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

BACKGROUND

While hepatotoxicity has been widely reported with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), the comparative risk among them remains unclear. This study aimed to directly compare the relative risk (RR) of hepatotoxicity between new-generation (afatinib, osimertinib, dacomitinib) and first-generation (gefitinib, erlotinib) EGFR-TKIs in non-small-cell lung cancer (NSCLC) and to evaluate their overall risk-benefit profile.

METHODS

PubMed, Embase, Cochrane library databases and clinicaltrials.gov were searched for trials up to September 2025. A study protocol was registered in PROSPERO: CRD42023457906. Among the 5371 records identified, 6 studies finally fulfilled the established criteria. Data extracted for each study included study characteristics, baseline patient information, interventions and data on all-grades alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) elevation, overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). RR, hazard ratio (HR) and 95% confidence interval (CI) were calculated using the inverse variance method.

RESULTS

Six trials involving 2528 patients were analyzed. Decreased risks of hepatotoxicity due to the elevation of AST and ALT were observed for each new-generation EGFR-TKI. The pooled RRs of all-grades ALT, AST and TB elevation were 0.36 (95% CI 0.24-0.52, P < 0.001), 0.44 (95% CI 0.36-0.54, P < 0.001) and 0.83 (95% CI 0.50-1.39, P = 0.48), respectively. New-generation TKIs did achieved benefit in PFS (HR 0.65, 95% CI 0.50-0.83, P < 0.0001) and ORR (RR 1.14, 95% CI 1.00-1.29, P = 0.04). The OS of patients with new-generation TKI treatment was extended (afatinib, HR 0.73, 95% CI 0.58-0.92, P = 0.008 and osimertinib, HR 0.71, 95% CI 0.53-0.95, P = 0.02), except dacomitinib (HR 0.97, 95% CI 0.72-1.29, P = 0.81).

CONCLUSIONS

New-generation EGFR-TKIs (afatinib, osimertinib, and dacomitinib) demonstrate a superior efficacy and safety profile, with a significantly lower risk of hepatotoxicity, compared to gefitinib and erlotinib.