Datroway (datopotamab deruxtecan)

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

Similar efficacy with T-DXd and SG in HER2-low MBC was observed, regardless of HR status. Safety profile, local drug-approval criteria and guidelines, patients' preferences and overall quality of evidence should ultimately guide therapeutic decision-making. Dato-DXd role remains uncertain.

In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases...Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized, biomarker-driven approaches offers the potential to further improve outcomes, even for complex cases.

P1, N=890, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Recruiting --> Active, not recruiting

P3, N=1350, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial completion date: Feb 2027 --> Nov 2027 | Trial primary completion date: Feb 2027 --> Nov 2027

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.

Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients.

P3, N=660, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P2, N=100, Active, not recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Active, not recruiting | Trial completion date: Nov 2025 --> Mar 2028 | Trial primary completion date: Nov 2022 --> Mar 2025

P2, N=20, Not yet recruiting, MedSIR

We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival.Clinical Trial Registration: NCT05555732 (ClinicalTrials.gov).

P3, N=630, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P2, N=490, Recruiting, AstraZeneca | Trial completion date: Dec 2029 --> May 2030 | Trial primary completion date: Dec 2029 --> May 2030

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

P1, N=890, Recruiting, Daiichi Sankyo Co., Ltd. | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

P2, N=490, Recruiting, AstraZeneca | Trial completion date: Dec 2028 --> Dec 2029 | Trial primary completion date: Dec 2028 --> Dec 2029

P3, N=660, Not yet recruiting, AstraZeneca

P3, N=732, Active, not recruiting, AstraZeneca | Trial primary completion date: Aug 2025 --> Jul 2024

P2, N=357, Not yet recruiting, Ana C Garrido-Castro, MD

P1/2, N=50, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris

P1/2, N=243, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.

P3, N=590, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jun 2024 --> Jun 2025

P3, N=637, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=210, Recruiting, Daiichi Sankyo | N=140 --> 210

To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

P3, N=582, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P3, N=675, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Trial primary completion date: May 2030 --> Apr 2028