Lancet Oncol. 2025 Nov;26(11):1454-1466. doi: 10.1016/S1470-2045(25)00465-6.
ABSTRACT
BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a novel antibody-drug conjugate targeting HER3, which is overexpressed in CNS metastases of advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the activity and safety of HER3-DXd in patients with advanced NSCLC and newly diagnosed brain metastases or brain metastases progressing after local therapy.
METHODS: TUXEDO-3 is a multicohort, multicentre, open-label, single-arm phase 2 trial. In this cohort (2 of 3), we enrolled adults (aged ≥18 years) with histologically documented squamous or non-squamous NSCLC, radiologically documented metastatic disease, newly diagnosed brain metastases or progressing brain metastases after local treatment, at least one brain lesion, no need for immediate local therapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received HER3-DXd 5·6 mg/kg intravenously once every 3 weeks. The threshold to meet the primary endpoint was at least 15% of patients having an intracranial response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. Activity and safety analyses were done in the full analysis set, which included all participants who received at least one dose of HER3-DXd. This trial (ClinicalTrials.govNCT05865990 and European Union Clinical Trials Register 2023-503251-10-00) is ongoing but no longer enrolling patients.
FINDINGS: Between Dec 27, 2023, and Sept 6, 2024, 20 patients were recruited; ten (50%) were female and ten (50%) were male. 16 (80%) of 20 patients were White; race was not reported in the remaining four patients. 13 (65%) of the 20 patients had brain metastases progressing after local therapy and seven (35%) had untreated brain metastases; five (25%) had activating driver mutations. Median follow-up was 5·3 months (IQR 2·0-8·5). The primary endpoint was met, with six (30%) of 20 patients having intracranial responses (objective response rate 30·0%, 95% CI 11·9-54·3). The six responders had non-squamous advanced NSCLC (two [33%] with untreated brain metastases and four [67%] with progressing brain metastases), of whom one (17%) had an activating driver mutation (KRAS G12C). Treatment-related adverse events occurred in 16 (80%) patients, the most common of which were nausea (seven [35%] patients), and diarrhoea and asthenia (each six [30%] patients). The most common grade 3 and 4 adverse events were neutropenia in three (15%) patients and febrile neutropenia in two (10%). There were no treatment-related deaths, and no new safety signals were identified.
INTERPRETATION: HER3-DXd showed promising clinical activity in patients with advanced NSCLC and active brain metastases, and could represent a novel treatment option in this setting.
FUNDING: Daiichi-Sankyo and Merck Sharp & Dohme.
PMID:41167214 | DOI:10.1016/S1470-2045(25)00465-6
