a meta-analysis found PFS HR 0.24 (95% CI 0.20–0.29) for Del19 versus 0.48 (95% CI 0.39–0.58) for L858R, and LUX-Lung 7 showed afatinib superiority over gefitinib with HR 0.73 (95% CI 0.57–0.95).
  • Uncommon mutations account for 12% of all EGFR mutations. G719X, Del18, E709K, Ins19, S768I, and L861Q showed moderate sensitivity to gefitinib or erlotinib with ORR 30%–50%, but afatinib appeared especially effective; for example, afatinib ORR was 78% (14/18) in G719X tumors in a combined LUX-Lung analysis.
  • Ins20 mutations accounted for 5.8% of EGFR mutations and had ORR of only 17% (10/59) to first-generation TKI and 10% to second-generation TKI, except A763_Y764insFQEA, which had ORR 86%; osimertinib may be effective for rare subtype D770_N771insNPG, and nazartinib (EGF816) is promising for major subtypes V769_D770insASV and D770_N771insSVD.
  • S768I and L861Q had ORR to first-generation TKI of 42% and 39%, respectively; afatinib ORR was 100% (8/8) for S768I and 56% (9/16) for L861Q in a combined LUX-Lung analysis, though the authors note limited single-mutation data.

Methods

  • Narrative review compiling data on frequency, in vitro sensitivity, and clinical treatment response for common and uncommon EGFR mutations.
  • Frequency estimates were drawn from recent large single-institution or multi-institutional studies using the same protocol and compared with the COSMIC database (n = 16,138); pretreatment T790M was excluded from the authors’ survey.
  • In vitro sensitivities were assessed using Ba/F3 cells expressing specific EGFR mutations, and clinical response data included a summary of first-generation EGFR-TKI responses in 396 patients with less common mutations (Table 3).

Limitations

  • Stated: frequency estimates are complicated by mutation detection methods, complex/co-mutations, and publication biases; COSMIC data should be interpreted cautiously; in vitro sensitivities require consideration of methodological differences and clinically available drug concentrations; evidence for rare mutations remains weak.
  • Stated: many uncommon-mutation clinical estimates come from small series, case reports, or post hoc analyses, and some mutation subtypes have limited or no single-mutation data.
  • Evident from the text: this is a narrative review without a described systematic search strategy or formal quality appraisal, so the compiled frequencies and response rates may be subject to selection and reporting bias.

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Integrity signals

Registry

Crossref · 10.1111/cas.12996

Cites

80 of 80 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 103 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Second generation EGFR-TKIs afatinib or neratinib are especially effective for EGFR exon 18 mutations compared with other EGFR-TKIs.

    “We recently reported that second generation EGFR‐TKI, afatinib or neratinib, are especially effective for EGFR exon 18 mutations compared with other EGFR‐TKI, indicating the significance of mutation‐specific EGFR‐TKI selection.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Kobayashi Y, Togashi Y, Yatabe Y et al 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 2015; 21: 5305– 13. 26206867 source

      Not checked in the free run.

  • Findingcitation

    The number of patients with Del19+T790M tumors enrolled in phase I/II trials for osimertinib and rociletinib was approximately twice as large as the number with L858R+T790M.

    “The number of patients with Del19 + T790M tumors who enrolled in phase I/II trials for osimertinib38 and rociletinib39 was approximately twice as large as the number of patients with L858R+T790M.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Janne PA, Yang JC, Kim DW et al AZD9291 in EGFR inhibitor‐resistant non‐small‐cell lung cancer. N Engl J Med 2015; 372: 1689– 99. 25923549 source

      Not checked in the free run.

    • cites [39] Sequist LV, Soria JC, Goldman JW et al Rociletinib in EGFR‐mutated non‐small‐cell lung cancer. N Engl J Med 2015; 372: 1700– 9. 25923550 source

      Not checked in the free run.

  • Findingcitation

    Rare variant delE746_S752insV may be less sensitive to gefitinib according to in vitro data.

    “Rare variant delE746_S752insV may be less sensitive to gefitinib according to the in vitro data (Table 2).56, 57, 58”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Yuza Y, Glatt KA, Jiang J et al Allele‐dependent variation in the relative cellular potency of distinct EGFR inhibitors. Cancer Biol Ther 2007; 6: 661– 7. 17495523 source

      Not checked in the free run.

