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Cited by 175Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentHER2/EGFR in Cancer Research

Patients with Exon 19 Deletion Were Associated with Longer Progression-Free Survival Compared to Those with L858R Mutation after First-Line EGFR-TKIs for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Open access
Zhang, Yaxiong, Sheng, Jin, Kang, Shiyang, Fang, Wenfeng, Yan, Yue, Hu, Zhihuang, Hong, Shaodong, Wu, Xuan +3 more·2014·PLoS ONE
DOI 10.1371/journal.pone.0107161PMC PMC4164616
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Abstract

BACKGROUNDS: It has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered. METHODS: Subgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively. RESULTS: A total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20-0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35-0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation = 0.59, 95% CI 0.38-0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies. CONCLUSIONS: For advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs.

AI snapshot

Written from the paper’s full text.

TL;DR

This meta-analysis compared progression-free survival (PFS) after first-line EGFR-TKIs in advanced NSCLC patients with EGFR exon 19 deletion versus exon 21 L858R mutation. It found exon 19 deletion was associated with longer PFS than L858R mutation in both indirect and direct comparisons.

Key findings

  • In six phase III RCTs (1,382 chemo-naïve advanced NSCLC patients), pooled HR for PFS with EGFR-TKIs versus chemotherapy was 0.28 (95% CI 0.20–0.38, P<0.001) for exon 19 deletion and 0.47 (95% CI 0.35–0.64, P<0.001) for exon 21 L858R mutation.
  • Indirect comparison showed longer PFS for exon 19 deletion than L858R mutation: HR19/21 = 0.59 (95% CI 0.38–0.92; P=0.019).
  • Direct meta-analysis of seven additional studies (549 advanced NSCLC patients) showed a similar result: HR19/21 = 0.75 (95% CI 0.65–0.85; P<0.001).
  • Subgroup analyses by TKI type showed similar trends but did not reach statistical significance: gefitinib HR19/21 = 0.76 (95% CI 0.47–1.21, P=0.244), erlotinib 0.53 (95% CI 0.18–1.61, P=0.264), afatinib 0.49 (95% CI 0.21–1.17, P=0.108).

Methods

  • Systematic search of PubMed, Embase, Cochrane Central Registry of Controlled Trials, Google Scholar, and reference lists; eligible studies included clinical trials or retrospective studies of locally advanced/metastatic (IIIB or IV) NSCLC receiving first-line EGFR-TKI monotherapy, with tumor-tissue EGFR mutation analysis and available HRs for PFS.
  • Thirteen studies were included: six phase III RCTs for indirect meta-analysis and seven clinical trials or retrospective studies for direct meta-analysis.
  • Random-effects models were used to pool HRs and 95% CIs; heterogeneity was assessed with forest plots and I²; adjusted indirect comparison used log HRs and standard errors; publication bias was assessed with funnel plots, Begg’s test, and Egger’s test.

Limitations

  • The authors state the meta-analysis was based on subgroup data from included articles, which might compromise the evidence level.
  • The authors state the small number of included studies negated statistical significance in subgroup analyses.
  • The authors state the indirect comparison assumed no significant differences in platinum-based chemotherapy efficacy between exon 19 deletion and L858R mutation, and this hypothesis needs confirmation. Evident from the text: the direct analysis included retrospective studies, and time to progression was considered PFS in two studies, with one study’s P-value assumed as 0.05 to calculate HR.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0107161

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

  • Findingown data

    In advanced NSCLC patients with EGFR exon 21 L858R mutation, the pooled hazard ratio for progression-free survival comparing EGFR-TKIs to conventional chemotherapy was 0.47 (95% CI 0.35-0.64, P<0.001).

    “0.47 (95% CI 0.35–0.64, P<0.001) in those with exon 21 L858R mutation”
    • Also stated in: § Indirect meta-analysis of EGFR exon 19 deletions vs. exon 21 L858R mutations under TKI therapy for PFS · plain
      “For another sensitive EGFR mutation type, L858R mutation in exon 21, the pooled HR were 0.47 (95% CI 0.35 to 0.64, P<0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    In advanced NSCLC patients with EGFR exon 19 deletion, the pooled hazard ratio for progression-free survival comparing EGFR-TKIs to conventional chemotherapy was 0.28 (95% CI 0.20-0.38, P<0.001).

    “the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20–0.38, P<0.001) in patients with 19 exon deletion”
    • Also stated in: § Indirect meta-analysis of EGFR exon 19 deletions vs. exon 21 L858R mutations under TKI therapy for PFS · plain
      “For advanced NSCLC patients with EGFR exon 19 deletion, the pooled HR of EGFR-TKIs compared to conventional chemotherapy were 0.28 (95% CI, 0.20–0.38, P<0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    In advanced NSCLC patients with EGFR exon 19 deletion, the hazard ratio for progression-free survival comparing gefitinib to chemotherapy was 0.40 (95% CI 0.30-0.55, P<0.001).

