e13020 Background: The optimal sequencing strategy for antibody-drug conjugates (ADCs) following progression on prior ADC therapy in advanced breast cancer remains uncertain. However, most pivotal trials excluded patients previously exposed to another ADC, leaving real-world evidence as the primary source to inform sequencing strategies, particularly across different HER2 expression levels. Methods: This single-center retrospective study included 82 patients with advanced breast cancer who received at least two different anti-HER2 ADCs sequentially between January 2019 and December 2023. Patients were stratified by HER2 status (HER2-positive, n = 51; HER2-low, n = 31). The second ADC (ADC2) treatments included trastuzumab deruxtecan (T-DXd, n = 43), trastuzumab emtansine (T-DM1, n = 9), disitamab vedotin (RC48, n = 26), and other agents including sacituzumab govitecan (n = 4). The primary endpoint was progression-free survival (PFS), analyzed as PFS on the first ADC (PFS1), PFS on the second ADC (PFS2), and total PFS from the initiation of the first ADC. Results: In the overall cohort, the median total PFS was 15.12 months for patients receiving T-DXd as ADC2, compared with 11.11 months for T-DM1 (P = 0.697) and 11.01 months for RC48 (P = 0.887), although these differences were not statistically significant. Analysis of sequential patterns revealed that the T-DM1 → T-DXd sequence (T-D pattern) was associated with the longest median total PFS (24.07 months). In the HER2-positive subgroup, T-DXd as ADC2 resulted in a median PFS2 of 15.98 months. Conversely, patients with HER2-low disease derived limited benefit from sequential ADC therapy, with a median PFS2 of 3–4 months and an objective response rate (ORR2) below 10%. Conclusions: In real-world clinical practice, sequential ADC therapy demonstrated clinically meaningful activity, particularly in HER2-positive advanced breast cancer. The T-DM1 → T-DXd sequence appears to be a promising approach. However, efficacy is significantly limited in the heavily pretreated HER2-low population, underscoring a "diminishing returns" phenomenon and the need for novel therapeutic strategies and a deeper understanding of cross-resistance mechanisms.
Li et al. (2026) studied this question.