Purpose:

Datopotamab deruxtecan (Dato-DXd) is a humanized anti–trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.

Experimental Design:

The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.

Results:

Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd–sensitive models. In isogenic cell lines derived from Dato-DXd–resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd–sensitive BCXs but not in a Dato-DXd–resistant BCX. In Dato-DXd–sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.

Conclusions:

Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Figures S1-S15

Supplementary Figure 1. Comparison of TROP2 membrane expression between patient tumors and matched patient derived xenografts. Supplementary Figure 2. Representative images of TROP2 IHC in the breast cancer xenografts shown in Figure 2. Images represent one of three cores of a TMA assessed, with IHC shown at 20X. Supplementary Figure 3. Genomic alterations in genes associated with DNA damage repair. Supplementary Figure 4 BRCAness in BCX models Supplementary Figure 5. Violin plot of BRCAness signature in responders and non-responders. Supplementary Figure 6. Homologous repair in BCX models Supplementary Figure 7. Antitumor activity of Datopotamab deruxtecan (Dato-DXd) and PARP inhibitor talazoparib Supplementary Figure 8. IHC of TROP2 Supplementary Figure 9. Necrosis analysis Supplementary Figure 10. Internalization assay Supplementary Figure 11. (A) Immunoblotting of TROP2 expression in xenografts of BCX.011CL-control and BCX.011-TROP2. The first two on the left are cell line samples as controls for immunoblotting. The remaining are PDX tumor samples. PDX tumors (treated as shown) were collected on day 25-day 28 of treatment. TROP2 IHC was perform and scored. All BCX.011CL-TROP2 tumors formed TROP2 positive xenograft except for a single tumor that grew back after regressing with the first 10 mg/kg Dato-DXd treatment (B). Supplementary Figure 12. Effect of exogenous TROP2 expression on Dato-DXd sensitivity. Supplementary Figure 13. TROP2 expression in isogenic cell lines Supplementary Figure 14. Conjugated DXd in BCXs Supplementary Figure 15. Additional immunohistochemistry analysis of pharmacodynamic changes associated with Dato-DXd treatment

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Supplementary Tables S1-S17

Supplementary Table 1. Antibodies used for immunohistochemistry. Supplementary Table 2. Additional Antibodies used for immunohistochemistry at Daiichi Sankyo. Supplementary Table 3. Biomarker and clinical history of PDX models. Supplementary Table 4. Treatment/control ratios of treated PDX models. Supplementary Table 5. Event-free survival (time to tumor doubling) of treated PDX models. Supplementary Table 6. Mutations in actionable genes in the BCXs. Supplementary Table 7. Copy number alterations in actionable genes in the BCXs. Supplementary Table 8. Mutations in DNA damage repair genes in the BCXs. Supplementary Table 9. Copy number alterations in DNA damage repair genes in the BCXs. Supplementary Table 10. Expression of SLFN11 by IHC. Supplementary Table 11. RPPA Results-Responder vs Non-responder PDX Models. Supplementary Table 12. Treatment/control ratios of BCX.011-CL control and TROP2 models. Supplementary Table 13. Event-free survival (time to tumor doubling) of BCX.011-CL control and TROP2 models. Supplementary Table 14. RPPA Results-Signaling changes common to the responder models. Red changes are common to responders and non-responders. Supplementary Table 15. RPPA Results- Signaling changes common to the Non-Responder models. Red changes are common to responders and non-responders. Supplementary Table 16. Treatment/control ratios of Dato-DXd and Olaparib combination experiments. Supplementary Table 17. Event-free survival (time to tumor doubling) of of Dato-DXd and Olaparib combination experiments.

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