Antibody drug conjugates treatment response score (ADC TRS) for sequencing trastuzuamb deruxtecan (T-DXd) and sacituzumab govitecan (SG) in advanced breast cancer (aBC).

Abstract

1053 Background: T-DXd, targeting HER2, is approved in hormone receptor positive or negative (HR+/-) HER2-low (1-2+ by immunohistochemistry [IHC]) and HR+/HER2-ultralow (0+ with membrane staining) aBC. SG, targeting TROP2, is approved in HR+/HER2 negative [ -; < 3+ by IHC] and triple negative BC (TNBC; HR-/HER2-). Given limitations in determining IHC 0-1+ status and lack of predictive biomarkers, biomarkers for sequencing these ADCs in those with HER2- aBC are needed. Recently, Thomas et al. reported the discovery of ADC TRS—a generalized model combining individual ADC target expression, proliferation, and adhesion to predict multi-ADC target/tumor type clinical benefit—as well as validation of SG and T-DXd TRS models (tuned by pan-tumor response rates) by a qRT-PCR based clinical trial assay (CTA; Strata Select ADC [SSA]) for predicting clinical benefit of first ADC (SG or T-DXd) in those with HER2- aBC (ASCO 2024 #3140; AACR 2025 #1014). Here, we evaluated ADC target expression and T-DXd/SG TRS status from SSA validation cohort HER2- BC patients stratified by clinical HR/HER2 IHC status. Methods: Adults with aBC from an observational trial (NCT03061305) with valid FFPE tumor tissue results from SSA validation cohort testing were included. aBC types were determined by HR/HER2 IHC results (by ASCO/CAP scoring), with those HER2 3+ or HER2 amplified (by Strata Select testing) considered HER2+. ADC target component expression ( HER2 or TROP2; pan-tumor scaled absolute expression) and T-DXd and SG TRS statuses (+ associated with more clinical benefit) by SSA were compared by IHC defined aBC types. Results: 230 patients with aBC from SSA validation testing were included (median age 58 yrs, 40% self-reported non-European;180 with definitive aBC type [see Table for distribution]). HER2 expression was significantly increased vs. TROP2 in HER2+ and HR+/HER2 aBC, and did not significantly differ in those with TNBC (see Table). Across all patients, 42%, 30%, 27% and 0.4% were T-DXd/SG TRS +/+, -/-, +/- and -/+, respectively. Results were similar in those with HER2 IHC 0+ (n = 37, median HER2 vs. TROP2 = 2.2 vs. 2.3, p = 0.51; 8% and 3% T-DXd/SG TRS +/- and -/+, respectively. Conclusions: Pan-tumor optimized, validated ADC TRS models support sequencing T-DXd before SG in nearly all patients with advanced HER2- BC, including those with TNBC and HER2 0+ IHC. Prospective evaluation of the CTA is warranted. ADC target expression ( HER2 or TROP2 ) and T-DXd | SG TRS status by SSA in BC patients. T-DXd/SG TRS Status BCa Type (n) HER2^ TROP2^ p-value^ +/+ -/- +/- -/- HER2+ 43 6.4 2.6 <0.0001 42% 7% 51% 0% IHC NA* 50 2.6 2.7 0.31 44% 40% 16% 0% HR+/HER2- 76 3.0 2.3 <0.0001 54% 20% 26% 0% TNBC 61 2.3 2.3 0.7 25% 52% 21% 2% Total 230 2.9 2.4 <0.0001 42% 30% 27% 0.4% ^Median, pan-tumor scaled HER2 and TROP2 target expression; Wilcoxon test. *IHC not available; HER2 not amplified.