Abstract PS2-04-16: Single institution retrospective analysis of antibody-drug conjugate (ADC) sequencing in HR+/HER2-low and HR-/HER2-low metastatic breast cancer

Abstract Purpose: Antibody-drug conjugates (ADC) have made a profound impact on the treatment landscape of HR+/HER2-low and HR-/HER2-low metastatic breast cancer. Sacituzumab govitecan (Trodelvy) and trastuzumab deruxtecan (Enhertu) are ADC with topoisomerase I payloads bound to anti-Trop-2 and anti-HER2 monoclonal antibodies, respectively. Enhertu received FDA approval in 2022 based on the results of the DESTINY-Breast04 study as did Trodelvy in 2023 per the TROPiCS-02 study. The optimal sequencing of these agents (ET versus TE) remains a topic of debate and investigation in this patient population. Methods: Our retrospective, single center study evaluated 100 patients with HR+/HER2-low and HR-/HER2-low metastatic breast cancer who were treated sequentially with Enhertu and Trodelvy (ET vs TE) at the City of Hope Comprehensive Cancer Center from 01/2019-12/2023. Both groups had received at least one prior line of therapy in the metastatic setting. The primary objective was to estimate the median combined time to progression following ET vs TE (PFS1+ PFS2) to determine if the PFS for the 2nd ADC declined significantly based on the sequence. PFS data was censored per the end-time point of the second treatment. Secondary endpoints included response rates (RR), treatment-related AE, and overall survival (OS). Patient demographics, treatment history, presence of visceral disease, and comorbidities were evaluated. Adverse event grading and investigator-assessed radiographic treatment response was determined using CTCAE v5.0 and RECIST 1.1 definitions, respectively. High-grade AE (hg-AE) was defined as Grade 3 or higher. HR and HER2 IHC status were assessed based on the most recent biopsy sample before each line of therapy. HR+ status included patients with 10% or greater ER/PR positivity and HER2-low included patients with IHC 1+/2+ with a negative FISH. Results: Most patients received ET (70/100) vs TE (30/100). The primary endpoint of PFS1 + PFS2 was comparable between the sequences (ET: 11.1 months vs TE: 8.2 months; log-rank p=0.7). The median PFS for Enhertu (ET: 6.8 months vs TE: 2.3 months; p < 0.0001) and Trodelvy (TE: 5.6 months vs ET: 2.5 months; p = 0.0006) was significantly increased when used first in the sequence. A similar trend was noted with RR for Enhertu (ET 65.7% vs TE 33.3%; p = 0.003) and Trodelvy (63.3% vs 25.7%; p = 0.0004) when given first in the sequence. Median OS was comparable between ET vs TE (22.9 months vs 17.5 months; p = 0.7). Neutropenia and GI toxicities were the most commonly reported AE with a similar rate of cumulative hg-AE in patients who received ET vs TE. In the ET group, there were significantly lower rates of hg-AE while on Enhertu compared to Trodelvy (28.5% vs 51.4%; p = 0.006), whereas rates were comparable (23.3% vs 40%; p = 0.2) in the TE group. The presence of baseline lung metastases was significantly higher in the ET group with 10 reported ILD events in the ET group vs 0 in the TE group. There were significantly more HR+ patients in the ET group, while HER2 IHC status was similar between groups (1+: 61% vs 2+: 28%). Conclusion: Patients with HR+/HER2-low and HR-/HER2-low metastatic breast cancer who received sequential ADC therapy with Enhertu and Trodelvy (ET or TE) had comparable PFS 1 + PFS2 and OS results. There were significant increases in PFS and RR with each ADC when used first compared to second in the treatment sequence. There were similar rates of cumulative hg-AE between the ET and TE groups with less hg-AE events in patients who received Enhertu with ET vs TE. Limitations of this study include the retrospective analysis and exclusion of patients who did not receive both drugs sequentially in the context of varied timelines of FDA approval. Prospective studies are needed to further evaluate the impact of ADC sequencing on treatment outcomes and toxicities. Citation Format: A. Kordic, N. Ruel, N. Kethireddy. Single institution retrospective analysis of antibody-drug conjugate (ADC) sequencing in HR+/HER2-low and HR-/HER2-low metastatic breast cancer. [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-04-16.