Objective:

To systematically evaluate the efficacy and safety of antibody-drug conjugates (ADCs) in patients with EGFR-mutant non-small cell lung cancer (NSCLC) after resistance to EGFR-tyrosine kinase inhibitors (TKIs).

Approach:

• Literature Search: Systematic search of PubMed, Embase, Cochrane Library, and Web of Science for clinical trials evaluating ADCs in EGFR-mutant NSCLC after TKI failure, published up to December 2025.
• Endpoints: Primary endpoint was objective response rate (ORR); secondary endpoints included median progression-free survival (mPFS), median overall survival (mOS), and hazard ratios (HR) for PFS and OS in randomized controlled trials (RCTs).
• Statistical Analysis: Pooled proportions estimated using Freeman-Tukey double arcsine transformation with DerSimonian-Laird random-effects model; subgroup analyses stratified by ADC target antigen.

Key Findings:

• Pooled ORR was 44.7% (95% CI 36.7%–52.9%; I² = 84.4%) with substantial heterogeneity.
• Higher ORR for TROP2-targeting ADCs (50.6%; 95% CI 40.3%–60.9%) compared to HER3-targeting ADCs (34.2%; 95% CI 28.8%–39.8%).
• Sacituzumab tirumotecan (Sac-TMT) showed improved PFS (HR 0.40; 95% CI 0.25–0.64) and OS (HR 0.57; 95% CI 0.44–0.76) over chemotherapy.
• Patritumab deruxtecan (HER3-DXd) improved PFS (HR 0.77; 95% CI 0.63–0.94) but OS data were immature.
• mPFS ranged from 5.5 to 11.1 months; mature mOS data available from only three studies (11.9–16.2 months).

Interpretation:

ADCs demonstrate substantial antitumor activity in EGFR-mutant NSCLC after TKI resistance, with efficacy varying by target and drug.

Limitations:

• High between-study heterogeneity.
• OS data were immature in most studies.

Conclusion:

ADCs, particularly TROP2-directed agents, are a key therapeutic option for EGFR-mutant NSCLC post-TKI resistance, highlighting the need for biomarker-guided patient selection.