Sequencing trastuzumab deruxtecan and sacituzumab govitecan in metastatic breast cancer: A systematic review and meta-analysis.

Abstract

e13074 Background: Antibody–drug conjugates (ADCs) have significantly improved outcomes in metastatic breast cancer (mBC), including tumors with HER2-low expression. Trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) are both approved across diverse mBC subtypes; however, no standard sequencing strategy exists for patients eligible for both agents. This systematic review and meta-analysis aimed to evaluate the clinical efficacy of T-DXd and SG used sequentially in patients with mBC in order to identify the sequencing patterns associated with improved progression-free survival (PFS) and, secondarily, overall survival (OS). Methods: A systematic literature research was conducted in December 2025 using PUBMED/MEDLINE, Scopus and Cochrane databases with additional searches of recent conferences. Prospective and retrospective clinical studies of patients receiving sequentially both ADCs, reporting PFS of the second and/or the first ADC were eligible. Published Kaplan–Meier curves were digitized to reconstruct pseudo–individual patient–level data. Outcomes of interest included PFS, following the first (PFS1) and second (PFS2) ADC, each defined as the time from initiation of the respective treatment until disease progression. Hazard ratios (HRs) were calculated for each study and pooled using fixed- and random-effects meta-analytic models. Study heterogeneity was assessed using the I² statistic. Sensitivity analyses were performed when required and feasible. Results: The literature search yielded 694 records; following duplicate removal and eligibility assessment, 17 studies were included in the final analysis. Seven studies including 474 patients were included in the PFS2 analysis (SG→T-DXd, n = 246; T-DXd→SG, n = 228). Median PFS2 was 3.3 months (95% CI: 2.9–3.7) for SG→T-DXd and 2.8 months (95% CI: 2.9–3.7) for T-DXd→SG (p = 0.008). The pooled fixed-effects HR favored SG→T-DXd (HR 1.49; 95% CI: 1.22–1.83), which was confirmed using a random-effects model (HR 1.72; 95% CI: 1.10–2.68), despite substantial heterogeneity (I² = 70.9%). Sensitivity analysis excluding one study reduced heterogeneity (I² = 0%) and yielded a pooled HR of 1.9. Conclusions: In previously treated mBC, sequencing T-DXd after SG was associated with improved PFS2 compared to the reverse sequence. These findings warrant further investigation on the optimal ADC sequence, but also underscore the need for predictive biomarkers to optimize treatment selection in each patient with mBC.