The phase II TUXEDO-3 trial has demonstrated promising intracranial activity for patritumab deruxtecan (HER3-DXd) in patients with brain metastases from breast and lung cancers, marking the first study to evaluate both intracranial and extracranial efficacy of this novel antibody-drug conjugate in patients with secondary central nervous system involvement. Results were presented at the American Society of Clinical Oncology (ASCO) 2025 annual meeting, with select findings simultaneously published in Nature Medicine.
Study Design and Patient Population
The TUXEDO-3 study, funded by Daiichi Sankyo and Merck (known as MSD outside the United States and Canada), evaluated HER3-DXd in patients with metastatic breast cancer (mBC) and advanced non-small cell lung cancer (aNSCLC) with active brain metastases, as well as patients with leptomeningeal disease from solid tumors. HER3-DXd is an investigational antibody-drug conjugate consisting of a fully human anti-HER3 IgG1 monoclonal antibody attached to topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
The drug targets HER3, a protein receptor found on the surface of cancer cells in brain metastases. The DXd ADC Technology payload causes tumor DNA damage, killing cancer cells within and surrounding the tumor microenvironment.
Primary Efficacy Results
The study met its primary objectives across multiple patient cohorts. In patients with active brain metastases from metastatic breast cancer, 23.8% achieved intracranial responses. For patients with advanced non-small cell lung cancer and brain metastases, the intracranial response rate was 30%. Additionally, 65% of patients with leptomeningeal disease remained alive after 3 months of treatment.
Intracranial responses were observed across all breast cancer subtypes, including luminal, HER2-positive, and triple-negative cancers. Notably, some patients with breast cancer who had previously received antibody-drug conjugates also responded to HER3-DXd, highlighting the potential of this agent to overcome resistance and expand treatment options in refractory disease.
Activity Across Tumor Types and Mutations
In patients with advanced non-small cell lung cancer and brain metastases, intracranial responses were observed in patients whose tumors contained no activating driver mutations as well as those with EGFR or KRAS mutations. This broad activity pattern suggests HER3-DXd may offer treatment options regardless of specific genetic alterations.
Safety and Quality of Life
Side effects were consistent with previous studies using HER3-DXd. Tests evaluating quality of life and neurocognitive functions showed that patients remained stable or improved during the treatment follow-up period, indicating the therapy's tolerability in this vulnerable patient population.
Clinical Significance
"This study represents a significant advancement in our understanding of how to treat brain metastases and leptomeningeal disease, and we are hopeful that our findings will pave the way for new, effective therapies for these patients," stated Dr. Matthias Preusser, Medical Oncologist and Head of the Clinical Division of Oncology at Medical University of Vienna and Principal Investigator of TUXEDO-3.
Dr. Rupert Bartsch, Consultant Hematology and Medical Oncology at Medical University of Vienna, added: "Brain metastases and leptomeningeal disease represent severe complications in cancer, leading to increased morbidity and mortality, and HER3-DXd could be a promising therapeutic alternative for these patients."
The results from the leptomeningeal cohort were published in Nature Medicine due to their potential benefit in patients with high unmet medical need, underscoring the clinical significance of these findings for a patient population with limited therapeutic options.
