Abstract 1768: Anti-tumor activity and biomarker analysis for datopotamab deruxtecan in breast cancer PDX models
Authors: Yuca Erkan , Evans Kurt , Akcakanat Argun , Raso Gabriela , Rizvi Yasmeen Q. , Yang Fei , Byers Lauren , Damodaran Senthil , Daisuke Okajima , Meric-Bernstam Funda 
Published: June 2022

Background: Trophoblast cell surface antigen (TROP2), is expressed on many tumors including breast cancer, thus TROP2 antibody drug conjugates are being pursued as a therapeutic strategy. Datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a highly potent topoisomerase I inhibitor payload (an exatecan derivative DXd) via a stable tetrapeptide-based cleavable linker. Dato-DXd has shown promise in the treatment of TROP2 expressing lung and breast cancers. However, the role of TROP2 as a predictor of therapeutic sensitivity is yet to be elucidated. We sought to determine efficacy of Dato-DXd in breast cancer patient-derived xenografts (PDXs) as well as explore biomarkers of response and combinations with PARP inhibitors.

Methods: Membrane expression of TROP2 was assessed in 31 breast cancer PDXs and matching patient tumors by immunohistochemistry (IHC). Schlafen family member 11 (SLFN11) nuclear expression was also assessed by IHC. The antitumor efficacy of two doses (1 and 10 mg/kg, q3wk, IV) of Dato-DXd and the isotype control-DXd (IgG-DXd) were tested against 9 breast cancer PDXs derived from residual tumors after neoadjuvant chemotherapy. The PDXs represented a range of TROP2 expression levels, including 3 TROP2 negative/low PDXs. The antitumor activity of Dato-DXd in combination with PARP inhibition (olaparib) was assessed in 3 PDXs with intermediate Dato-DXd activity. Tumor volumes were measured twice weekly; antitumor activity was assessed by treatment-to-control ratio (T/C) and event-free survival (EFS-2). T/C ratio was calculated as (Vt,21/Vt,0)/(Vc,21/Vc,0), where t = treatment, c = control (no treatment or IgG-DXd), and V = tumor volume (mm3). Stable disease (SD) and response (R) were based on day 21 (-30- to 20% and &lt;-30%, respectively). An event was defined as tumor doubling.

Results: TROP2 H-score in PDXs correlated with TROP2 expression in matched patients (r= 0.7264, p&lt;0.0001), however expression was lower in PDXs (p= 0.04). Dato-DXd caused R/SD in 2 of 9 models at 1 mg/kg, and in 4 of 9 models at 10 mg/kg. All models that regressed with Dato-DXd expressed TROP2. TROP2 expression was associated with higher antitumor activity compared to IgG-DXd based on T/C ratio (r= -0.7448, p= 0.0213) and EFS-2 (r= 0.9318, p= 0.0068) at 10 mg/kg but not at 1 mg/kg. Three models with low TROP2 expression had &gt;50% SLFN11 positivity in the nucleus by IHC; 2 of 3 had doubling of EFS-2 both by Dato-DXd and IgG-DXd. The combination of Dato-DXd and olaparib had improved activity over single agents in 2 of 3 models. Additional comparative predictive and pharmacodynamic biomarker studies will be presented.

Conclusion: Dato-DXd is a promising therapy for breast cancer patients including those resistant to standard chemotherapy. Additional biomarkers may better integrate DXd sensitivity into patient selection.

Citation Format: Erkan Yuca, Kurt Evans, Argun Akcakanat, Gabriela Raso, Yasmeen Q. Rizvi, Fei Yang, Lauren Byers, Senthil Damodaran, Okajima Daisuke, Funda Meric-Bernstam. Anti-tumor activity and biomarker analysis for datopotamab deruxtecan in breast cancer PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1768.