    • cites [57] Engelman JA, Zejnullahu K, Gale CM et al PF00299804, an irreversible pan‐ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67: 11924– 32. 18089823 source

      Not checked in the free run.

    • cites [58] Li D, Ambrogio L, Shimamura T et al BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702– 11. 18408761 PMC2748240 source

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  • Findingnone given

    When background mutations in tumors with acquired resistance by T790M were examined, Del19 was more common than L858R.

    “However, when background mutations in tumors with acquired resistance by T790M were examined, Del 19 was more common than L858R.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Even second-generation TKIs achieve objective response rate of only 10% for Ins20.

    “Even 2G‐TKI achieve ORR of only 10%.18, 66”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non‐small‐cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13: e23– 31. 21764376 source

      Not checked in the free run.

    • cites [66] Yang JC, Sequist LV, Geater SL et al 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 2015; 16: 830– 8. 26051236 source

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  • May combine two claims. 32
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingcitation

    Del19 and L858R account for 44.8% (2573/5741) and 39.8% (2283/5741) of EGFR mutations, respectively.

    “Del19 and L858R account for 44.8% (2573/5741) and 39.8% (2283/5741) of EGFR mutations, respectively.29, 45, 46, 47, 48”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Kobayashi Y, Togashi Y, Yatabe Y et al EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib and neratinib as compared with first or third generation TKIs. Clin Cancer Res 2015; 21: 5305– 13. 26206867 source

      Not checked in the free run.

    • cites [45] Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. 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 2011; 17: 3812– 21. 21531810 source

      Not checked in the free run.

    • cites [46] Arcila ME, Nafa K, Chaft JE et al EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013; 12: 220– 9. 23371856 PMC3714231

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    There is a discrepancy in the frequency of Del19 and L858R between conventional published data and COSMIC; in COSMIC, Del19 accounts for approximately half of L858R.

    “For example, there was a discrepancy in the frequency of Del19 and L858R in conventional published data.20 Del19 accounts for approximately half of L858R (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004; 64: 8919– 23. 15604253

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    S768I and L861Q account for 1.1% (39/3712) and 0.9% (34/3712) of EGFR mutations, respectively.

    “S768I and L861Q account for 1.1% (39/3712) and 0.9% (34/3712), respectively (Fig. 1).46, 47, 48”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Arcila ME, Nafa K, Chaft JE et al EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013; 12: 220– 9. 23371856 PMC3714231

      Not checked in the free run.

    • cites [47] Shi Y, Au JS, Thongprasert S et al A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non‐small‐cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9: 154– 62. 24419411 PMC4132036

      Not checked in the free run.

    • cites [48] Lee B, Lee T, Lee SH, Choi YL, Han J. Clinicopathologic characteristics of EGFR, KRAS, and ALK alterations in 6595 lung cancers. Oncotarget 2016; Epub ahead of print. PMC5029670 26992209

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Most E709X mutations present as complex mutations and the paired mutations tend to be G719X or L858R.

    “Most E709X present as complex mutations and the paired mutations tend to be G719X or L858R.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    G719X includes many variants, 97% of which are G719A/S/C and can be detected by diagnostic kits.

    “Although G719X includes many variants, 97% of them are G719A/S/C which can be detected by diagnostic kits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Objective response rate to first-generation TKIs in S768I and L861Q tumors were only 42% and 39%, respectively.

    “ORR to 1G‐TKI in S768I and L861Q tumors were only 42 and 39%, respectively (Table 3).26, 29, 61, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] Kobayashi S, Canepa HM, Bailey AS et al Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013; 8: 45– 51. 23242437 PMC3531043 source

      Not checked in the free run.

    • cites [29] Kobayashi Y, Togashi Y, Yatabe Y et al EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib and neratinib as compared with first or third generation TKIs. Clin Cancer Res 2015; 21: 5305– 13. 26206867 source

      Not checked in the free run.

    • cites [61] Beau‐Faller M, Prim N, Ruppert AM et al 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 2014; 25: 126– 31. 24285021 PMC3868323 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Insertional mutations in exon 20 (Ins20) account for 5.8% (134/2307) of all EGFR mutations and consist of 44 types of mutations.

