Datroway (datopotamab deruxtecan)

P2, N=78, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

The clinical success of trastuzumab DXd (Enhertu®) and datopotamab DXd (Datroway®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, resistance, and manufacturing scalability. This review discusses the mechanisms of action, clinical progress, and challenges of DXd-based ADCs, highlighting their transformative role in modern oncology and exploring future directions to optimize their efficacy and accessibility.

P3, N=660, Recruiting, AstraZeneca | Trial primary completion date: May 2033 --> Nov 2031

P1/2, N=804, Recruiting, AstraZeneca | Trial completion date: Mar 2027 --> Jun 2027 | Trial primary completion date: Mar 2027 --> Jun 2027

Dato-DXd is active against primary and metastatic uterine and ovarian CS overexpressing TROP2 in vitro and in vivo. Our preclinical results warrant future clinical trials for patients with advanced/recurrent gynecologic CS resistant to chemotherapy.

Dato-DXd demonstrated meaningful clinical activity in patients with EGFR-mutated advanced/metastatic NSCLC who had progressed on EGFR-directed therapies and chemotherapy, with an acceptable safety profile.

P1/2, N=119, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Dec 2025

ADCs like sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) target cytotoxic payloads with specificity, whereas PARPis like olaparib, rucaparib, niraparib, and talazoparib cause synthetic lethality in homologous recombination repair (HRR)-deficient tumors. Future directions include biomarker-driven patient selection, combination with immune checkpoint inhibitors, and advancement in next-generation ADCs. The synergistic potential of ADC-PARPi combinations provides a new avenue for overcoming TNBC resistance, enhancing treatment outcomes, and widening therapeutic strategies for this challenging disease.

P3, N=1900, Recruiting, AstraZeneca | Trial completion date: Aug 2030 --> Nov 2032 | Trial primary completion date: Mar 2028 --> Nov 2028

In the phase II NeoCOAST-2 platform study, 202 patients with untreated, resectable stage IIA-IIIB non-small-cell lung cancer (NSCLC) were randomized to receive neoadjuvant durvalumab plus platinum-doublet chemotherapy with oleclumab, a CD73 inhibitor (Arm 1), or with monalizumab, a NKG2A inhibitor (Arm 2), or neoadjuvant durvalumab plus single-agent platinum chemotherapy with the TROP-2 antibody-drug conjugate (ADC) datopotamab deruxtecan (Arm 4), followed by surgical resection and adjuvant durvalumab with oleclumab or monalizumab (Arms 1 and 2) or durvalumab alone (Arm 4). In NeoCOAST-2, the first neoadjuvant trial examining an ADC plus chemo-immunotherapy in resectable NSCLC, pCR rates were highest in the datopotamab-deruxtecan-containing arm, warranting further investigation in larger trials of ADCs and checkpoint inhibition in the neoadjuvant setting. ClinicalTrials.gov identifier: NCT05061550 .

Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd)...Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel...While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations.

P2, N=60, Not yet recruiting, Brown University

In addition, for both ER+ and ER- metastatic breast cancer (MBC) with nonoverexpressed human epidermal growth factor receptor 2 (HER2), this review highlights pivotal trials investigating antibody-drug conjugates (ADCs)-including trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan-and the challenges related to control arm selection and crossover that may affect outcome interpretation. Finally, for patients with HER2-positive disease, the review explores first-line and maintenance strategies-including insights from landmark trials like CLEOPATRA and PATINA-and addresses the impact of brain metastases on sequencing decisions. By critically appraising current data and identifying gaps in biomarker-guided and sequencing-specific strategies, this review provides practical insights to inform clinical practice and optimize personalized treatment plans for patients with MBC.

P2, N=100, Active, not recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Mar 2028 --> Sep 2028 | Trial primary completion date: Mar 2025 --> Sep 2025

Regulatory review of datopotamab deruxtecan in breast cancer is underway in Canada and China. This article summarizes the milestones in the development of datopotamab deruxtecan leading to this first approval for the treatment of HR positive, HER2 negative breast cancer.

P3, N=625, Recruiting, AstraZeneca | Trial completion date: Apr 2029 --> Mar 2031 | Trial primary completion date: Sep 2026 --> Dec 2026

P2, N=140, Not yet recruiting, Queen Mary University of London

These data demonstrate Dato-DXd to be highly active against TROP2 overexpressing USC in vitro and in vivo. Our preclinical activity results warrant future clinical trials for patients with advanced or recurrent USC.

Patients (⩾18 years) will be randomized 1:1 to receive Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) or investigator's choice of chemotherapy (ICC; paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) plus pembrolizumab (200 mg IV Q3W). The findings of this trial could lead to a new treatment option for these patients. ClinicalTrials.gov identifier: NCT06103864 (Date of registration: 27 October 2023).

