Background:Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of diffuse large B-cell lymphoma (DLBCL) with limited frontline treatment options and high relapse rates (Ferreri et al., Nat Rev Dis Primers 2023; Ferreri et al., Lancet Haematol 2017). Although median overall survival (OS) has improved to approximately 26 months and the 5-year OS rate approaches 30% (Calimeri et al., ESMO Open 2021), durable responses remain challenging, particularly in patients ineligible for high-dose methotrexate-based regimens. Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell receptor signaling and the pathogenesis of PCNSL (Xing et al., Front Oncol 2024). Orelabrutinib, a next-generation, highly selective BTK inhibitor with strong central nervous system penetration, has demonstrated encouraging activity in B-cell malignancies. Combining orelabrutinib with immunotherapy and chemotherapy may offer synergistic effects. This study evaluated the safety and efficacy of orelabrutinib plus anti–PD-1 antibody and fotemustine for newly diagnosed PCNSL.

Methods:This is an open-label, single-arm, phase I/II trial including adults (≥18 years) with histologically confirmed PCNSL. The study comprised a 3+3 dose-escalation phase (phase I) evaluating orelabrutinib at 100 mg, 150 mg, and 200 mg daily, followed by a dose-expansion phase (phase II) at the recommended phase 2 dose (RP2D). No dose-limiting toxicities were observed during phase I. However, two patients in the 200 mg cohort developed grade 4 thrombocytopenia requiring dose reductions. The RP2D was therefore established at 150 mg. In the phase II cohort, patients were administered orelabrutinib 150 mg daily, anti–PD-1 antibody 200 mg on day 1, and fotemustine 100 mg/m² on day 2, repeating every 21 days for 6 cycles, followed by maintenance therapy. Complete responders continued with orelabrutinib for 3 months and anti-PD-1 therapy for 1 year, while partial responders received the same regimen plus whole-brain radiotherapy. Patients with stable or progressive disease were discontinued and given salvage treatment. The primary endpoint was the objective response rate (ORR), secondary endpoints included disease control rate (DCR), progression-free survival (PFS), OS, and safety as assessed by adverse events (AEs) per NCI-CTCAE version 5.0.

Results:As of April 2025, 31 patients were enrolled and received protocol treatment. Twenty-seven patients had post-treatment efficacy assessment (100 mg cohort, n = 4; 150 mg cohort, n = 17; 200 mg cohort, n = 6). The 27 efficacy-evaluable patients had a median age of 62 years (range: 37-70), median KPS of 70 (range: 40–90), and 15 (55.6%) were male. Fifteen patients had double-expressor lymphoma, and 22 (81.5%) had deep brain involvement. Complete response (CR) was observed in 1 (25%) patient in 100 mg cohort, 12 (70.6%) in the 150 mg cohort and 5 (83.3%) in the 200 mg cohort; partial response (PR) was observed in 1 (25%), 3 (17.6%) and 1 (16.7%) in each cohort, respectively. The ORR in each cohort was 50% (100 mg cohort), 88.2% (150 mg cohort) and 100% (200 mg cohort). In total, ORR was 85.2% and DCR was 88.9% among 27 efficacy-evaluable patients. At cutoff date, the median follow-up duration was 33.3 months (95% CI: 30.5–36.1). The median PFS was 8.9 months (95% CI: 7.4–10.4) and the median OS was 22.8 months (95% CI: 0.8–44.8). The 1-year and 2-year PFS rates were 40.0% and 32.0%, respectively, with corresponding OS rates of 68.0% and 48.0% at 1 and 2 years. Of 31 as-treated patients, the most common hematologic AEs were leukopenia (80.6%), anemia (80.6%), thrombocytopenia (74.2%), and neutropenia (51.6%). Grade 3/4 hematologic AEs were primarily thrombocytopenia (45.2%) and leukopenia (25.8%). Non-hematologic AEs included elevated alanine aminotransferase (54.8%), pulmonary infection (48.4%), elevated aspartate aminotransferase (38.7%), fatigue (38.7%), nausea/vomiting (29.0%), and alkaline phosphatase increased(12.9%). Grade 3/4 non-hematologic AEs were mainly pulmonary infections (38.7%).

Conclusion:Orelabrutinib plus anti–PD-1 antibody and fotemustine demonstrated promising activity and acceptable safety in newly diagnosed PCNSL, with a high objective response rate. These findings support the potential of orelabrutinib-based chemoimmunotherapy as a promising frontline strategy. The study is still ongoing and final results will be presented in the future. ClinicalTrials.gov registration: NCT04831658.

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2025
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