The safety of trastuzumab deruxtecan (T‐DXd) in breast cancer brain metastases with a focus on interstitial lung disease/pneumonitis: A systematic review and meta‐analysis

Background Although trastuzumab deruxtecan (T‐DXd) demonstrated unprecedented intracranial efficacy in HER2‐positive breast cancer brain metastases (BCBM), its association with interstitial lung disease (ILD)/pneumonitis posed a critical safety concern in this high‐risk population. Previous safety assessments lacked BCBM‐specific analysis of ILD. Methods This systematic review and meta‐analysis (PROSPERO identifier CRD420251130832) followed Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The authors searched the PubMed, Embase, Web of Science, and Cochrane databases and major oncology conferences through July 2025 for studies that reported T‐DXd‐related, treatment‐emergent adverse events (TEAEs) in patients with HER2‐positive BCBM, focusing on ILD/pneumonitis incidence and severity. Pooled rates were calculated using random effects models. Results In total, nine studies involving 684 patients with BCBM were included. The pooled incidence rates for all‐grade and grade ≥3 ILD/pneumonitis were 10% (95% confidence interval [CI], 5%–16%) and 2% (95% CI, 1%–4%), respectively. ILD/pneumonitis led to discontinuation in 11% (95% CI, 0%–24%) of patients with BCBM. No fatal ILD events were reported. Overall, any‐grade TEAEs occurred in 97% of patients, with grade ≥3 TEAEs occurring in 48%. Fatigue and nausea were the most prevalent all‐grade TEAEs, with incidences of 67% and 60%, respectively. Conclusions In patients with BCBM, T‐DXd–associated ILD/pneumonitis occurred in 10% of patient and frequently necessitated treatment modification. Although no fatal ILD was observed, the high discontinuation rate underscored the imperative for vigilant monitoring and protocol‐guided management to mitigate pulmonary toxicity while preserving intracranial efficacy.