Among the many ADCs being developed, several can cause ILD of varying grades and intensity. Knowledge of their risks, diagnostic and therapeutic modalities is required in order to quickly detect and treat ADC-induced ILD.

Recent clinical trials of agents like trastuzumab deruxtecan, datopotamab deruxtecan, and sacituzumab govitecan have demonstrated meaningful objective response rates and manageable toxicity, offering hope for patients with advanced NSCLC and SCLC. ADCs are transforming the treatment landscape for lung cancer, offering a blend of targeted delivery and potent therapeutic effects. With ongoing efforts to improve safety, efficacy, and antigen targeting, ADCs have the potential to become a cornerstone of lung cancer therapy and pave the way for innovative multimodal approaches in the future.

P2, N=46, Not yet recruiting, Latin American Cooperative Oncology Group | Initiation date: Feb 2025 --> Jun 2025 | Trial primary completion date: Apr 2027 --> Jul 2028

P3, N=732, Active, not recruiting, AstraZeneca | Trial completion date: Aug 2025 --> Dec 2025

It provides a promising alternative for patients who have failed prior endocrine or chemotherapy, offering enhanced efficacy than traditional treatments. However, additional studies are required to thoroughly assess the drug's safety and efficacy, as well as to establish the most current information regarding its optimal dosage and administration guidelines.

P3, N=630, Not yet recruiting, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences); Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sci

P3, N=590, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jun 2025 --> Jan 2026

The combination of TKI/chemotherapy (osimertinib/carboplatine-pemetrexed) and TKI/bispecific antibodies (e.g., amivantamab/lazertinib) are alternatives under evaluation, with benefits in PFS but increased toxicity. Other emerging approaches include conjugated antibodies (patritumab deruxtecan, datopotamab deruxtecan) and next-generation TKIs. In the future, personalized treatment based on the molecular profile and early response to TKIs could optimize management, particularly by integrating predictive markers such as EGFR clearance under treatment.

Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

Ongoing studies continue to collect data on Dato-DXd-associated stomatitis to further characterize clinical features and possible mechanisms of this toxicity. Appropriate management may reduce the incidence, duration, and severity of events, improve quality of life, and support patient adherence to treatment.

P1/2, N=490, Recruiting, AstraZeneca | Trial completion date: Aug 2026 --> Feb 2027 | Trial primary completion date: Aug 2026 --> Feb 2027

OBI-992, an investigational TROP2-targeted ADC, is composed of a novel TROP2 antibody (R4702) conjugated to the topoisomerase I (TOP1) inhibitor exatecan through a hydrophilic enzyme-cleavable linker...ADCs sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) were used as benchmarks for OBI-992...Moreover, substantial enhancement of cytotoxicity and DNA damage was found in the combination of OBI-992 with a poly (ADP-ribose) polymerase (PARP) inhibitor (talazoparib). Taken together, the findings in this study support further clinical development of OBI-992.

P2, N=137, Active, not recruiting, Daiichi Sankyo | Trial completion date: Dec 2024 --> Dec 2025

This review explores the application of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), in treating breast cancer among elderly populations. Emerging ADCs, including datopotamab deruxtecan and ARX-788, show promise but lack extensive geriatric-specific data. While the ADCs offer encouraging results in terms of efficacy and safety, with appropriate dose adjustments, further research is needed to optimize their use in elderly patients with breast cancer.

P1, N=145, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jun 2025 --> Apr 2026 | Trial primary completion date: Jun 2025 --> Apr 2026

P3, N=660, Recruiting, AstraZeneca | Trial primary completion date: Oct 2031 --> May 2033

P2, N=46, Not yet recruiting, Latin American Cooperative Oncology Group

Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. The findings of this trial could lead to promising treatment options for these patients. ClinicalTrials.gov identifier: NCT06112379.

P3, N=1168, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Trastuzumab-deruxtecan has been proven meaningfully superior to chemotherapy either in 1st and later lines after progression to CDK4/6i in HER2-low ABC and results with other ADCs as Sacituzumab Govitecan and Datopotamab-deruxtecan are promising, but the definition of cross-resistance between these drugs sharing either antibody or payload is crucial before implementing them in a useful sequence. On the other hand, the results obtained with immune checkpoint inhibitors (ICIs) in HR+/HER2-ABC contrarily to the early setting are disappointing up to now, but investigations of ICIs in combination with other targeted drugs which may increase immune response and the search for better markers of activity are under way. Moreover the anticipation in upfront treatment of ADCs or PARPi in patients with features of putative endocrine resistance and/or of less sensitiviy to CDK4/6i and the choice of therapy in patients recurring during or soon after adjuvant CDK4/6i and olaparib represent further challenges for the future.

P1/2, N=243, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2024 --> Feb 2027

This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models...The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.

P1/2, N=490, Recruiting, AstraZeneca | Trial completion date: Jan 2026 --> Aug 2026 | Trial primary completion date: Jan 2026 --> Aug 2026