Third-generation versus first-generation EGFR tyrosine kinase inhibitors in Asian patients with advanced EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled trials

Mengwei Xu; Wei Ding; Linlin Wan; Wenxiong Zhang

doi:10.1007/s12672-025-03767-7

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Third-generation versus first-generation EGFR tyrosine kinase inhibitors in Asian patients with advanced EGFR mutant non-small cell lung cancer: a meta-analysis of randomized controlled trials

Mengwei Xu, Wei Ding, Linlin Wan, Wenxiong Zhang

Springer Nature (2025) • Volume 16, Issue 1, Pages 1932-1932

SynthesisMetaAnalysisPDF AvailableGrade Eligible⚠️ Moderate Risk Flags

Overall Assessment

Adequate Methodological Quality

Assessment created by PaperScores Medical AI v0 on Dec 14, 2025

C

62/100

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Quality Dimensions

Bias & Integrity

COI handling, outcome switching, selective reporting

C60

Methods Rigour

Protocol clarity, sampling, controls

B78

External Validity

Generalisability, setting, population

B-70

Transparency & Reproducibility

Data/code/materials availability, preregistration

D42

Significance & Novelty

Contribution vs prior art; context if known

C+65

Statistical Validity

Models, assumptions, multiplicity, CI priority

B-72

Integrity & Transparency

Integrity checks

P-hacking risk?

?

None suspected

Signs of selective hypothesis testing or analysis choices that could inflate false positive rates.

Outcome switching?

?

Review recommended

Evidence that primary outcomes were changed during or after the study, potentially distorting results.

Conflict of interest?

?

None suspected

Authors have financial or other relationships that could bias research findings.

Data integrity issues?

?

None suspected

Concerns about the accuracy, completeness, or authenticity of the reported data.

Open science signals

Research data

?

Open access

Raw data used in the analyses is publicly available or accessible upon request.

Analysis code

?

Not shared

Code or scripts used to analyze the data are shared for reproducibility.

Study materials

?

Not applicable

Protocols, questionnaires, and other materials are publicly available.

Premise

Primary Research Question

Do third-generation EGFR-TKIs improve survival, response, and safety vs first-generation TKIs in Asian EGFR-mutant advanced NSCLC?

Hypothesis is Falsifiable

✓Yes

Effect sizes (HR/RR) testable against null via pooled analyses.

PICO Framework

Population✓Yes

Previously untreated Asian EGFR-mutant advanced NSCLC.

Intervention✓Yes

Third-generation EGFR-TKIs (osimertinib, aumolertinib, etc.).

Comparison✓Yes

First-generation EGFR-TKIs (gefitinib/erlotinib/icotinib).

Outcome✓Yes

PFS, OS, CNS-PFS, ORR, DOR, AEs are clinically meaningful.

Literature Positioning

Literature Review Balanced

Well covered

Contexts prior RCTs (FLAURA, AENEAS, FURLONG) and global MAs.

Evidence: pp.2–4; refs 10–13.

Research Gap Clearly Stated

Well covered

Focus on Asian-only phase 3 RCT evidence incl. newer TGETs.

Evidence: p.3: aim to synthesise Asian RCTs.

Stated Contribution Clear

Well covered

Updates efficacy/safety of TGET vs FGET in Asians with CNS outcomes.

Evidence: Abstract & p.3.

Study Provenance

Peer reviewed venueFunding disclosedNo conflicts declared6 affiliations listed

Authors & Affiliations

Dept. of Oncology, Xinyu People’s Hospital; Dept. of Thoracic Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University (p.1).

Funding Statement

Not applicable (Funding).

Conflicts of Interest

Authors declare no competing interests (p.17).

Peer Review

✓Journal article with received/accepted dates; typical external peer review.

Evidence: p.17: Received 30 Jul 2025 / Accepted 29 Sep 2025.

Methodological Assessment

Systematic Review / Meta-AnalysisPRISMASR/MA

17 applicable checklist items.

Yes 13 · No 2 · Unclear 2

Protocol & Search

✗

Protocol Registered (PROSPERO/OSF)

No PROSPERO or protocol cited.

Evidence: Methods lacks registration statement.

✓

Search Strategy Reproducible

Databases + keywords; Table S1 lists strategy.

Evidence: 2.1; Table S1.

✓

Inclusion/Exclusion Criteria Clear

PICOS criteria clearly stated.

Evidence: 2.2 Selection criteria.

✓

PRISMA Flow Diagram Provided

PRISMA 2020 flow diagram provided.

Evidence: Fig.1.

✓

Duplicate Screening & Extraction

Two independent reviewers; third resolves.

Evidence: 2.3 Data extraction.

Quality Assessment

✓

Risk of Bias Assessed

Cochrane RoB + Jadad used.

Evidence: 2.5; Fig S1; Table S2.

✓

RoB Tool Used and Applied

Cochrane tool explicitly applied to RCTs.

Evidence: 2.5; Figure S1.

✓

GRADE Certainty Assessed

GRADE performed; moderate–high certainty.

Evidence: 2.5; Table S3.

Synthesis & Analysis

✓

Heterogeneity Assessed

I² and Q used to assess heterogeneity.

Evidence: 2.6 Statistical analysis.

✓

Model Choice Justified (Fixed/Random)

Random-effects if I²>50%/p<0.10; else fixed.

Evidence: 2.6.

✗

Prediction Interval Reported

No prediction intervals reported.

Evidence: Results/figures lack PI.

✓

Publication Bias Assessed

Funnel plots for survival and responses.

Evidence: Fig.6.

?

Subgroup Pre-specified & Multiplicity Addressed

Multiple subgroup tests; prespecification/multiplicity not stated.

Evidence: 2.4; 3.3; Table 2.

✓

Sensitivity Analyses Robust

Leave-one-out/sensitivity showed stable estimates.

Evidence: 3.6; Figure S7.

?

Duplicate Data/Overlap Handled

Overlap handling not explicitly discussed.

Evidence: 3.1 includes Asian subsets + China RCTs.

✓

Effect Metric Harmonised Appropriately

HRs for time-to-event, RRs for binary endpoints.

Evidence: 2.6.

✓

Exposure of Interest Consistent

Exposure consistently TGET vs FGET across trials.

Evidence: 2.2; Table 1.

Modules without applicable checklist items (8)

These designs were fully marked as not applicable but remain available for reference.

Abstract

Compared with FGETs, TGETs significantly improve PFS, CNS control, response outcomes, and maintain a comparable safety profile for Asian patients with advanced EGFR-mutated NSCLC.

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Study Overview

Study Design

Meta Analysis

Primary classification used to evaluate this research.

Population

Asian adults with advanced EGFR-mutant NSCLC receiving first-line third- vs first-generation EGFR-TKIs in phase 3 RCTs.

Brief summary of who or what was studied.

Sample Size

2,434

Number of participants included in the study analyses.

Pre-registration

Not registered

Indicates whether the protocol or trial was registered before data collection.

Follow-up

Trial follow-up ~15–25 months across studies (Table 1).

Duration of observation or follow-up for outcomes.

Primary Outcome

Primary outcome was pre-specified in the protocol or registry.

Effect Size

PFS HR: HR 0.47 (95% CI 0.42–0.52)

Reviewer Notes

Systematic review and meta-analysis pooling phase 3 RCTs; no new allocation/blinding.

Publication Details

DOI

10.1007/s12672-025-03767-7

Published

October 21, 2025

Citations

0 citations

External Resources

DOI Link OpenAlex

Disclaimer: This assessment is generated by AI and should not be the sole basis for clinical or research decisions. Always review the original paper and consult with domain experts.

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