Patritumab deruxtecan (HER3-DXd), a HER3-directed antibody-drug conjugate, has demonstrated clinically meaningful activity in patients with leptomeningeal metastatic disease (LMD) from solid tumors, according to results from the first prospective trial specifically designed to evaluate this challenging indication. The findings from cohort 3 of the phase 2 TUXEDO-3 trial, published in Nature Medicine, represent a significant advance for a patient population with historically dismal outcomes and limited therapeutic options.
Primary Endpoint Achievement
The international, multicenter, single-arm trial enrolled 20 patients with newly diagnosed and untreated LMD from various solid tumors across seven sites in Austria and Spain between January and July 2024. The study met its primary endpoint, with 65% of patients alive at three months after treatment initiation, substantially exceeding the predefined 25% threshold considered to indicate clinically relevant activity.
"The Kaplan-Meier-estimated 3-month OS rate was 69.6% (95% confidence interval: 52.0–93.2; P < 0.001)," the researchers reported. At six months, the overall survival rate was 58.9%, with the Kaplan-Meier curves showing a prolonged plateau with approximately 60% of patients alive even after 10 months.
The patient population reflected the typical epidemiology of LMD, with breast cancer representing the primary tumor in 60% of patients, lung cancer in 30%, and melanoma and ovarian cancer each accounting for 5%. Of the enrolled patients, 45% had type I LMD (requiring positive CSF cytology or leptomeningeal biopsy) and 55% had type II LMD (based on clinical findings and neuroimaging only).
Secondary Efficacy Outcomes
Beyond survival benefits, patritumab deruxtecan demonstrated objective responses across multiple disease sites. The investigator-assessed confirmed objective response rate for intracranial lesions was 11.1% (95% CI: 1.4–34.7) among 18 patients with parenchymal CNS lesions at baseline. For extracranial disease assessment, the objective response rate reached 30.8% (95% CI: 9.1–61.4), while the overall disease objective response rate was 26.3% (95% CI: 9.2–51.2).
Clinical benefit rates were particularly encouraging, reaching 50.0% for intracranial lesions, 38.5% for extracranial disease, and 47.4% for overall disease assessments. Disease control rates were 61.1%, 69.2%, and 68.4%, respectively. Notably, none of the patients who achieved objective responses had received previous antibody-drug conjugates.
Median progression-free survival varied by assessment site: 9.9 months for intracranial lesions, 6.8 months for extracranial disease, and 6.2 months overall. The median overall survival was 10.5 months, with the upper bound of confidence intervals not estimable due to insufficient events.
Neurological Function and Quality of Life
A critical aspect of LMD treatment involves managing the debilitating neurological symptoms that characterize this condition. At baseline, 60% of patients presented with neurological symptoms. Structured neurological assessments using the Neurologic Assessment in Neuro-Oncology (NANO) scale revealed encouraging results: two patients (10%) showed neurological response, 11 patients (55%) maintained neurological stability, and no patients experienced neurological progression among those evaluable.
Quality of life assessments using QLQ-C30 and QLQ-BN20 questionnaires demonstrated improvements in global health status, emotional functioning, and cognitive functioning over the treatment period. These findings are particularly significant given the palliative setting and high symptom burden typically associated with LMD.
Safety Profile
The safety profile of patritumab deruxtecan in this patient population was consistent with previous trials and showed no new safety signals. Treatment-emergent adverse events of any grade occurred in 95.5% of patients, with 68.2% experiencing grade ≥3 events. The most common adverse events included anemia (40.9%), nausea (31.8%), neutropenia (27.3%), diarrhea (27.3%), asthenia (27.3%), thrombocytopenia (22.7%), and headache (22.7%).
Treatment-related adverse events were reported in 81.8% of patients, with the most frequent being nausea (27.3%), anemia (31.8%), neutropenia (27.3%), and thrombocytopenia (18.2%). Serious treatment-related adverse events occurred in 18.2% of patients, including dyspnea, interstitial lung disease, and febrile neutropenia, all of which resolved.
Importantly, adverse events affecting the nervous system were not more common or severe than in trials using patritumab deruxtecan in patients without CNS involvement. Dose interruptions due to adverse events occurred in 27.3% of patients, while permanent discontinuation due to adverse events was necessary in only 4.5% of patients. No deaths were attributed to patritumab deruxtecan.
Clinical Context and Significance
Leptomeningeal metastatic disease affects up to 10% of patients with solid cancers and is associated with median overall survival ranging from 4-6 weeks in untreated patients to 2-6 months in those responding to currently available treatments. The condition is characterized by high morbidity and debilitating neurological symptoms, with therapeutic options limited primarily to radiotherapy, intrathecal or intravenous pharmacotherapy, and palliative care.
The biological rationale for targeting HER3 in LMD is supported by evidence that HER3 facilitates CNS colonization by cancer cells and is frequently overexpressed in brain metastases. Previous research showed HER3 overexpression in 75% and 73% of brain metastases from breast cancer and non-small-cell lung cancer, respectively, with higher expression rates in CNS metastases compared to extracranial tumor sites.
Lead study author Dr. Matthias Preusser from the Medical University of Vienna noted during the 2025 ASCO Annual Meeting presentation that the trial's rapid enrollment, completing accrual within six months despite initially projecting a longer timeline, "reflects the high unmet clinical need to identify new therapies for patients with LMD and supports the conduct of clinical trials with novel investigational agents in a first-line treatment setting."
Future Implications
The TUXEDO-3 results position patritumab deruxtecan as a potentially valuable treatment option for patients with LMD, offering hope for improved outcomes in a condition with historically poor prognosis. The study's design, allowing enrollment of patients irrespective of HER3 expression levels, aligns with evidence that patritumab deruxtecan can achieve responses across a wide range of baseline tumor HER3 expression levels and may enable a higher bystander effect than other antibody-drug conjugates.
While the study's limitations include a small sample size, heterogeneous patient population, and relatively limited follow-up time, the results provide compelling evidence for further investigation of patritumab deruxtecan in this indication. The researchers emphasize that prospective, adequately powered comparative studies will be necessary to define optimal treatment recommendations and compare the efficacy of different systemic treatments for patients with LMD.
