Abstract PS08-04: Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)
Authors: Huppert Laura , Mahtani Reshma , Fisch Samantha , Dempsey Naomi , Premji Sarah , Raimonde-Taylor Angelina , Jacob Saya , Quintal Laura , Chien Jo , Melisko Michelle , Sandoval-Leon Ana , Carcas Lauren , Ahluwalia Manmeet , Harpalani Natasha , Hoppenworth Jenna , Idossa Dame , Rao Ruta , Giridhar Karthik , Rugo Hope 
Published: May 2024

Abstract
Introduction.
T-DXd is FDA-approved for patients (pts) with hormone receptor positive (HR+) or HR- HER2-low (IHC 1+ or 2+, ISH-) MBC and SG is FDA-approved for pts with HR+/HER2- and triple negative MBC. However, several outstanding questions impact the use of these drugs in clinic, including: 1) what is the efficacy and safety of these agents in real-world populations with diverse pt characteristics not well represented in the pivotal phase III trials, and 2) what is the impact of sequential treatment with ADCs on the efficacy and safety of these agents.
Methods.
In this multicenter retrospective cohort study, we identified pts with HR+/HER2-low and HR-/HER2-low MBC who had received both T-DXd and SG monotherapy (in either order, with or without intervening therapies) treated at 5 academic centers between 2020-2023. Pts received treatment per standard of care or on a clinical trial with ADC monotherapy. We describe pt demographic and clinical characteristics, treatment history, key safety parameters, and response and survival data by HR+ status and ADC sequence order.
Results.
Sixty pts with MBC treated sequentially with T-DXd and SG were included in this analysis, including 45 pts with HR+/HER2-low MBC (75.0%) and 15 pts with HR-/HER2-low MBC (25.0%). Most pts were female (n=59; 98.3%), non-Hispanic (n=49, 81.7%), and white (n=43, 71.7%). Median age at start of ADC #1 was 56.6 years (range 23-82). Prior to treatment with ADC #1, most pts had visceral disease (n=45, 75.0%) and 16 (26.7%) had central nervous system metastases.
Among pts with HR+/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 49.0 months, with 4 median lines of prior therapy in the metastatic setting (2 endocrine, 2 chemo). Approximately half of the HR+ pts received T-DXd prior to SG (n=22, 48.9%; median 3.0 prior lines of therapy for MBC, range 1-9) while the other half received SG prior to T-DXd (n=23, 51.1%; median 4.5 prior lines of therapy for MBC, range 1-10). 44% (n=20) received an intervening therapy between ADCs. For HR+ pts who received T-DXd prior to SG, response and survival data is as follows for T-DXd and SG respectively: Overall response rate (ORR) [54.5% and 21.1%], time to next treatment (TTNT) [4.3 mo and 1.6 mo], and real-world overall survival (rwOS) [19.8 mo and 4.9 mo]. For HR+ pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [78.3% and 42.9%], TTNT [8.6 mo and 2.8 mo], and rwOS [22.3 mo and 7.3 mo].
Among pts with HR-/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 8.2 months with 2 median lines of prior therapy in the metastatic setting (2 chemotherapy); 66.7% (n=10) received prior immunotherapy. Most HR- pts received SG prior to T-DXD (n=14, 93.3%) and 40.0% (n=6) received an intervening therapy between ADCs. For HR- pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [64.3% and 38.5%], TTNT [6.2 mo and 2.7 mo, and rwOS [15.7 mo and 6.5 mo].
In terms of key safety parameters during treatment with T-DXd, 13.3% of pts (8/60) required a dose reduction. 16.7% (10/60) were diagnosed with interstitial lung disease (ILD)/pneumonitis of any grade including 3 pts with grade 3-4 ILD (5.0%) and 3 pts with grade 5 ILD (5.0%). During treatment with SG, 40.0% of pts (24/60) required a dose reduction. 83.3% (50/60) received growth factor support (24 pts primary prophylaxis; 26 pts secondary prophylaxis); 9 pts (15%) required treatment delay due to neutropenia.
Conclusion.
This study represents the largest multicenter series to date of pts treated with sequential ADCs for HR+/HER2-low or HR-/HER2-low. ORR was higher and TTNT was longer for ADC #1 than ADC #2 in all subgroups, regardless of HR+ status and ADC sequence order. An additional ~30 pts will be reported at time of final analysis. Future prospective studies are planned to further clarify the efficacy and safety of sequential ADC use and to identify biomarkers of response and resistance.
Key demographic, clinical and treatment characteristics in pts with HR+ and HR- HER2-low MBC treated sequentially with T-DXd and SG (in either order, with or without intervening therapies)
Abbreviations: T-DXd (trastuzumab deruxtecan), SG (sacituzumab govitecan), MBC (metastatic breast cancer), ADC (antibody drug conjugate), HR (hormone receptor), HER2 (human epidermal growth factor receptor 2), CNS (central nervous system), ET (endocrine therapy), ORR (overall response rate), TTNT (time to next treatment), rwOS (real world overall survival), CI (confidence interval) * Several pts on ADC #2 with ongoing treatment and first scan pending, hence smaller denominator for response assessment
Citation Format: Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Sarah Premji, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Karthik Giridhar, Hope Rugo. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-04.