The HER3-directed antibody-drug conjugate patritumab deruxtecan demonstrated clinical efficacy in treating patients with leptomeningeal metastatic disease of solid tumors, according to findings from a cohort of the phase II TUXEDO-3 trial. Researchers were also encouraged by the intracranial responses among patients with brain metastases.
This was the first prospective study of an antibody-drug conjugate in patients with leptomeningeal metastatic disease, the study authors noted in their report published in Nature Medicine.
Background and Study Details
Limited treatment options exist for patients with leptomeningeal metastatic disease resulting from solid tumors—most commonly lung cancer, breast cancer, and melanoma—leading to poor outcomes for these patients.
HER3-directed therapy is of interest for treating leptomeningeal metastatic disease, as HER3 has been found to facilitate central nervous system colonization by cancer cells, and overexpression of HER3 is frequently found in brain metastases from breast and lung cancers.
Previously, patritumab deruxtecan demonstrated preliminary central nervous system activity in the phase II HERTHENA-Lung01 trial of patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC), with an intracranial objective response rate of 33.3%.
The TUXEDO-3 trial consisted of three cohorts of patients: cohort 1 included patients with metastatic breast cancer and active brain metastases, cohort 2 included patients with advanced NSCLC and active brain metastases, and cohort 3 included patients with advanced solid tumors and leptomeningeal metastatic disease. The primary endpoint in cohorts 1 and 2 was intracranial overall response rate, but in the third cohort, the primary endpoint was the 3-month overall survival rate.
Key Study Findings
After 3 months, 65% of patients with leptomeningeal metastatic disease were still alive, meeting the primary endpoint for cohort 3. At 3 months, the overall survival rate was 69.6%, and 58.9% at 6 months. The intracranial overall response rate was 11.1%, the extracranial rate was 30.8%, and 26.3% for overall lesions. The intracranial clinical benefit rate was 50%, 38.5% for extracranial benefit, and 47.4% for overall lesions.
“If you look at the Kaplan-Meier curves, you can see a prolonged plateau with 60% of patients alive even after 10 months. There was no statistically significant difference between type 1 and type 2 leptomeningeal metastatic disease. Looking at secondary efficacy endpoints, we see that the intracranial response rate in patients with active brain metastases was a bit higher than that in extracranial metastases. And the disease control rate, which is stable disease or better, or the clinical benefit rate, which is stable disease or better for at least half a year, was encouraging in this heavily pretreated patient population,” lead study author Matthias Preusser, MD, Professor of Medical Oncology, Department of Medicine 1, Division of Oncology, Medical University of Vienna in Vienna, Austria, said during a presentation of the trial findings during the 2025 ASCO Annual Meeting (Abstract 2005).
Neurological symptoms and quality-of-life measurements remained stable or improved with treatment. No new neurological adverse events were observed.
The most common adverse events in the cohort were anemia (40.9%), nausea (31.8%), neutropenia (27.3%), diarrhea (27.3%), asthenia (27.3%), thrombocytopenia (22.7%), and headache (22.7%).
Disclosure: For full disclosures of the study authors, visit nature.com.
