Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

In a phase II TUXEDO-3 study (NCT05865990) funded by Daiichi Sankyo and Merck, findings from the ASCO 2025 conference show promising CNS activity. Between December 2023 and July 2024, 61 evaluable patients were enrolled from 8 Austrian and Spanish sites. This international, multicenter, single-arm, phase II trial is designed to evaluate the efficacy and safety of HER3-DXd in three cohorts who currently have poor treatment options: Cohort 1 [(metastatic breast cancer brain metastases (mBC  BM)], Cohort 2 [advanced non-small cell lung cancer (aNSCLC) BM], and Cohort 3 [leptomeningeal disease (LMD)]. 

1. In Cohort 1, 23.8% experienced intracranial responses, with 40% of responders having previously received another topoisomerase I-based ADC. 

2. In Cohort 2 (aNSCLC BM), 30% showed intracranial responses. 

3. In Cohort 3 (LMD), 65.0% were still alive at the three-month mark, indicating promising outcomes in this group.

HER3-DXd was well-tolerated, with no unexpected safety concerns arising. Patients maintained or showed improvement in neurological symptoms, cognitive function, and overall quality of life throughout treatment. Biomarker analysis revealed that tumor HER3 expression was not linked to treatment response, indicating that central nervous system efficacy might extend beyond HER3-high tumors. 

KOL insights: 

“The efficacy and safety profile of HER3-DXd makes this ADC an optimal candidate for further, larger trials in patients with hormone receptor–positive, HER2-negative advanced breast cancer after failure of CDK4/6 inhibitors,” – Expert Opinion

"This study represents a significant advancement in our understanding of how to treat brain metastases and leptomeningeal disease, and we are hopeful that these findings will pave the way for new, effective therapies for these patients"– Expert Opinion

Conclusion: 

HER3-DXd emerges as a promising therapy for metastatic breast cancer with brain involvement, showing consistent clinical benefit and good tolerability across patients. Its activity appears independent of HER3 expression, underscoring its potential for broad clinical use in this hard-to-treat population. The therapy was neurologically safe, maintaining cognitive function and quality of life throughout the study.