With this technology, we developed trastuzumab deruxtecan, the first DXd-ADC directed toward HER2. Additionally, Dato-DXd showed TROP2-dependent antitumor activity in multiple human cancer cell line-derived and patient-derived xenograft mouse models. Clinically, the global phase III trial targeting hormone receptor-positive, HER2-negative, unresectable or recurrent breast cancer led to its first approval in Japan in December 2024, followed by the approvals in the US and Europe later.

In contrast, TROP2-directed ADCs demonstrate negligible cardiac signals. Given the elevated fatality rate of serious cardiac events associated with T-DXd observed in real-world data, we propose a risk-stratified cardiac monitoring algorithm incorporating high-sensitivity troponin and global longitudinal strain for patients receiving next-generation ADCs.

While TROP2-targeted antibody-drug conjugates (ADCs), such as sacituzumab govitecan, sacituzumab tirumotecan, and datopotamab deruxtecan (DXD), achieved clinical success, the mechanisms underlying resistance to these therapies remain incompletely understood. R7059-DXD is a differentiated, epitope-distinct TROP2-targeted ADC with the potential to overcome resistance to existing therapies. These findings support its further clinical development as a novel treatment for TROP2-expressing malignancies, including in patients previously treated with sacituzumab- or datopotamab-based regimens.

P1, N=19, Not yet recruiting, Shanghai Gynecologic Oncology Group

TROP2 promotes CRC bone metastasis by interacting with bone marrow-derived FN-integrin axis. Through its adhesive function, TROP2 may coordinate with the specialized bone niche to facilitate metastatic colonization and establish a permissive environment for stromal-tumor interactions. Targeting this axis offers a promising therapeutic strategy for managing bone metastasis in CRC and potentially other TROP2-overexpressing malignancies.

Dato-DXd showed marked antitumor activity in a treatment-resistant LGSOC PDX model. Clinical evaluation in patients with recurrent LGSOC is warranted.

P2, N=348, Not yet recruiting, Akeso

In pooled analyses from TROPION-Lung01 and TROPION-Lung05, Dato-DXd achieved an objective response rate of ~45% and a median duration of response of 6.5 months, which compares favorably with historical outcomes with docetaxel. Dato-DXd is being evaluated in combination with osimertinib in the first-line and post-osimertinib settings, following encouraging activity in the phase II ORCHARD platform trial evaluating therapeutic strategies for EGFR-TKI-resistant disease...Current research aims to elucidate the mechanisms underlying these toxicities and to identify modifiable risk factors to further improve tolerability. The biological mechanisms contributing to the differential efficacy of Dato-DXd are also under investigation and may further inform its clinical role.Expert opinion: Determining how best to integrate Dato-DXd within existing treatment sequences has the potential to meaningfully address persistent unmet needs in EGFR-mutated NSCLC.

P2, N=43, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

Importantly, early clinical studies demonstrated that the EGFR-targeted ADC MRG003 and the TROP2-targeted ADC Sac-TMT showed notable efficacy in patients with refractory ACC and high expression of these targets. This pioneering study introduces a biomarker-based stratification system, categorizing ACC patients by histological subtype and target expression profiles, EGFR/TROP2 for non-solid ACC and B7-H4/Nectin-4 for solid ACC, to inform ADC therapy decisions.

P3, N=1170, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2029 --> May 2031

P2, N=75, Not yet recruiting, Fudan University