Abstract
BACKGROUND: Numerous Antibody–Drug Conjugates (ADCs) have been investigated for non-small cell lung cancer (NSCLC), yielding mixed results. This study comprehensively evaluated the efficacy and safety of ADC therapies in NSCLC patients, particularly focusing on specific populations. METHODS: A literatures search was conducted to identify prospective trials published between January 2000 and June 2025. Only randomized and non-randomized phase II-IV clinical trials involving adult NSCLC patients treated with ADCs were selected. Efficacy endpoints were categorized based on the primary outcomes of the included studies. RESULTS: The analysis included 16 studies with 1872 participants. The pooled analysis showed a Objective Response Rate (ORR) was 34% (95% CI: 26%-42%) with high heterogeneity (I(2) = 91.7%). Subgroup analyses revealed significant variations in ORR between different ADC agents (P < 0.0001). In specific NSCLC subgroups, the ORR was 35% for Epidermal Growth Factor Receptor (EGFR)-mutant patients and 36% for those with actionable genomic alterations (AGAs). Notably, HER2-mutant patients achieved a significantly higher ORR of 55%, compared to 21% in populations lacking these mutations (P < 0.0001). ADC therapy may have limited efficacy against squamous cell carcinoma. All-grade and grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 95% and 43% of patients, respectively, both showing high heterogeneity. The incidence of all-grade interstitial lung disease (ILD) was 10%, with the grade ≥ 3 incidence being 2%. The gastrointestinal system was the most frequently involved, but these were predominantly low-grade. In contrast, hematologic and respiratory system involvement were more common among grade ≥ 3 AEs. Pneumonitis and ILD were the leading causes of both treatment-related mortality and discontinuation. CONCLUSION: ADC monotherapy has demonstrated considerable efficacy in previously treated NSCLC. Patients with non-squamous histology, EGFR mutations, or HER2 mutations may derive greater benefit from ADC therapy. However, it should be noted that the partially pooled results, derived from highly heterogeneous data, require cautious interpretation. Close monitoring and proactive management of hematologic and respiratory system-related toxicities are essential. PROSPERO REGISTRATION: CRD420251101467 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-15461-6.