Real-world antibody-drug conjugate (ADC) sequential use in metastatic breast cancer.

e13122 Background: The advent of antibody-drug conjugates (ADCs) has significantly expanded the therapeutic landscape for metastatic breast cancer (MBC). With the approval of multiple ADCs, cross-resistance and the optimal sequencing has become a critical clinical question. Methods: A single-institution retrospective study of patients (pts) with MBC treated with more than one ADC at Cedars-Sinai Medical Center from 2018 to 2025 was conducted. Clinicopathological variables, treatment history, and clinical outcome were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. “Cross-resistance” was defined as progressive disease (PD) observed at the first restaging scan on the second ADC after the first ADC. Results: A total of 63 pts were included (HR+HER2-, n = 20; TNBC, n = 18; HER2+, n = 25). The median age at initiation of ADC1 was 56, ADC2 was 57. The median prior lines of chemotherapy for ADC1 was 1 (0-5), and 2 for ADC2 (1-6). In the HR+HER2- cohort, 17 pts (85%) received trastuzumab deruxtecan(T-DXd) as the 1st ADC followed by sacituzumab govitecan (SG). While in the TNBC cohort, 12 pts (66.7%) received SG as the 1st ADC, followed by T-DXd. No significant difference in PFS in either ADC1 (PFS1) (p = 0.16) or ADC2 (PFS2) (p = 0.39) was observed between HR+HER2- and TNBC cohorts. The median PFS1 was 6.5 mo [95%CI 3.9, 9.0], compared to median PFS2 of 3.4 mo [95%CI 2.1, 7.4] (p = 0.09). Cross-resistance was present in 21 pts (55.3%), absent in 12 pts (31.6%), 3 pts pending. Of this cohort, 23 pts (60.5%) received ADC2 immediately after ADC1, and 15 pts (39.5%) received intervening treatment (IntTx) between ADC1 and ADC2. Cross-resistance with ADC2 was observed in 60% pts who received IntTx and 52.2% of those who did not. The median PFS2 was 3.5 mo with IntTx compared to 2.3 mo without (p = 0.37), with no significant difference observed in OS either (p = 0.63). Among pts received both SG and T-DXd (n = 37), no significant difference was observed in OS of ADC1 (OS1) in either order SG - > T-DXd (median OS1 31.3 mo) or T-DXd - > SG (median OS1 36.8 mo) (p = 0.94). In TNBC cohort (n = 17), median OS1 for SG - > T-DXd was 31.3 mo compared to 12.7 mo for T-DXd - > SG (p = 0.57). Additionally, 4 pts were treated with an experimental trop-2 ADC with MMAE payload, all of whom had received SG prior to trial enrollment. Among these, cross-resistance was present in 2/4 pts, and 1 pt discontinued due to intolerance. Conclusions: This study reveals the patterns of sequential ADC use in MBC and demonstrated considerable prevalence of cross-resistance associated with sequential ADC therapy. While intervening therapy modestly improved PFS2 compared to immediate sequential ADC use, no reduction in cross-resistance was observed. The sequential use of SG followed by T-DXd trended toward better OS in TNBC. Further validation of these findings is required to better understand cross-resistance mechanisms and optimize ADC sequencing use.