Photorealistic, artistic rendition of brain metastases – Generated with Adobe Firefly
Patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate (ADC), has demonstrated clinically relevant activity and a manageable safety profile in patients with leptomeningeal metastatic disease (LMD) from solid tumors, according to results from cohort 3 of the phase 2 TUXEDO-3 trial (NCT05865990).1,2
LMD, a severe complication of advanced solid cancers, is associated with poor prognosis and limited treatment options, highlighting a significant unmet clinical need.
The study, which accrued 20 evaluable patients between January and July 2024, met its primary end point, with 65.0% of patients alive after 3 months. This survival rate surpassed the predefined 25% threshold for clinical relevance, offering a new potential avenue for patients facing this challenging diagnosis.
Study Design and Key Findings
LMD involves the spread of cancer cells to the leptomeninges or cerebrospinal fluid (CSF), leading to debilitating neurological symptoms and a median overall survival often ranging from only 2 to 6 months with current treatments. Patients with LMD are frequently excluded from clinical trials, underscoring the importance of studies like TUXEDO-3.
The TUXEDO-3 trial is an international, multicenter, single-arm, multicohort phase 2 study investigating patritumab deruxtecan in various central nervous system (CNS) metastatic settings. Cohort 3 specifically focused on patients with treatment-naive LMD or LMD progressing after radiotherapy from any solid tumor. Patients aged 18 or older with an ECOG performance status of 0 to 2 received patritumab deruxtecan 5.6 mg/kg intravenously every 3 weeks. The median follow-up time was 5.4 months.
Key patient characteristics revealed a majority with breast (60%) and lung (30%) cancers, aligning with the common primary tumor types observed in LMD. A total of 45% had type I LMD (positive CSF cytology or biopsy), and 55% had type II LMD (clinical findings and neuroimaging only).
Beyond the primary end point, the Kaplan-Meier-estimated 3-month and 6-month overall survival rates were 69.6% and 58.9%, respectively. Objective response rates were observed in 11.1% of intracranial lesions, 30.8% of extracranial lesions, and 26.3% of overall lesions. The clinical benefit rate was 50.0% for intracranial, 38.5% for extracranial, and 47.4% for overall lesions. Neurological symptoms and quality of life largely remained stable or improved during treatment, and no new neurological adverse events were reported.
“Overall, our data show clinically relevant activity of HER3-DXd in patients with LMD of solid cancers and may open the path to novel treatment options for this condition characterized by high morbidity and mortality,” study authors wrote.1
Safety Profile
The safety profile of patritumab deruxtecan in this cohort was consistent with previous trials, with no new safety signals identified. The most common adverse events (AEs) of any grade were
- Anemia: 40.9% (9 patients), with 4.5% (1 patient) experiencing grade ≥3.
- Nausea: 31.8% (7 patients), with no grade ≥3 events.
- Neutropenia: 27.3% (6 patients), with 13.6% (3 patients) experiencing grade ≥3.
- Diarrhea: 27.3% (6 patients), with 4.5% (1 patient) experiencing grade ≥3.
- Asthenia: 27.3% (6 patients), with no grade ≥3 events.
- Thrombocytopenia and headache: 22.7% (5 patients each), with 4.5% (1 patient each) experiencing grade ≥3.
Serious treatment-related AEs occurred in 18.2% of patients, including dyspnea, interstitial lung disease, and febrile neutropenia, all of which resolved. There were no treatment-related deaths. Dose interruptions due to AEs occurred in 27.3% of patients, and permanent discontinuation in 4.5%.
Implications for Clinical Practice
The positive results from TUXEDO-3 are particularly encouraging given the historically poor prognosis for patients with LMD and the limited treatment landscape. The ability of patritumab deruxtecan to maintain or improve patient well-being, coupled with demonstrable intracranial and extracranial responses, suggests its potential as a valuable systemic treatment option.
While current guidelines often recommend radiotherapy or intrathecal pharmacotherapy, the high accrual rate of previously untreated LMD patients in this trial underscores the urgent need for novel first-line systemic therapies. The study’s inclusion of various solid tumor types also reflects the real-world heterogeneity of LMD.
Further prospective and adequately powered studies are needed to compare patritumab deruxtecan with other emerging therapies, such as trastuzumab deruxtecan (T-DXd; Enhertu), a HER2-targeting ADC, and to refine treatment guidelines for this challenging patient population. The findings from TUXEDO-3 pave the way for continued investigation into HER3 as a therapeutic target in CNS metastases.