Intrathecal (IT) therapy–associated pseudoprogression (PsP) in leptomeningeal metastases (LM) from solid tumors.

2037 Background: Intracranial PsP following systemic immunotherapy has been recognized. IT therapy is a cornerstone of LM management, and prior studies support the safety and feasibility of IT immunotherapy. The occurrence of PsP specifically after IT immunotherapy for LM remains unreported. This study aims to characterize the clinical and proteomic profile of IT therapy–associated PsP (IT-PsP). Methods: This prospective case series consecutively enrolled LM patients receiving IT therapy between February 2024 and January 2026. Patients were treated with IT pemetrexed (PM) alone or combined with immunotherapy (PD-1 inhibitors, PD-1/CTLA-4, or PD-1/VEGF antibodies). Treatment response was assessed per RANO-LM criteria. Based on the iRANO criteria, IT-PsP was considered as radiographic progression without significant worsening of LM-related symptoms or neurological deficits. Furthermore, patients were defined as IT-PsP only if they also met at least one of the following criteria without salvage LM-directed therapy: sustained conversion of cerebrospinal fluid (CSF) cytology to negative, subsequent neuroimaging improvement, or absence of progressive neurological symptoms/signs with stable disease for ≥3 months. CSF proteomics was analyzed via Olink Target 96 Immuno-Oncology panel. Results: Of 144 enrolled patients, 75 received IT PM and 69 received IT immunotherapy plus PM. IT–PsP was identified in 12 patients (8.3%). Median age was 53.5 years (range 30–66) and 10 were female. Primary tumors were lung adenocarcinoma (n=11) and breast cancer (n=1). None received concurrent systemic immunotherapy. The median time to PsP occurrence was 5.2 months (range 1.5–12) after the first IT treatment. PsP incidence was significantly higher in the combination group (15.9%, 11/69) than with IT PM alone (1.3%, 1/75) (P=0.002). 6 (50%) achieved sustained conversion to negative CSF cytology. Radiographically, lesions improved in 7 patients (58.3%) and remained stable in 2 (16.7%). All PsP patients were followed up for a median of 7.1 months (range 1–13.6) with no neurological progression. Median overall survival from enrollment and from PsP onset were not reached. CSF proteomic profiling revealed that IT-PsP samples, compared to both progressive LM and pre-treatment samples, showed significant downregulation of tumor-associated proteins (CCL20, LAP TGF-beta-1, IL8, CCL4). Furthermore, compared to post-treatment response samples, IT-PsP was associated with significant upregulation of inflammatory markers, including Gal-9, IL15, and ADA. Conclusions: This study characterizes the clinical features and distinct CSF proteomic signature of IT-PsP in LM. The significantly higher PsP incidence with IT immunotherapy underscores that, in the immunotherapy era, relying exclusively on neuroimaging to define LM progression necessitates careful re-evaluation.