Datroway (datopotamab deruxtecan-dlnk)

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.

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.

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

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.

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

With the expanding use of trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) across HER2-positive, HER2-low, and hormone-receptor-positive disease, management of treatment-related toxicities has become a critical determinant of outcomes. Integrating these findings, we propose practical algorithms for managing pulmonary, gastrointestinal, hematologic, ocular, and mucosal adverse events. This review consolidates evidence into a clinician-oriented reference for ADC toxicity management, emphasizing multidisciplinary coordination, early recognition, and system-specific mitigation strategies to enhance treatment safety and adherence.

P3, N=740, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting | Trial completion date: Apr 2028 --> Mar 2032 | Trial primary completion date: Feb 2028 --> Mar 2030

Late-phase ADCs include trastuzumab deruxtecan (targeting HER2 [human epidermal growth factor receptor 2]), datopotamab deruxtecan and sacituzumab govitecan (targeting TROP2 [trophoblast cell-surface antigen 2]), patritumab deruxtecan (targeting HER3), telisotuzumab vedotin (targeting c-MET [cellular-mesenchymal epithelial transition factor]), and sigvotatug vedotin (targeting IB6 [integrin beta-6]). Ongoing, biomarker-driven trials and combination strategies with immunotherapy or tyrosine kinase inhibitors hold the potential to further enhance the efficacy of ADCs. In this review, the authors highlight the current landscape and future directions of ADCs in NSCLC, emphasizing available results for compounds in late-stage clinical development and different disease settings.

TROPION-Lung14 will assess 1L osimertinib + Dato-DXd versus osimertinib alone in patients with EGFR-mutated LA/M NSCLC, potentially providing a new treatment option. ClinicalTrials.gov identifier: NCT06350097 (Registration Date: April 5, 2024).

Datopotamab deruxtecan represents a clinically meaningful therapeutic option based on the targeted delivery of cytotoxic chemotherapy for patients with endocrine-resistant HR-positive/HER2-negative breast cancer. Ongoing studies are required to define optimal treatment sequencing, combination strategies, and long-term safety outcomes.

Trastuzumab deruxtecan expanded therapeutic utility across HER2-low and HER2-ultralow disease, whereas sacituzumab govitecan and datopotamab deruxtecan provide later-line options. Ultimately, management of hormone receptor-positive/HER2-negative MBC requires dynamic integration of tumor biology, systemic therapy advances, and patient-defined goals of care. As therapeutic complexity increases, shared decision making and equitable access to evidence-based and supportive care services remain essential for delivering high-quality, individualized oncology care.

P1, N=145, Active, not recruiting, Daiichi Sankyo | Trial completion date: Apr 2026 --> Dec 2026