Efficacy and safety of orelabrutinib combined with sintilimab in patients with relapsed/refractory primary central nervous system lymphoma: a prospective multicenter phase ii study

Relapsed or refractory primary central nervous system lymphoma (R/R PCNSL) has a poor prognosis, with limited effective salvage treatments. Bruton tyrosine kinase inhibitors (BTKis) showed considerable efficacy, although the duration of effect was unsatisfactory. Orelabrutinib, a new, highly selective BTK inhibitor, has demonstrated an improved ability to cross the blood-brain barrier. PD-1 inhibitors demonstrate efficacy in the treatment of PCNSL. The combination of BTK inhibitors with PD-1 blockade produces synergistic effects. BTK inhibition suppresses tumor proliferation, promotes T-cell infiltration, and reverses T-cell exhaustion, thereby enhancing the effectiveness of PD-1. This phase II study aims to evaluate the efficacy and safety of this combination in R/R PCNSL. This prospective, multicenter, single-arm phase II study (NCT04899427) enrolled 28 consecutive patients with R/R PCNSL who received orelabrutinib combined with sintilimab between March 2021 and October 2023. The primary endpoint was the overall response rate (ORR) after 4 treatment cycles. Secondary endpoints included 1-year progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. The median age was 61.0 years, with 92.9% experiencing relapse and 7.1% having refractory disease. Among 28 evaluable patients, the ORR after 4 cycles was 60.7% (17/28), including 8 (28.6%) with complete responses, 2 (7.1%) with unconfirmed complete responses, and 7 (25.0%) with partial responses. The median PFS was 8.4 months; the 1- and 2-year PFS rates were 49.7% and 40.7%, respectively. Median OS was not reached, with 1- and 2-year OS rates of 77.4% and 73.3%. The median DOR was notably prolonged at 42.4 months. The combination of orelabrutinib and sintilimab was well tolerated. Treatment-emergent adverse events (TEAEs) of any grade occurred in 75.0% (21/28) of patients, with 71.4% (20/28) experiencing grade 1-2 events and 14.3% (4/28) experiencing grade 3-4 events. One grade 5 event (COVID-19 infection) was reported. No immune-related adverse events occurred. This prospective phase II study showed that combining orelabrutinib with sintilimab provided significant clinical benefits for patients with R/R PCNSL, including high response rates and notably durable responses. The manageable safety profile further supports this combination as a valuable treatment option for this challenging population. ClinicalTrials.gov NCT04899427. Last Update Posted: May 24, 2021.