Abstract:

Background and purpose: Intrathecal chemotherapy is one of the mainstay treatment options for leptomeningeal metastases (LM) from solid tumors. A previous phase Ⅰ study demonstrated the safety and potential efficacy of intrathecal anti-programmed death receptor 1 (anti-PD-1) for LM from melanoma. The synergistic efficacy of systemic chemotherapy combined with anti-PD-1 has been widely known. This study aimed to evaluate the safety and feasibility of intrathecal chemotherapy (pemetrexed) and anti-PD-1 (toripalimab) for LM patients from solid tumors. Methods: The subjects were patients with LM from solid tumors who were treated at Affiliated Huizhou Hospital of Guangzhou Medical University/Third People’s Hospital of Huizhou City. A 3+3 dose de-escalation strategy was implemented to determine the recommended dose with an initial dose of PD-1 inhibitor (toripalimab) 40 mg and pemetrexed 15 mg. Pemetrexed was administered twice weekly for the initial 2 weeks of induction therapy, once weekly for the subsequent 4 weeks of consolidation therapy, and once monthly during maintenance therapy. PD-1 inhibitor was initiated at the 4th administration of pemetrexed, administered every 2 weeks for 6 weeks; subsequently, responders continued monthly maintenance therapy alongside pemetrexed. The primary objective was to assess safety based on adverse events and the recommended dose. All participants were observed to investigate the clinical response rate (CRR), disease control rate (DCR) and overall survival (OS). This study was approved by the ethics committee of Affiliated Huizhou Hospital of Guangzhou Medical University/Third People’s Hospital of Huizhou City (ethics number: 2024-KY-029-01). Results: Seven patients (male: 3, female: 4, median age: 57 years) were enrolled between June and September 2024, including non-small cell lung cancer (6) and breast cancer (1). All patients presented with positive cerebrospinal fluid (CSF) cytology. Six patients presented LM-related neurological dysfunction. Five patients showed LM-related neuroimaging findings. Six patients completed the induction and consolidation therapy, and subsequently received maintenance therapy. One patient, due to bacterial meningitis, did not complete the final administration of toripalimab during consolidation therapy, and maintenance therapy was administered after infection control. Adverse events rate was 100% (7/7), including myelosuppression (100.00%, n=7), elevation of hepatic aminotransferases (42.86%, n=3), fatigue (28.57%, n=2) and hypothyroidism (14.29%, n=1). Three (42.86%) patients had grade 3 adverse events (myelosuppression). The immune-related adverse event (irAE) rate was 14.29%, manifested as hypothyroidism (Grade 2). No dose-limiting toxicity (DLT) was observed. Thus, no de-escalation was applied. The recommended dose was determined to be PD-1 inhibitor 40 mg in combination with pemetrexed 15 mg. Three patients showed improved neurological dysfunction, 1 with CSF cytological response, and 2 with neuroimaging improvement. CRR was 57.14% (4/7) by response assessment in neuro-oncology (RANO) proposal criteria. DCR was 100% (7/7). Three patients exhibited abscopal effects with regression of brain metastasis lesions, primary lung lesion and mediastinal lymph nodes, respectively. As of April 10, 2025, 1 patient died. The median follow-up time was 7.7 (5.9-9.3) months. The median OS was not reached with a 6-month OS rate of 85.71%. Conclusion: The combination therapy of intrathecal pemetrexed and a PD-1 inhibitor was well-tolerated and feasible, while also exhibiting potential clinical efficacy in treating LM from solid tumors including non-small cell lung cancer.

Key words: Solid tumors, Leptomeningeal metastases, Intrathecal therapy, Anti-programmed death-1, Pemetrexed, Phase Ⅰ study