Pulmonary Toxicities of Antibody-Drug Conjugates in Small Cell and Non-Small Cell Lung Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Antibody-drug conjugates (ADCs) are increasingly used in the treatment of small cell (SCLC) and non-small cell lung cancer (NSCLC). Despite their targeted design, clinically significant pulmonary adverse events (AEs) have been reported, but the incidence and toxicity profile in lung cancer remain incompletely defined. We aimed to quantify the incidence and severity of pulmonary AEs associated with ADCs and to evaluate differences by tumor type and drug design features. METHODS: We performed a PRISMA-guided systematic review and meta-analysis registered in PROSPERO (CRD42024543340). MEDLINE (Ovid), Embase (Ovid), and Cochrane CENTRAL were searched for studies published through January 2, 2025. Eligible studies included randomized controlled trials and prospective single-arm clinical trials evaluating ADCs in patients with SCLC or NSCLC. The primary outcome was the pooled incidence of pulmonary AEs using random-effects models. RESULTS: Twenty-four studies comprising 4,048 patients and 2,855 treated with ADCs were included. The pooled incidence of any-grade pulmonary AEs was 30.9% (95% CI, 21.5-42.3). Grade ≥3 pulmonary AEs occurred in 6.9% (95% CI, 4.6-10.3). Pneumonitis/ILD occurred in 8.0% overall, with 2.8% grade ≥3. Treatment discontinuation due to pulmonary toxicity occurred in 6.2%, and pulmonary AE-related mortality in 1.96%. Any-grade pulmonary AEs were more frequent in SCLC than in NSCLC (52.1% vs 22.5%, p = 0.005), whereas pneumonitis was more common in NSCLC than in SCLC (12.1% vs 2.8%, p < 0.001). CONCLUSIONS: Pulmonary AEs are common and clinically meaningful in lung cancer patients treated with ADCs. Pneumonitis/ILD represents the key clinically actionable toxicity, with risk influenced by tumor subtype and drug characteristics.