Hepatotoxicity and efficacy associated with first- and new-generation EGFR-TKIs in patients with NSCLC: a systematic

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Zhe Wang1, Jipeng Meng2, Guanlin Liu3

  • 1School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Shenhe District, 110016, China. wangzhe108@sina.cn.

BMC Cancer
|December 30, 2025
PubMed
Abstract

Insights

New-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show significantly lower hepatotoxicity risk compared to older EGFR-TKIs. These newer agents also improve progression-free survival and objective response rates in non-small-cell lung cancer patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Medicine

Background:

  • Hepatotoxicity is a known side effect of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
  • The comparative risk of liver injury among different generations of EGFR-TKIs is not well-established.
  • This study addresses the need for direct comparison of hepatotoxicity risks between new-generation and first-generation EGFR-TKIs.

Purpose of the Study:

  • To directly compare the relative risk of hepatotoxicity between new-generation (afatinib, osimertinib, dacomitinib) and first-generation (gefitinib, erlotinib) EGFR-TKIs.
  • To evaluate the overall risk-benefit profile of these EGFR-TKIs in non-small-cell lung cancer (NSCLC).
  • To assess the impact on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

Main Methods:

  • Systematic literature search of PubMed, Embase, Cochrane Library, and clinicaltrials.gov up to September 2025.
  • Inclusion of 6 trials involving 2528 patients diagnosed with NSCLC.
  • Meta-analysis calculating relative risks (RR) and hazard ratios (HR) for hepatotoxicity (ALT, AST, TB elevation) and efficacy outcomes (OS, PFS, ORR).

Main Results:

  • New-generation EGFR-TKIs showed significantly reduced risks for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation (RR 0.36 and 0.44, respectively).
  • No significant difference was observed in total bilirubin (TB) elevation risk (RR 0.83).
  • New-generation TKIs demonstrated improved PFS (HR 0.65) and ORR (RR 1.14), and extended OS for afatinib and osimertinib.

Conclusions:

  • New-generation EGFR-TKIs (afatinib, osimertinib, dacomitinib) offer a superior safety profile with significantly lower hepatotoxicity compared to first-generation agents (gefitinib, erlotinib).
  • These newer agents provide enhanced efficacy, improving PFS and ORR.
  • The findings support the use of new-generation EGFR-TKIs for improved outcomes in NSCLC patients.
Keywords:
EGFR-TKIsHepatotoxicityMeta-analysisNSCLC

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