Abstract PD4-05: Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM)
Authors: Kabraji Sheheryar , Ni Jing , Sammons Sarah , Van Swearingen Amanda ED , Wang Yanzhi , Pereslete Alyssa M , Hsu Liangge , Lascola Chris , Moore Heather , Hughes Melissa , Raghavendra Akshara S , Gule-Monroe Maria , Murthy Rashmi K , Winer Eric P , Anders Carey K , Zhao Jean J , Lin Nancy U 
Published: March 2022

Abstract
Purpose: Up to half of patients (pts) with HER2+ metastatic breast cancer (MBC) will develop BCBM. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) with demonstrated efficacy in previously treated pts with HER2+ MBC. However, few pts with stable/treated brain metastases, and no pts with active (untreated or progressive) brain metastases, were included in completed clinical trials of T-DXd. Thus, central nervous system (CNS) efficacy of T-DXd is not well-characterized. Methods: We tested T-DXd in orthotopic pt BCBM-derived xenograft (PDX) models of HER2+, and HER2-low, BCBMs. To further validate T-DXd single agent CNS activity, we described clinical outcomes of T-DXd in a multi-institutional retrospective cohort of 16 patients with BCBM. Consecutive pts who initiated T-DXd between 1 Jan 2020 - 1 Nov 2020 (Duke) or 1 Jan 2020 - 15 June 2020 (Dana-Farber Cancer Institute) were included. Data cut-off date was 31 Dec 2020. CNS response was measured by via central radiology review at each participating institution. Up to 5 CNS target lesions were included. CNS partial response (PR) required &gt;30% reduction in sum of CNS target lesions. Results: Treatment with 10 mg/kg T-DXd significantly prolonged survival in HER2+ BCBM PDX models DFBM-354 (67 vs 154 days, p=0.0018) and DFBM-355 (78 vs 156 days, p=0.0067) vs. vehicle control. We then tested TDX-d in a HER2 low BCBM PDX model (IHC 2+/FISH ratio &lt;2) and found that c.f. vehicle, TDX-d significantly prolonged survival (72 v 141 days, p = 0.02). Finally, we treated DFBM-355 with trastuzumab emtansine (T-DM1) to generate resistance followed by treatment with T-DXd. We found that c.f. vehicle or continued T-DM1, T-DXd significantly prolonged survival in a T-DM1 resistant BCBM PDX model (63 vs 99 vs 215 days, p=0.01). In the retrospective cohort, median age was 44 (33-69 years). 15/16 pts had confirmed HER2 IHC 3+ or FISH-positive primary or metastatic tissue. 9/16 (56%) pts had either progressive or untreated HER2+ BCBMs on initiation of T-DXd. Median number of prior metastatic therapies was 4 (0-10). 14/16 (88%) had received previous T-DM1; 11/16 (69%) had received previous HER2-targeted tyrosine kinase inhibitor. Median time from previous CNS radiation was 15.1 months (1.3 - 45.2). At the time of data cutoff, 7 pts remained on T-DXd. Median number of cycles was 7 (2-17+). Responses are shown in Table 1. The overall intracranial clinical benefit rate (CR/PR or stable disease) was 75%, including 89% (8/9) of those with progressive or untreated BCBM at baseline. Conclusions: In a multi-institution cohort of 16 pts with HER2+ BCBMs treated with T-DXd, we find preliminary evidence of CNS efficacy, including in pts with progressive or untreated BCBMs. Additional pt data and further follow up will be presented at the meeting. Using BCBM PDX models we find that T-DXd prolongs survival in untreated HER2+ BCBM PDX models as well as in T-DM1 treated models. We also demonstrate efficacy of T-DXd in a HER2 low BCBM PDX model. Together, these data suggest that T-DXd has intracranial efficacy against HER2+ BCBMs. Prospective clinical trials in this pt population are warranted.
Table 1.Best CNS Response of study cohortOverall population (n=16)Pts with progressive or untreated CNS disease at baseline (N=9)Pts with stable/treated CNS disease at baseline (N=7)Complete response (CR)0 (0)00 (0)Partial response (PR)10 (63)6 (67)#4 (57)+Stable disease (SD)2 (13)2 (22)0 (0)Progressive disease (PD)1 (6)0 (0)1 (14)No measurable CNS disease at baseline2 (13)0 (0)2 (29)Lost to follow-up1 (6)1 (11)0 (0).#Among these 6 pts, interval between most recent radiation and T-DXd initiation was 14.3 months, 12.4 months, 17 months, 18.2 months, and 8.2 months (one pt was radiation-naïve). +Among these 4 pts, interval between most recent radiation and T-DXd initiation was 19.1 months, 15.1 months, 1.5 months, and 16.9 months, respectively.
Citation Format: Sheheryar Kabraji, Jing Ni, Sarah Sammons, Amanda ED Van Swearingen, Yanzhi Wang, Alyssa M Pereslete, Liangge Hsu, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S Raghavendra, Maria Gule-Monroe, Rashmi K Murthy, Eric P Winer, Carey K Anders, Jean J Zhao, Nancy U Lin. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-05.