Efficacy and safety of antibody-drug conjugates in EGFR-mutant non-small cell lung cancer after tyrosine kinase inhibitor resistance: a systematic review and meta-analysis.

Background: Patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) inevitably develop resistance to EGFR-tyrosine kinase inhibitors (TKIs). Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic strategy in this setting; however, no meta-analysis has systematically evaluated ADC efficacy and safety specifically in this population. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science for clinical trials evaluating ADCs in patients with EGFR-mutant NSCLC after TKI failure, published up to December 2025. The 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). Pooled proportions were estimated using the Freeman-Tukey double arcsine transformation with a DerSimonian-Laird random-effects model, and subgroup analyses were stratified by ADC target antigen. A random-effects meta-regression was used to assess whether the median number of prior treatment lines explained heterogeneity. Results: Nine studies encompassing 1,092 patients were included. The pooled ORR was 44.7% (95% CI 36.7%-52.9%; I² = 84.4%), with substantial heterogeneity driven by between-target differences. Subgroup analysis demonstrated a significantly higher ORR for TROP2-targeting ADCs (50.6%; 95% CI 40.3%-60.9%) than for HER3-targeting ADCs (34.2%; 95% CI 28.8%-39.8%) (P for interaction = 0.006). Among three RCTs, the two trials of sacituzumab tirumotecan (Sac-TMT) versus chemotherapy yielded a pooled HR of 0.40 (95% CI 0.25-0.64) for PFS and 0.57 (95% CI 0.44-0.76; I² = 0%) for OS, both favouring ADC therapy; by contrast, the phase III HERTHENA-Lung02 trial of patritumab deruxtecan (HER3-DXd) improved PFS (HR 0.77; 95% CI 0.63-0.94; P = 0.011), but OS data were immature at the time of the analysis. Across studies, mPFS ranged from 5.5 to 11.1 months, and mature mOS data were available from only three studies (range 11.9-16.2 months). Conclusions: ADCs demonstrate substantial antitumour activity in EGFR-mutant NSCLC after TKI resistance, but efficacy appears target- and drug-specific rather than a uniform class effect. Among the agents studied, only the TROP2-ADC sacituzumab tirumotecan has shown improvement in both PFS and OS over chemotherapy, whereas the HER3-ADC patritumab deruxtecan improved PFS without an OS benefit. Given high between-study heterogeneity and OS immaturity in most studies, these findings support ADCs-particularly TROP2-directed agents-as a key therapeutic option for this difficult-to-treat population, while underscoring the need for biomarker-guided patient selection.