Real-world safety and efficacy profiles of trastuzumab deruxtecan in patients with advanced breast cancer

Background: Trastuzumab deruxtecan (T-DXd) is an effective therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive/low advanced breast cancer (ABC), but it is associated with a specific toxicity profile, particularly interstitial lung disease (ILD). Patients and methods: We conducted a retrospective, observational cohort study to evaluate safety and efficacy profiles of T-DXd in patients with HER2-positive/low ABC treated at the European Institute of Oncology from December 2019 to April 2025. Endpoints included: cumulative incidence of ILD, grade ≥3 neutropenia in all patients, and real-world progression-free survival (rwPFS) by BC subtype. ILD was assessed across age, smoking status, lung metastases, subtype, prior immunotherapy, and prior chemotherapy lines. Grade ≥3 neutropenia was assessed across age and neutrophil-to-lymphocyte ratio (NLR) at cycle 3 day 1 (C3D1). Results: A total of 112 patients were included, 43% (n = 48) with HER2-positive and 57% (n = 64) with HER2-low ABC. The median number of prior lines for ABC was 3.0 [interquartile range (IQR) 2.0-5.0]. A prior antibody–drug conjugate line was administered in 58% (n = 28) and in 17% (n = 11) of patients with HER2-positive and HER2-low ABC, respectively. De novo ABC was diagnosed in 23% (n = 26) of patients. After a median follow-up of 9 months (IQR 5.1-21.7 months), the 12-month cumulative incidence of ILD was 13% [95% confidence interval (CI) 7.2% to 20.6%] and two reported grade 5 cases (2%). At multivariable analysis, prior immunotherapy (hazard ratio 3.22, 95% CI 1.06-9.72, P = 0.052) and smoking (HR 2.71, 95% CI 1.00-7.34, P = 0.062) were associated with a higher risk of ILD. Grade ≥3 neutropenia occurred in 10 patients (9%), being associated with a low NLR at C3D1 (HR 0.10, 95% CI 0.02-0.53, P < 0.001). rwPFS was 21.82 months (95% CI 17.98 months-not reached) and 6.90 months (95% CI 4.93-10.19 months) for HER2-positive and HER2-low ABC, respectively. Conclusion: Our real-world analysis confirms the safety and efficacy profiles of T-DXd in patients with ABC. Prior immunotherapy and smoking emerged as risk factors for ILD, and NLR for neutropenia grade ≥3, and merit further investigation.