    “Insertional mutations in exon 20 (Ins 20) account for 5.8% (134/2307) of all EGFR mutations and, based on our survey, consist of 44 types of mutations (Fig. 1).59, 60, 61, 62”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [59] Oxnard GR, Lo PC, Nishino M et al Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 2013; 8: 179– 84. 23328547 PMC3549533

      Not checked in the free run.

    • cites [60] Pan Y, Zhang Y, Li Y et al Prevalence, clinicopathologic characteristics, and molecular associations of EGFR exon 20 insertion mutations in East Asian patients with lung adenocarcinoma. Ann Surg Oncol 2014; 21(Suppl 4): S490– 6. 24419753

      Not checked in the free run.

    • cites [61] Beau‐Faller M, Prim N, Ruppert AM et al 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 2014; 25: 126– 31. 24285021 PMC3868323 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Objective response rate to first-generation TKIs in patients with G719X tumors as a single mutation and Del18 were only 32% and 25%, respectively.

    “ORR to 1G‐TKI in patients with G719X‐tumors as a single mutation and Del18 were only 32% and 25%, respectively (Table 3).29, 61, 69, 70, 71, 72, 73”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Kobayashi Y, Togashi Y, Yatabe Y et al EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib and neratinib as compared with first or third generation TKIs. Clin Cancer Res 2015; 21: 5305– 13. 26206867 source

      Not checked in the free run.

    • cites [61] Beau‐Faller M, Prim N, Ruppert AM et al 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 2014; 25: 126– 31. 24285021 PMC3868323 source

      Not checked in the free run.

    • cites [69] Cheng C, Wang R, Li Y et al EGFR exon 18 mutations in East Asian patients with lung adenocarcinomas: a comprehensive investigation of prevalence, clinicopathologic characteristics and prognosis. Sci Rep 2015; 5: 13959. 26354324 PMC4564802

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Relatively high objective response rates of 53% for E709X and 59% for G719X were observed in patients with complex mutations.

    “Relatively high ORR of 53% (for E709X) and 59% (for G719X) were observed in patients with complex mutations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    S768I and L861Q can be coupled with G719X, but the actual frequency of the complex mutation remains uncertain.

    “These mutations can be coupled with G719X but the actual frequency of the complex mutation remains uncertain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    G719X, Del18 and E709X are present in 3.1% (100/3186), 0.3% (9/3186) and 0.3% (9/3186) of EGFR mutations, respectively.

    “These genotypes are present in 3.1% (100/3186), 0.3% (9/3186) and 0.3% (9/3186), respectively (Fig. 1).29, 61, 69”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Kobayashi Y, Togashi Y, Yatabe Y et al EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib and neratinib as compared with first or third generation TKIs. Clin Cancer Res 2015; 21: 5305– 13. 26206867 source

      Not checked in the free run.

    • cites [61] Beau‐Faller M, Prim N, Ruppert AM et al 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 2014; 25: 126– 31. 24285021 PMC3868323 source

      Not checked in the free run.

    • cites [69] Cheng C, Wang R, Li Y et al EGFR exon 18 mutations in East Asian patients with lung adenocarcinomas: a comprehensive investigation of prevalence, clinicopathologic characteristics and prognosis. Sci Rep 2015; 5: 13959. 26354324 PMC4564802

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    Only four types of Ins20 are detectable using approved diagnostic kits, accounting for only 49% (66/134) of Ins20 mutations.

    “As mentioned above, only four types are detectable using approved diagnostic kits, accounting for only 49% (66/134).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only 1 patient had S768I as a single mutation, and the remaining 7 patients had S768I+G719X or L858R; half of the patients had L861Q as a single mutation.

    “However, only 1 patient had S768I as a single mutation, and the remaining 7 patients had S768I+G719X or L858R. On the other hand, half of the patients had L861Q as a single mutation.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingnone given

    Afatinib appeared to be especially effective for tumors with G719X, Del18, E709K, Ins19, S768I or L861Q mutations.

    “However, afatinib appeared to be especially effective for these tumors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Approximately one-third of G719X mutations are present as complex mutations and they tend to be in combination with S768I or L861Q.

    “Approximately one‐third of G719X mutations are present as complex mutations and they tend to be in combination with S768I or L861Q (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Somatic mutations in the kinase domain of EGFR are detected in approximately 40% of lung adenocarcinoma in Asians and 17% in Caucasians.

