Patritumab deruxtecan (HER3-DXd) demonstrated central nervous system (CNS) activity in patients with metastatic breast cancer with brain metastases, according to findings from cohort 1 of the phase 2 TUXEDO-3 trial (NCT05865990) presented during the 2025 ASCO Annual Meeting.1
At a median follow-up of 4.9 months (range, 1.4-14.5), patients with breast cancer with brain metastases (n = 21) achieved an intracranial response rate of 23.8% per RANO-BM criteria. The median overall survival (OS) in cohort 1 was not reached (NR; 95% CI, 5.9-NR).
Additional data showed that patients with intracranial lesions (n = 21) achieved a median progression-free survival (PFS) of 4.0 months (95% CI, 1.4-8.5). Patients with extracranial (n = 21) and bicopartmental (n = 21) lesions experienced a median PFS of 4.7 months (95% CI, 1.8-NR) and 4.3 months (95% CI, 1.6-8.5), respectively.
The overall response rates (ORR) among patients with intracranial, extracranial, and bicopartmental lesions were 23.8%, 11.8%, and 14.3%, respectively. The respective disease control rates (DCR) were 61.9%, 64.9%, and 66.7%. The clinical benefit rates (CBR) were 33.3%, 29.4%, and 28.6%, respectively.
“[Data from cohort 1] met the [study’s] primary end point, with 23.8% of patients showing intracranial responses,” Matthias Preusser, MD, professor of Medical Oncology and head of the Clinical Division of Oncology at the Medical University of Vienna in Austria, said during an oral presentation of the data.“It was interesting [to note] that amongst the responders, we had patients with newly diagnosed brain metastases or recurring brain metastases after local treatment and patients of 3 different breast cancer subtypes. We also saw patients respond who [received] prior antibody-drug conjugates.”
TUXEDO-3 Study Design and Cohort 1 Baseline Characteristics
TUXEDO-3 enrolled adult patients with histologically documented metastatic breast cancer, advanced non–small cell lung cancer, or any advanced solid tumor with type I or II leptomeningeal disease. Patients in cohort 1 were required to have at least 1 measurable brain lesion of at least 10 mm, received at least 1 line of systemic treatment in the advanced setting, an ECOG performance status of 0 to 2, a Karnofsky performance score of at least 70%, and a left ventricular ejection fraction of at least 50%.
Patients received intravenous HER3-DXd at 5.6 mg/kg every 21 days. Treatment continued until disease progression, treatment discontinuation, or death.
The primary end point in cohort 1 was intracranial ORR. Secondary end points in all cohorts included CBR, DCR, duration of response, time to response, PFS, OS, best percentage change in tumor burden, and safety and tolerability.
At baseline, the median age in cohort 1 was 57.0 years (range, 35.0-75.0) and all patients were female. Most patients had an ECOG performance status of 0 (61.9%) and experienced progression of brain metastases after local therapy (71.4%). The median number of prior lines of treatment for advanced disease was 4 (range, 1-13). Breast cancer subtypes consisted of HER2-positive (42.9%), luminal (23.8%), or triple-negative (33.3%) disease.
Additional Findings and Safety Data
In terms of safety, the incidence of any-grade adverse effects (AEs) in cohort 1 was 85.7%. Any-grade treatment-emergent AEs (TEAEs) occurred in 85.7% of patients, 4.8% of which were related to HER3-DXd. Grade 3 or higher TEAEs occurred in 42.9% of patients; 28.6% of these were deemed related to HER3-DXd.
Any-grade AEs of special interest and deaths due to TEAEs were both reported at rates of 4.8%. TEAEs leading to dose reduction (19.0%), interruption (9.5%), and discontinuation (4.8%) also occurred. The most common grade 3 or higher TEAEs in cohort 1 included neutropenia, diarrhea, and fatigue.
“The safety profile [of HER3-DXd] was well in line with [what was reported] in other trials of this drug,” Preusser said.
Disclosures: Preusser received honoraria from AbbVie, Adastra Pharmaceuticals, AstraZeneca, Bayer, BMJ Journals, Bristol-Myers Squibb, CMC Contrast, Daiichi Sankyo, Gan & Lee, Gerson Lehrman Group, GlaxoSmithKline, Lilly, Medahead, MedMedia, Merck Sharp & Dome, Mundipharma, Novartis, Roche, Sanofi, SERVIER, Telix Pharmaceuticals, and Tocagen. He has consulting or advisory roles with AbbVie, Adastra Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, CMC Contrast, Daiichi Sankyo/Astra Zeneca, Gan & Lee, Gerson Lehrman Group, GlaxoSmithKline, Lilly, Merck Sharp & Dome, Mundipharma, Novartis, Roche, Sanofi, SERVIER, and Tocagen. He received research funding from AbbVie (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Daiichi Sankyo (Inst), GlaxoSmithKline (Inst), Merck Sharp & Dohme, Novartis (Inst), Roche (Inst), and Telix Pharmaceuticals (Inst). He received travel, accommodations, and/or expenses from Bristol-Myers Squibb, GlaxoSmithKline, MSD, Mundipharma, Roche, and Servier.
Reference
Preusser M, Garde J, Gion M, et al. Patritumab deruxtecan (HER3-DXd) in active brain metastases (BM) from metastatic breast (mBC) and non–small cell lung cancers (aNSCLC), and leptomeningeal disease (LMD) from advanced solid tumors: results from the TUXEDO-3 phase II trial. J Clin Oncol. 2025,43(suppl 16):2005. doi:10.1200/JCO.2025.43.16_suppl.2005