Intrathecal (IT) PD-1/CTLA-4 antibody combined with pemetrexed (PM) for leptomeningeal metastases (LM) from solid tumors: Preliminary results of two single-center phase I studies.

2624 Background: IT PD-1 inhibitors, alone or combined with IT PM, have shown safety and feasibility in LM from solid tumors. Cadonilimab (AK104) and iparomlimab/tuvonralimab (QL1706) are novel bispecific PD-1/CTLA-4 antibody. Our preclinical animal studies demonstrated the safety of IT administration of these agents. This study evaluated the feasibility and potential clinical benefit of combing IT PD-1/CTLA-4 antibody with PM in patients with LM from solid tumors. Methods: Eligible patients had histologically confirmed solid tumors and positive CSF cytology. A rapid dose-escalation design was employed across three dose levels: AK104 at 15.625 mg, 31.25 mg and 62.5 mg; QL1706 at 25 mg, 37.5 mg and 50 mg. One patient was enrolled in each of the first two dose cohorts, while six were enrolled at the third dose cohort. The protocol would revert to a standard 3+3 design if any dose-limiting toxicities (DLT) occurred. IT PM was given at a fixed dose of 15 mg twice weekly for two weeks (induction), then weekly for four weeks (consolidation), followed by monthly maintenance until progression or death. IT PD-1/CTLA-4 antibody began at the fourth IT PM dose, administered every two weeks for six weeks, then monthly until progression or death. Continuation of previously administered systemic therapies was permitted during the study. Results: A total of 17 patients were enrolled (AK104: n=8; QL1706: n=9). Median age was 54 years (range 37–73); 13 were female. Primary tumors included lung adenocarcinoma (n=13) and breast cancer (n=4). 16 patients (94.1%) completed induction and consolidation therapy. No DLT occurred. Grade ≥3 adverse events (AEs) occurred in 64.7% (11/17) of patients. Specifically, grade ≥3 AEs attributed to IT PM were observed in 58.8% (10/17), primarily hematological toxicity (n=10), elevated hepatic aminotransferase (n=1) and fatigue (n=1). For IT PD-1/CTLA-4 antibody-related AEs, grade ≥3 occurred in 11.8% (2/17; rash n=1, diarrhea n=1), and grade 1-2 in 17.6% (3/17; rash n=3, fever n=1, diarrhea n=1). Clinical response rate was 41.2% (7/17) by RANO-LM criteria. Disease control rate was 82.4% (14/17). As of January 15, 2026, 8 patients had died, with 1 due to LM, 3 due to systemic progressive disease, and 4 due to non-cancer-related causes. Median follow-up time was 8.53 months (95%CI: 8.07-NA), and median overall survival was 8.53 months (95%CI: 6.3-NA). Conclusions: The study demonstrates the manageable safety and feasibility of IT PD-1/CTLA-4 antibody combined with PM, with no unexpected systemic or neurological toxicities observed. Preliminary results suggest potential clinical benefits, with a high clinical response rate and notable treatment responses even among those with severe conditions. ClinicalTrials.gov registration: NCT06762080/NCT06809530. Clinical trial information: NCT06809517 / NCT06809530 .