datopotamab deruxtecan (DS-1062a)

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

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 .

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 .

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

P3, N=630, Not yet recruiting, AstraZeneca

P2, N=531, Recruiting, AstraZeneca | Trial completion date: Mar 2025 --> Aug 2026 | Trial primary completion date: Mar 2025 --> Aug 2026

Patients (Pts) received Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with Pt-CT (triplet; cisplatin 75 mg/m 2 or carboplatin AUC 5) Q3W across 6 cohorts. As 1L therapy for aNSCLC, Dato-DXd plus pembro with or without Pt-CT continues to demonstrate durable antitumor activity. Efficacy was observed regardless of PD-L1 expression. Tolerability of the combinations was as expected based on known profiles of the individual agents, with no new safety signals observed.

P1/2, N=240, Recruiting, AstraZeneca | Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2024 --> Nov 2024

In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 (datopotamab deruxtecan and sacituzumab govitecan [SG]) and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing...The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

P3; Trial completion date: Jun 2026 --> Apr 2028 | Trial primary completion date: Jun 2026 --> Feb 2028

P1, N=140, Recruiting, Daiichi Sankyo | Trial completion date: Feb 2029 --> Nov 2028 | Trial primary completion date: Feb 2029 --> Nov 2028

P3, N=675, Not yet recruiting, AstraZeneca

P2, N=137, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2026 --> Dec 2024

P1, N=140, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P3, N=582, Not yet recruiting, AstraZeneca

P2, N=137, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2024 --> May 2026