    “Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene are detected in approximately 40% and 17% of lung adenocarcinoma in Asians1 and in Caucasians,2 respectively.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Yatabe Y, Kerr KM, Utomo A et al EGFR mutation testing practices within the Asia Pacific Region: results of a multicenter diagnostic survey. J Thorac Oncol 2015; 10: 438– 45. 25376513 PMC4342317

      Not checked in the free run.

    • cites [2] Kris MG, Johnson BE, Berry LD et al Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014; 311: 1998– 2006. 24846037 PMC4163053 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% of lung adenocarcinomas in Caucasians and 40% in East Asians.

    “Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Premisecitation

    Rociletinib development was abandoned because the initially reported objective response rate of 59% was reduced to 45% due to unconfirmed partial responses.

    “In contrast, the development of rociletinib was abandoned because the initially reported ORR of 59% was reduced to 45%: initial data were not unconfirmed partial responses although partial responses must be maintained on a second scan obtained at least 4 weeks later.42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Sequist LV, Soria JC, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med 2016; 374: 2296– 7. 27195670

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The largest study by Chung et al. reported that objective response rate to first-generation TKIs in Del starting at E746 was lower than in Del starting at L747 (68.2% and 79.6%, respectively), whereas other groups showed the opposite tendency.

    “The clinical data are controversial: the largest study by Chung et al. reported that ORR to 1G‐TKI in Del starting at E746 were lower than those in Del starting at L747 (68.2% and 79.6%, respectively),53 whereas other groups showed the opposite tendency.54, 55”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [53] Chung KP, Wu SG, Wu JY et al Clinical outcomes in non‐small cell lung cancers harboring different exon 19 deletions in EGFR. Clin Cancer Res 2012; 18: 3470– 7. 22510346

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    • cites [54] Kaneda T, Hata A, Tomioka H et al Possible differential EGFR‐TKI efficacy among exon 19 deletional locations in EGFR‐mutant non‐small cell lung cancer. Lung Cancer 2014; 86: 213– 8. 25304185

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    • cites [55] Lee VH, Tin VP, Choy TS et al Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first‐line tyrosine kinase inhibitor in metastatic non‐small‐cell lung cancer. J Thorac Oncol 2013; 8: 1148– 55. 23945384

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  • May combine two claims.

    Premisecitation

    Deletions starting at E746, E747 and others are present in 73% (272/373), 25% (92/373) and 2% (9/373) of Del19, respectively.

    “Deletion starting at E746 (the majority of them are delE746_A750), E747 and others are present in 73% (272/373), 25% (92/373) and 2% (9/373), respectively.53, 54, 55”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Chung KP, Wu SG, Wu JY et al Clinical outcomes in non‐small cell lung cancers harboring different exon 19 deletions in EGFR. Clin Cancer Res 2012; 18: 3470– 7. 22510346

      Not checked in the free run.

    • cites [54] Kaneda T, Hata A, Tomioka H et al Possible differential EGFR‐TKI efficacy among exon 19 deletional locations in EGFR‐mutant non‐small cell lung cancer. Lung Cancer 2014; 86: 213– 8. 25304185

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    • cites [55] Lee VH, Tin VP, Choy TS et al Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first‐line tyrosine kinase inhibitor in metastatic non‐small‐cell lung cancer. J Thorac Oncol 2013; 8: 1148– 55. 23945384

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

    Premisecitation

    Olmutinib was approved for T790M-positive tumors in South Korea and received FDA breakthrough therapy designation.

    “Recently, olmutinib (BI1482694/HM61713) was approved for T790M‐positive tumors in South Korea and received FDA breakthrough therapy designation.43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Park K, Lee JS, Lee KH et al BI 1482694 (HM61713), an EGFR mutant‐specific inhibitor, in T790M+ NSCLC: efficacy and safety at the RP2D. J Clin Oncol 2016; 34; (suppl; abstr 9055).

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  • May combine two claims.

    Premisecitation

    LUX-lung 3 and 6 studies showed a survival benefit of afatinib in patients with Del19 tumors but not for those with L858R tumors.

    “LUX‐lung 3 and 6 studies showed a survival benefit of afatinib in patients with Del19‐tumors but not for those with L858R‐tumors.52”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Yang JC, Wu YL, Schuler M et al Afatinib versus cisplatin‐based chemotherapy for EGFR mutation‐positive lung adenocarcinoma (LUX‐Lung 3 and LUX‐Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16: 141– 51. 25589191 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pretreatment T790M was more frequent in L858R tumors than in Del19 tumors, although the differences were observed only in studies using methods with a detection limit <5%.

