Phase I/II study of concurrent intrathecal toripalimab and pemetrexed (PM) for leptomeningeal metastases (LM) from solid tumors.

2621 Background: Intrathecal (IT) programmed death-1 (PD-1) inhibitors have demonstrated safety and feasibility in leptomeningeal metastases (LM) from melanoma or lung cancer. However, no studies have yet reported on the combination of IT PD-1 inhibitors with IT chemotherapy for LM from solid tumors. This study evaluated the feasibility and potential clinical benefit of combining IT toripalimab with pemetrexed (PM) in this patient population. Methods: Phase I followed a 3+3 dose de-escalation design to determine the dose-limiting toxicity (DLT) and the recommended phase II dose (RP2D). Patients received IT PM (15 mg flat dose) twice weekly for 2 weeks (induction), then weekly for 4 weeks (consolidation), followed by monthly maintenance. The administration of IT toripalimab (40 mg initial dose) was initiated concurrently with the fourth dose of IT PM, on an every-two-week schedule for 6 weeks (induction/consolidation), switching to monthly dosing during the maintenance phase. Continuation of previously administered systemic therapies was permitted during the study. The primary endpoints were RP2D and safety. Secondary endpoints included clinical response rate (CRR), disease control rate (DCR) and overall survival (OS). Results: From June 2024 to September 2025, 45 patients were enrolled (40 non-small cell lung cancer, 4 breast cancer, and 1 small cell lung cancer). Median age was 52 years (range 30–69), and 35 patients were female. In phase I, no DLTs were observed; the RP2D was established as toripalimab 40 mg plus PM 15 mg. All patients completed induction therapy, 42 completed consolidation therapy, and 41 received maintenance therapy. No treatment-related deaths occurred. All grade ≥3 adverse events (AEs) were attributable to IT PM, with an overall incidence of 55.6% (25/45), including leukopenia (n = 16), thrombocytopenia (n = 10), decreased hemoglobin (n = 7), and elevated hepatic aminotransferases (n = 5). Immune-related AEs were limited to grades 1-2, occurring in 24.4% (11/45) of patients, and included rash (n = 5), fever (n = 3), hypothyroidism (n = 3), and pneumonia (n = 1). According to Response Assessment in Neuro-Oncology (RANO) criteria, the CRR was 66.7% (30/45), including 11 patients with neurological dysfunction improvement, 16 with CSF cytological response, and 18 with neuroimaging improvement. The DCR was 93.3% (42/45). As of January 20, 2026, 19 patients had died. Median follow-up was 11.1 months (95% CI: 7.7–17.0). Median OS was 13.1 months (95% CI: 9.9–not applicable). Conclusions: IT toripalimab combined with PM showed a manageable safety profile and promising clinical activity in patients with LM from solid tumors. Based on the encouraging interim OS observed, further clinical investigation of intrathecal immunotherapy is warranted for patients with LM. Clinical trial information: NCT06462222 .