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.

Abstract

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. 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. 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. 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.