The phase II TUXEDO-3 trial is the first trial demonstrating notable CNS activity with patritumab deruxtecan (HER3-DXd) in patients with brain metastases (BM) from metastatic breast cancer (mBC) and advanced non-small cell lung cancer (NSCLC), and leptomeningeal disease (LMD) from solid tumours.
BM and LMD are severe complications of solid tumours, associated with high morbidity, poor prognosis and limited treatment options.1 HER3-DXd, an ADC combining an anti-HER3 antibody with topoisomerase I inhibitor, has shown promising activity in HER2-positive mBC and advanced NSCLC.2-4 The phase II TUXEDO-3 trial evaluated the efficacy and safety of HER3-DXd in patients with BM from mBC and advanced NSCLC, and LMD from any solid tumour. At ASCO 2025, the results of the TUXEDO-3 trial were presented.5
TUXEDO-3 (NCT05865990) is an international, multicentre, single-arm phase II trial enrolling patients with active BM from mBC (cohort 1), advanced NSCLC (cohort 2), and LMD from any solid tumour (cohort 3). Eligible patients (>18 years old) had histologically confirmed disease, ECOG PS 0-2, and left ventricular ejection fraction >50%. Cohorts 1 and 2 included patients with newly diagnosed or progressing BM (>1 lesion >10 mm) and prior systemic therapy. Cohort 3 enrolled patients with leptomeningeal disease per EANO-ESMO criteria. Patients received HER3-DXd (5.6 mg/kg, IV every three weeks) until progression, unacceptable toxicity, or withdrawal. Primary endpoints were intracranial overall response rate (IC-ORR) in cohort 1 and 2, and three-month overall survival (OS) in cohort 3.
A total of 61 patients were enrolled in the study, with a median age of 57.0, 59.5, and 51.5 years for cohorts 1 (N= 21), 2 (N= 20), and 3 (N= 20), respectively. IC responses were observed in 23.8% of patients in cohort 1 (regardless of breast cancer subtype), and 30.0% in cohort 2. In cohort 3, 65.0% of patients achieved three-month OS, irrespective of LMD type. Median OS was not reached in cohort 1, and was 6.7 and 10.5 months in cohort 2 and 3, respectively. No new safety signals were observed with the use of HER3-DXd. Grade >3 treatment-emergent adverse events (TEAEs), considered to be HER3-DXd related occurred in 28.6%, 40.0%, and 31.8% of patients in cohorts 1, 2, and 3, respectively, with neutropenia being the most frequent across all cohorts. TEAEs led to permanent treatment discontinuation in only one patient per cohort. Neurological symptoms, quality of life (QoL), and neurocognitive function remained stable or improved throughout treatment. No correlation was observed between HER3 tumour expression and treatment response.
TUXEDO-3 is the first trial to assess efficacy and safety of HER3-DXd in patients with BM or LMD. HER3-DXd demonstrated notable CNS activity in both parenchymal metastases and LMD, suggesting its potential as a novel treatment option for CNS involvement in this setting.
References
1. Le Rhun E, Preusser M, van den Bent M, et al. How we treat patients with leptomeningeal metastases. ESMO Open. 2019;4(Suppl 2):e000507.
2. Niikura N, Yamanaka T, Nomura H, et al. Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM). NPJ Breast Cancer. 2023;9(1):82.
3. Harbeck N, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024;30(12):3717-27.
4. Vaz Batista M, Pérez-García JM, Garrigós L, et al. The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis. Med. 2025;6(1):100502.
5. 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. Presented at ASCO 2025; abstract 2005.
Top