    “Interestingly, Chen et al. reported that pretreatment T790M was more frequent in L858R‐tumors than in Del19‐tumors, although the differences were observed only in studies using methods with a detection limit <5%.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Chen LY, Molina‐Vila MA, Ruan SY et al Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non‐small cell lung cancer: a systematic review and meta‐analysis. Lung Cancer 2016; 94: 46– 53. 26973206 source

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

    Premisecitation

    Nazartinib (EGF816) and ASP8273 are undergoing clinical evaluation.

    “Other 3G‐TKI, nazartinib (EGF816) and ASP8273, are undergoing clinical evaluation.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Yu HA, Spira AI, Horn L et al Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation‐positive non‐small cell lung cancer: interim results from an ongoing phase 1 study. J Clin Oncol 2016; 34 (suppl; abstr 9050).

      Not checked in the free run.

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

    Premisenone given

    Numeration for multiple EGFR mutations is not defined: some studies include them as part of the representative mutation, such as Del19 or L858R, and others count these mutations independently.

    “Numeration for these mutations is not defined: some studies include them as a part of the representative mutation, such as Del19 or L858R, and others count these mutations independently (i.e. double‐counting).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Multiple EGFR mutations are sometimes detected in the same tumor and are referred to as co-mutations, complex mutations or compound mutations.

    “Multiple EGFR mutations are sometimes detected in the same tumor and these mutations have been referred to as co‐mutations, complex mutations or compound mutations.23, 24, 25, 26”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Huang SF, Liu HP, Li LH et al High frequency of epidermal growth factor receptor mutations with complex patterns in non‐small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 2004; 10: 8195– 203. 15623594

      Not checked in the free run.

    • cites [24] Wu SG, Chang YL, Hsu YC et al Good response to gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist 2008; 13: 1276– 84. 19060236

      Not checked in the free run.

    • cites [25] Chen Z, Feng J, Saldivar JS, Gu D, Bockholt A, Sommer SS. EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one‐third of doublets occur at five pairs of amino acids. Oncogene 2008; 27: 4336– 43. 18372921

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  • May combine two claims.

    Premisecitation

    A meta-analysis including seven randomized trials comparing EGFR-TKI to platinum doublet chemotherapy found that the hazard ratio of progression-free survival for Del19 tumors was 0.24 (95% CI 0.20-0.29) and for L858R tumors was 0.48 (95% CI 0.39-0.58); the Del19 hazard ratio was 50% greater.

    “The study revealed that the HR of PFS for tumors with Del19 was 50% greater (HR 0.24, 95% CI 0.20–0.29) than for tumors with L858R (HR 0.48, 95% CI 0.39–0.58).51”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Lee CK, Wu YL, Ding PN et al Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR‐mutant lung cancer: a meta‐analysis. J Clin Oncol 2015; 33: 1958– 65. 25897154 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Not all data on specific EGFR genotypes reaches the published literature: common genotypes are often included in prospective trials, less common or rare genotypes may be described in observational series or case reports, and the completeness of data in meta-analyses depends on selection criteria and publication biases.

    “Not all data on specific genotypes reaches the published literature: common genotypes are often included in prospective trials; less common or rare genotypes may be described in observational series or case reports; and the completeness of the data in meta‐analyses inherently depends upon selection criteria as well as publication biases.27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Oxnard GR, Janne PA. Power in numbers: meta‐analysis to identify inhibitor‐sensitive tumor genotypes. Clin Cancer Res 2013; 19: 1634– 6. 23403632 PMC4327821

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pretreatment T790M was excluded from the survey because the majority of such mutations exist as complex mutations and their frequency varies widely from 3.9% to 64% based on assay sensitivities.

    “Pretreatment T790M was excluded from our survey because the majority of them exist as complex mutations and the frequency vary widely from 3.9% to 64% based on the sensitivities of assays.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Chen LY, Molina‐Vila MA, Ruan SY et al Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non‐small cell lung cancer: a systematic review and meta‐analysis. Lung Cancer 2016; 94: 46– 53. 26973206 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In prospective trials of common EGFR mutations, gefitinib, erlotinib and afatinib showed objective response rates of approximately 60% and progression-free survival of 9-13 months.

