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

Primary central nervous system lymphoma (PCNSL) is an aggressive, immune-privileged, large B-cell lymphoma with limited frontline treatment options. 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/m² intravenously on day 2 every 21 days for six cycles. The primary endpoint was the objective response rate. 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%). Orelabrutinib combined with PD-1 blockade and fotemustine demonstrated high antitumor activity with manageable toxicity, supporting its potential as a frontline regimen for PCNSL.