    “HRgefitinib/chemotherapy = 0.40, 95% CI 0.30 to 0.55, P<0.001”
    Quote in the paperNot a substantial claim
  • Findingown data

    Direct meta-analysis of seven studies showed that advanced NSCLC patients with EGFR exon 19 deletion had longer progression-free survival than those with exon 21 L858R mutation after first-line EGFR-TKIs (HR19/21 = 0.75, 95% CI 0.65-0.85; P<0.001).

    “Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies.”
    • Also stated in: § Direct meta-analysis of EGFR exon 19 deletions vs. exon 21 L858R mutations under TKI therapy for PFS · plain
      “advanced NSCLC patients with exon 19 deletion benefited from longer PFS than those with exon 21 L858R mutation (HR19/21 = 0.75, 95% CI 0.65 to 0.85; P<0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    Indirect comparison showed that advanced NSCLC patients with EGFR exon 19 deletion had longer progression-free survival than those with exon 21 L858R mutation after first-line EGFR-TKIs (HR19/21 = 0.59, 95% CI 0.38-0.92; P=0.019).

    “Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation = 0.59, 95% CI 0.38–0.92; P = 0.019).”
    • Also stated in: § Indirect meta-analysis of EGFR exon 19 deletions vs. exon 21 L858R mutations under TKI therapy for PFS · plain
      “Indirect comparison revealed that patients with exon 19 deletion had more favorable outcome for PFS than those with exon 21 L858R mutation (HR19/21 = 0.59, 95% CI 0.38 to 0.92; P = 0.019) under TKIs therapy.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: There is no significant difference in the efficacy of platinum-based chemotherapy between EGFR exon 19 deletion and exon 21 L858R mutation in advanced NSCLC patients.
  • May combine two claims. 2
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Interpretationown data

    Similar trends of favorable progression-free survival outcome for EGFR exon 19 deletion among different first-line EGFR-targeted agents (gefitinib, erlotinib and afatinib) were presented, but statistical significances were not approached.

    “similar trends of favorable outcome of PFS in exon 19 deletion among different first-line EGFR-targeted agents (gefitinib, erlotinib and afatinib), were presented in our work, but the statistical significances were not approached.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    There was no publication bias for outcome measures, as the funnel plot analysis showed a symmetrical appearance and all p values were greater than 0.05 in Begg's test and Egger's test.

    “There was no publication bias for outcome measures, as the funnel plot analysis showed a symmetrical appearance and all p values were greater than 0.05 in Begg's test and Egger's test.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The meta-analysis was based on subgroup data of included articles, which might compromise the evidence level.

    “our meta-analysis was based on subgroup data of included articles, which might compromise the evidence level.”
    Quote in the paperNot a substantial claim
3 of 3

  • The authors state this as an assumption.

    There is no significant difference in the efficacy of platinum-based chemotherapy between EGFR exon 19 deletion and exon 21 L858R mutation in advanced NSCLC patients.

    “Based on the assumption that no significant difference of chemotherapy efficacy existed between exon 19 deletions and L858R mutations, we calculated the adjusted indirect comparison using the following formulas as previously described [17].”
    “our work was conducted based on the assumption that there were no significant differences in the efficacy of platinum-based chemotherapy between exon 19 deletion and L858R mutation for advanced NSCLC patients.”
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?

  • Patients harboring exon 19 deletions are associated with a reduced progression risk than those with exon 21 point mutations and a longer overall survival.

    “Recent meta-analyses addressed this question and reported that patients harboring exon 19 deletions are associated with a reduced progression risk than those with exon 21 point mutations [21–23] and a longer OS [22, 23].”

    From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [21]

  • The exact mechanism of the association between exon 19 deletions and better outcome remains largely elusive and might involve differential sensitivity to EGFR TKIs, different mechanisms of acquired resistance, and different frequency of compound mutations.

    “However, the exact mechanism of this association remains largely elusive and might involve differential sensitivity to EGFR TKIs, different mechanism of acquired resistance as well as different frequency of compound mutations [21].”

    From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [21]

Cites

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Cited by

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Authors
Zhang, Y., Sheng, J., Kang, S., Fang, W., Yan, Y., Hu, Z., Hong, S., Wu, X., Qin, T., Liang, W., & Zhang, L.
Affiliations
Sun Yat-sen University Cancer Center (CN)
Corresponding author
  • Liang, Wenhua
  • Zhang, Li
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-09-15
Volume
9
Issue
9
Pages
e107161
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0107161
PMC
PMC4164616
OpenAlex
W2022572106
Cited by
175
References
42
Citations by year
2026: 6 · 2025: 10 · 2024: 14 · 2023: 10 · 2022: 17 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 21 · 2016: 25 · 2015: 19 · 2014: 1
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Massachusetts Institute of Technology
  • University of Texas MD Anderson Cancer Center
  • Wu Jieping Medical Foundation (320.6750)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
EGFR exon 19 deletion, L858R mutation, EGFR tyrosine kinase inhibitors, advanced non-small cell lung cancer, progression-free survival, first-line therapy
MeSH terms
Erlotinib Hydrochloride, Gefitinib, Afatinib, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Mutation, Quinazolines, Proportional Hazards Models, Disease-Free Survival, ErbB Receptors

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