    “Evidence of these common mutations has been developed in prospective trials: gefitinib, erlotinib and afatinib showed ORR of approximately 60% and PFS of 9–13 months.5, 6, 7, 8, 9, 10, 11”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Maemondo M, Inoue A, Kobayashi K et al Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380– 8. 20573926 source

      Not checked in the free run.

    • cites [6] Mitsudomi T, Morita S, Yatabe Y et al Gefitinib versus cisplatin plus docetaxel in patients with non‐small‐cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121– 8. 20022809 source

      Not checked in the free run.

    • cites [7] Zhou C, Wu YL, Chen G et al Erlotinib versus chemotherapy as first‐line treatment for patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer (OPTIMAL, CTONG‐0802): a multicentre, open‐label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735– 42. 21783417 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As of May 2016, approximately 16,000 EGFR mutations are registered in COSMIC, and as many as 594 types of EGFR mutations are reported.

    “As of May 2016, approximately 16 000 EGFR mutations are registered. According to this database, as many as 594 types of EGFR mutations are reported.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Catalogue of Somatic Mutations in Cancer, release version 76. [Online; cited 1 April 2016.] Available from URL: http://cancer.sanger.ac.uk/cosmic.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Three factors complicate estimations of the true frequencies of each EGFR mutation in clinics: methods for detecting mutations, the presence of complex mutations, and publication biases.

    “Three factors appear to complicate estimations of the true frequencies of each EGFR mutation in clinics: methods for detecting mutations, the presence of complex mutations and publication biases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    C797S mutation appeared sensitive to first-generation TKIs, and C797S+T790M in trans can be treated with a combination of first- and third-generation TKIs.

    “Furthermore, C797S mutation appeared to be sensitive to 1G‐TKI, and even C797S+T790M in trans can be treated with a combination of 1G and 3G‐TKI.41”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Niederst MJ, Hu H, Mulvey HE et al The allelic context of the C797S mutation acquired upon treatment with third‐generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res 2015; 21: 3924– 33. 25964297 PMC4587765 source

      Not checked in the free run.

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

    Premisecitation

    The frequency of germline T790M remains unclear.

    “In addition, the frequency of germline T790M remain unclear.31, 32, 33”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Bell DW, Gore I, Okimoto RA et al Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005; 37: 1315– 6. 16258541

      Not checked in the free run.

    • cites [32] Oxnard GR, Miller VA, Robson ME et al Screening for germline EGFR T790M mutations through lung cancer genotyping. J Thorac Oncol 2012; 7: 1049– 52. 22588155 PMC3354706

      Not checked in the free run.

    • cites [33] Yu HA, Arcila ME, Harlan Fleischut M et al Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol 2014; 9: 554– 8. 24736080 PMC4412273

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR mutations shift the equilibrium of protein structures from an inactive state into an active state, resulting in increased and sustained phosphorylation of EGFR and other HER family proteins without ligand stimulation.

    “EGFR mutations shift the equilibrium of protein structures from an inactive state into an active state, resulting in the increased and sustained phosphorylation of EGFR and other HER family proteins without ligand stimulation.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non‐small‐cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13: e23– 31. 21764376 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neratinib development for lung cancer was abandoned because it was not effective for common EGFR-mutant tumors, although it was effective for G719X tumors.

    “Neratinib is also one of the 2G‐TKI. However, its development for lung cancer was abandoned because it was not effective for common EGFR‐mutant tumors, although it was effective for G719X tumors.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Sequist LV, Besse B, Lynch TJ et al 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 2010; 28: 3076– 83. 20479403

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The Ba/F3 cell assay is a valid safeguard for assessing oncogenic ability of EGFR mutations: Ba/F3 cells depend on IL-3 for survival and growth, so growth of Ba/F3 cells transfected with a specific EGFR mutation in the absence of IL-3 indicates oncogenic ability and can exclude artifactual mutations.

    “Notably, the murine pro‐B cell line Ba/F3 depends on interleukin‐3 (IL‐3) for its survival and growth. Accordingly, the growth of Ba/F3 cells transfected with specific EGFR mutation in the absence of IL‐3 indicates oncogenic ability, which can exclude artifactual mutations.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Ins20 mutations except insFQEA have been regarded as resistant mutations.

