Datopotamab deruxtecan may be a novel improvement for inoperable breast cancer

1. Compared to chemotherapy, patients with inoperable hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer receiving the antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) experienced significant improvements in progression-free survival (PFS) with a favourable and manageable safety profile.

Evidence Rating Level: 1 (Excellent)

Study Rundown: In recent years, the standard of care for patients living with HR+/HER2- breast cancer in the post-endocrine therapy setting has been single-agent chemotherapy. However, such an approach has been associated with limited clinical benefit and high toxicity, necessitating the need for novel treatment options. This study therefore sought to investigate whether treatment with Dato-DXd, a novel ADC directed against trophoblast cell surface antigen 2 (TROP2), would improve survival outcomes compared to the investigator’s choice of chemotherapy (ICC) in patients with previously treated inoperable HR+/HER2- breast cancer.

In this global, phase 3, open-label, randomized clinical trial, 732 patients over the age of 18 with inoperable HR+/HER2- negative breast cancer who had received one or two previous lines of chemotherapy in the inoperable setting were randomly allocated to receive intravenous Dato-DXd or single-agent ICC. The dual primary endpoints were PFS and overall survival (OS). Compared with ICC, Dato-DXd demonstrated a 37% reduction in risk of progression or death with a PFS that was 2 months longer with Dato-DXd than with ICC. Although OS data was immature at analysis, a trend favouring Dato-DXd was observed. The median duration of treatment with Dato-DXd was longer than with ICC, with the rate of grade 3 or higher treatment-related adverse events (TRAEs) with Dato-DXd being half of that with ICC.

Overall, this study found that treatment of previously treated inoperable HR+/HER2- breat cancer patients with Dato-DXd significantly improved PFS compared with ICC, with a favourable and manageable safety profile. 

Click to read the study in Journal of Clinical Oncology

Relevant Reading: First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01

In-Depth [phase 3 clinical trial]: The standard of care for patients living with HR+/HER2- breast cancer in the post-endocrine therapy setting has, until recent years, been single-agent chemotherapy. However, chemotherapy in this setting has been associated with limited clinical benefit and significant toxicity, necessitating the need for novel treatment options. One emerging strategy revolves around ADCs that may target chemotherapy agents to specific cell markers, such as TROP2 which is expressed in many solid tumours. This study therefore sought to investigate whether treatment with Dato-DXd, a novel ADC directed against trophoblast cell surface antigen 2 (TROP2), would improve survival outcomes compared to the investigator’s choice of chemotherapy (ICC) in patients with previously treated inoperable HR+/HER2- breast cancer.

In this global, phase 3, open-label, randomized clinical trial, 732 patients were randomly allocated to receive intravenous Dato-DXd (n = 365) or single-agent ICC (n = 367). Patients must have been over the age of 18, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, have inoperable HR+/HER2- breast cancer and have received one or two previous lines of chemotherapy in the inoperable setting to be eligible for the study. The dual primary endpoints were PFS and overall survival (OS). Compared with ICC, Dato-DXd demonstrated a 37% reduction in risk of progression or death (HR, 0.63 [95% CI, 0.52 to 0.76]; P < .0001) with a PFS of 6.9 months (95% CI, 5.7 to 7.4) with Dato-DXd compared to a PFS of 4.9 months (95% CI, 4.2 to 5.5) with ICC. Although OS data was not mature at analysis, a trend favouring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). TRAEs were observed in 93.6% of patients receiving Dato-DXd and 86.3% of patients receiving ICC. However, the rate of grade ≥3 TRAEs was 20.8% with Dato-DXd and 44.7% with ICC. The median duration of treatment with Dato-DXd was 6.7 months (range, 0.7-15.6) compared to 4.1 months (range, 0.2-17.4) with ICC.

Image: PD

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