Real-world outcomes and cross-resistance of sequential antibody-drug conjugate therapy in HER2-low and triple-negative breast cancer: A systematic review.

e12548 Background: Antibody–drug conjugates (ADCs) have demonstrated superior efficacy over chemotherapy in HER2-low and triple-negative breast cancer (TNBC). However, real-world outcomes of sequential ADC use and the extent of cross-resistance remain poorly defined. We performed a systematic review to evaluate randomized and real-world evidence on efficacy, safety, and cross-resistance of ADC sequencing. Methods: Phase III randomized controlled trials and retrospective real-world studies evaluating ADCs in HER2-low and TNBC were reviewed. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using an inverse-variance method. Response rates, safety outcomes, and real-world sequencing data were synthesized narratively. Risk of bias was assessed using ROB-2. Results: Pooled analysis of three phase III trials demonstrated a significant OS benefit with ADCs compared with chemotherapy (HR 0.66, 95% CI 0.50–0.87; P = 0.004), representing a 34% reduction in mortality risk. PFS was also significantly improved (HR 0.45, 95% CI 0.33–0.63; P < 0.00001), with substantial heterogeneity (OS I² = 80%; PFS I² = 87%). ADCs showed higher objective response rates, including sacituzumab govitecan in ASCENT (31% vs 4%) and trastuzumab deruxtecan with ORR up to 57.3% in DESTINY-Breast studies. All trials were open-label, resulting in some risk of bias. Real-world data revealed reduced efficacy with sequential ADC therapy. In a multicenter retrospective cohort, 53% of patients exhibited cross-resistance to a second ADC. A separate institutional cohort showed shorter real-world PFS with second ADC use in ~75% of patients, with PTEN loss associated with resistance. ADCs demonstrated manageable toxicity profiles and favorable patient-reported outcomes compared with chemotherapy. Conclusions: Although ADCs improve survival outcomes in HER2-low and TNBC, real-world evidence suggests substantial cross-resistance with sequential use. Prospective sequencing trials are essential for defining optimal treatment strategies and overcoming resistance.