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First-line third-generation EGFR-TKIs for advanced EGFR-mutated non-small cell lung cancer: a systematic review and

Xiaomin Liu1, Qingfang Zhao1, Wei Sun1

  • 1Department of Oncology, Capital Medical University Beijing Ditan Hospital, Beijing, China.

Journal of Thoracic Disease
|July 14, 2026
PubMed
Abstract

Insights

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) significantly improve progression-free survival (PFS) in non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. Efficacy and safety are comparable among third-generation agents.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • First-line treatment for EGFR-mutated unresectable non-small cell lung cancer (NSCLC) often involves epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).
  • Head-to-head comparisons of third-generation EGFR-TKIs are limited, necessitating a comprehensive analysis of available agents.
  • This study addresses the need for evidence-based references in clinical decision-making for advanced EGFR-mutated NSCLC.

Purpose of the Study:

  • To conduct a network meta-analysis comparing the efficacy and safety of first-line third-generation EGFR-TKIs.
  • To provide evidence-based references for clinical decision-making in EGFR-mutated NSCLC.
  • To evaluate progression-free survival (PFS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs).

Main Methods:

  • A systematic literature search was performed across major databases (PubMed, EMBASE, Web of Science, CENTRAL) up to April 2026.
  • Randomized controlled trials (RCTs) comparing first-line third-generation EGFR-TKIs with first-generation EGFR-TKIs in advanced EGFR-mutated NSCLC were included.
  • Network meta-analysis (NMA) was conducted using a fixed-effect model, with treatment ranking based on surface under the cumulative ranking curve (SUCRA).

Main Results:

  • Eleven RCTs involving 4,663 patients were analyzed.
  • All investigated third-generation EGFR-TKIs demonstrated superior PFS compared to first-generation TKIs.
  • No statistically significant differences in PFS, ORR, or ≥ G3 TEAEs were observed among third-generation agents or between third- and first-generation TKIs.

Conclusions:

  • Most third-generation TKIs offer superior PFS over first-generation agents for EGFR-mutated NSCLC.
  • Efficacy and safety profiles, particularly concerning high-grade adverse events, appear similar across third-generation TKIs.
  • Subgroup analyses indicated no significant PFS benefit for specific agents (befotertinib, furmonertinib) in certain patient populations (L858R subgroup, elderly patients).
Keywords:
EGFR mutationNon-small cell lung cancer (NSCLC)network meta-analysis (NMA)third-generation tyrosine kinase inhibitor (third-generation TKI)

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