A first‐line regimen combining Bruton's tyrosine kinase and programmed cell death protein‐1 inhibitors with chemotherapy excluding methotrexate achieves high response rates in primary central nervous system lymphoma

Abstract Background Primary central nervous system lymphoma (PCNSL) is an aggressive, immune‐privileged, large B‐cell lymphoma with limited frontline treatment options. Methods This study was an open‐label, single‐arm, phase 1/2 trial evaluating orelabrutinib combined with an anti–programmed cell death protein‐1 (PD‐1) antibody and a non‐methotrexate chemotherapeutic agent (fotemustine) in patients with newly diagnosed PCNSL (ClinicalTrials.gov identifier NCT04831658). Orelabrutinib was tested at three dose levels (100, 150, and 200 mg), and the recommended phase 2 dose was determined as 150 mg. In phase 2, patients received orelabrutinib 150 mg orally once daily, a PD‐1 inhibitor 200 mg intravenously on day 1, and fotemustine 100 mg/m 2 intravenously on day 2 every 21 days for six cycles. The primary endpoint was the objective response rate. Results From February 2021 to October 2023, 31 patients (median age, 62 years; age range, 37–70 years) were treated, and 27 were evaluable for efficacy. The objective response rate was 85.2% (complete response, 66.7%; partial response, 18.5%). The median progression‐free survival was 9.4 months (95% confidence interval, 5.4–13.4 months), and the median overall survival was 22.8 months (95% confidence interval, 1.1–44.5 months). The 1‐year and 2‐year overall survival rates were 68.0% and 48.0%, respectively. The most common grade 3/4 adverse events were thrombocytopenia (45.2%), pulmonary infection (38.7%), and leukopenia (25.8%). Conclusions Orelabrutinib combined with PD‐1 blockade and fotemustine demonstrated high antitumor activity with manageable toxicity, supporting its potential as a frontline regimen for PCNSL.