    “Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The objective response rate to first-generation TKIs for Ins19 is 40%, although only limited data are available.

    “Although only limited data are available, ORR to 1G‐TKI is 40%.28, 82, 83, 84”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] He M, Capelletti M, Nafa K et al EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res 2012; 18: 1790– 7. 22190593 PMC3306520

      Not checked in the free run.

    • cites [82] Chan AW, Tong JH, Lo SH, To KF. An uncommon insertion mutation in exon 19 of EGFR showed stable disease after TKI treatment. J Thorac Oncol 2013; 8: e107– 8. 24389445

      Not checked in the free run.

    • cites [83] Iyevleva AG, Mitiushkina NV, Karaseva NA et al Lung carcinomas with EGFR exon 19 insertions are sensitive to gefitinib treatment. J Thorac Oncol 2014; 9: e31– 3. 24736087

      Not checked in the free run.

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

    Premisecitation

    Yasuda et al. reported an additional 31 types of Ins20 mutations.

    “In addition, Yasuda et al. reported an additional 31 types of mutations.18, 63”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non‐small‐cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13: e23– 31. 21764376 source

      Not checked in the free run.

    • cites [63] Yasuda H, Park E, Yun CH et al Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013; 5: 216ra177. PMC3954775 24353160 source

      Not checked in the free run.

40 of 40

  • The paper relies on this without support.

    EGFR mutations have conventionally been classified as sensitive, less sensitive, and resistant based on their responses to first-generation TKIs.

    “Conventionally, EGFR mutations have been classified as sensitive, less sensitive and resistant mutations based on their responses to 1G‐TKI.”
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.

  • The smaller hazard ratio is described as greater

    Minor

    The stated hazard ratio for Del19 is 0.24, half the 0.48 stated for L858R, not 50% greater. The intended comparison may be treatment benefit, but the sentence explicitly compares hazard ratios.

  • S768I complex-mutation response rate is overstated

    Minor

    The row has 9 partial responses, 8 stable diseases and 1 progressive disease: 9 responses among 18 patients, or 50%, rather than 53%.

    Reported 53 · recomputed 50

  • G719X subgroup counts exceed the stated total

    Minor

    The non-overlapping G719X rows list 48 partial responses, 49 stable diseases and 51 progressive diseases for single mutations, plus 1 complete response, 33 partial responses, 18 stable diseases and 6 progressive diseases for complex mutations. These total 206 patients, not the stated 202.

    Reported 202 · recomputed 206

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. 10.1158/1078-0432.CCR-15-1046 · DOI · Paper page
  2. Park K, 2016, BI 1482694 (HM61713), an EGFR mutant‐specific inhibitor, in T790M+ NSCLC: efficacy and safety at the RP2D, J Clin Oncol, 34
  3. Yu HA, 2016, Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation‐positive non‐small cell lung cancer: interim results from an ongoing phase 1 study, J Clin Oncol, 34
  4. Banno E, 2016, Sensitivities to various EGFR‐TKIs of uncommon EGFR mutations L861Q and S768I: What is the optimal EGFR‐TKI?, Cancer Sci

Cited by

Sorted by citations

Authors
Kobayashi, Y., & Mitsudomi, T.
Affiliations
Kindai University (JP)
Corresponding author
Mitsudomi, Tetsuya
ORCID
Venue
Cancer Science
Publisher
Wiley
Published
2016-08-09
Volume
107
Issue
9
Pages
1179-1186
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
DOI
10.1111/cas.12996
PMC
PMC5021039
OpenAlex
W2507541911
Cited by
413
References
80
Citations by year
2026: 24 · 2025: 38 · 2024: 45 · 2023: 35 · 2022: 68 · 2021: 43 · 2020: 57 · 2019: 49 · 2018: 25 · 2017: 24 · 2016: 3
FWCI
5.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Science (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords
EGFR mutation, lung adenocarcinoma, EGFR tyrosine kinase inhibitors, targeted therapy, exon 19 deletion, L858R mutation, uncommon EGFR mutations, afatinib, gefitinib, erlotinib, osimertinib, personalized treatment, drug sensitivity
MeSH terms
Antineoplastic Agents, Humans, Lung Neoplasms, Mutation, Signal Transduction, Genetic Heterogeneity, Protein Kinase Inhibitors, Precision Medicine, Molecular Targeted Therapy, Mutation Rate, 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.

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