CTIM-19. INTRATHECAL PD-1 INHIBITOR COMBINED WITH PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMORS: PRELIMINARY RESULTS FROM A PHASE I/II STUDY (NCT 06462222)

Abstract BACKGROUND This study evaluated the safety and feasibility of intrathecal programmed death 1 (PD-1) inhibitor plus pemetrexed for leptomeningeal metastases (LM) from solid tumors. METHODS In phase I, a 3 + 3 dose de-escalation design determined dose-limiting toxicity (DLT) and recommended dose for phase II. Patients received intrathecal pemetrexed (15 mg flat dose) twice weekly for 2 weeks (induction), then weekly for 4 weeks (consolidation), followed by monthly maintenance. Intrathecal PD-1 inhibitor (40 mg initial dose) was given every 2 weeks for 6 weeks (induction/consolidation), then monthly during maintenance. Selected patients received involved-field radiotherapy. Primary endpoints were recommended dose and safety based on adverse events (AEs). Clinical response rate (CRR), disease control rate (DCR), and overall survival (OS) were evaluated. RESULTS From 6/2024 to 3/2025, 31 patients were enrolled (26 non-small cell lung cancer, 4 breast cancer, and 1 small cell lung cancer). At the initial dose level of phase I, 7 patients were enrolled. No DLT was observed. The recommended dose was intrathecal 40 mg PD-1 inhibitor plus 15 mg pemetrexed. All patients completed induction therapy, 27 completed consolidation therapy, and 28 received maintenance therapy, 14 patients received radiotherapy. No treatment-related deaths occurred. Grade ≥3 AEs occurred in 52% (16/31), primarily hematologic toxicity (n=14) and elevated hepatic aminotransferases (n=3). Grade 1–2 immune-related AEs occurred in 32% (10/31), including rash (n=5), fever (n=3), hypothyroidism (n=1), and pneumonia (n=1). CRR was 61% (19/31) per Response Assessment in Neuro-Oncology proposal criteria, including neurological dysfunction improvement (n=8), CSF cytological response (n=10), and neuroimaging improvement (n=11), 74% (23/31) of patients showed improvement in LM-related neurological symptoms. DCR was 87% (27/31). As of 5 June 2025, 6 patients died. Median follow-up time was 5.4 (2.0-11.2) months. Median OS was not reached. CONCLUSION Intrathecal PD-1 inhibitor plus pemetrexed showed feasibility for LM from solid tumors with potential activity.