An orelabrutinib plus sintilimab combination produced high response rates and durable disease control in relapsed or refractory primary CNS lymphoma, according to a prospective phase 2 study at four Chinese centers published October 28, 2026 in BMC Cancer. The study enrolled 28 patients between March 2021 and October 2023.
The authors, whose corresponding authors Wei Zhang and Daobin Zhou work in the Department of Hematology at Peking Union Medical College Hospital in Beijing, described the combination of orelabrutinib and sintilimab as an effective and well-tolerated treatment option for patients with relapsed or refractory primary CNS lymphoma (PCNSL). They reported no unexpected toxicities.
Who Was Treated, and How
Eligible patients were 18 to 75 years old with histologically or cytologically confirmed PCNSL, no evidence of systemic lymphoma, and at least one measurable lesion. Their disease had relapsed or progressed after at least one methotrexate-containing regimen. Anyone previously treated with a BTK inhibitor or PD-1 inhibitor was excluded.
Patients received orelabrutinib 150 mg orally once daily plus sintilimab 200 mg intravenously on day 1 of each 21-day cycle, continuing until progression, unacceptable toxicity or withdrawal. Concurrent radiotherapy was not allowed. Brain MRI with contrast assessed responses under International Primary CNS Lymphoma Collaborative Group criteria.
The primary end point was overall response rate after four cycles.
Median age was 61.1 years (range, 48-78), and patients had a median of 2 prior therapy lines (range, 1-5). By International Extranodal Lymphoma Study Group score, 32.1% were low risk, 39.3% intermediate and 28.6% high risk.
Age, Performance Status and LDH Tied to Worse Survival
In exploratory univariate analyses, ECOG performance status of 2 or higher was linked to worse progression-free survival (HR, 4.56; 95% CI, 1.13-18.41; P = .033). Worse overall survival was associated with age 65 or older (HR, 6.86; 95% CI, 1.32-35.57; P = .022) and with elevated lactate dehydrogenase (HR, 9.96; 95% CI, 1.19-83.12; P = .034).
Four patients moved to orelabrutinib alone after finishing the planned combination, and three of them relapsed later. The authors said this may point to a benefit of continued PD-1 blockade, but the sample was too small for conclusions.
Authors Acknowledge Single-Arm Design and Small Sample
The authors listed a single-arm design with no control group, a small sample with few events, many patients with unclassified molecular subtype, no central pathology review, and cerebrospinal fluid exams done only when clinically indicated.
They placed the observed response rate within the 50% to 70% range reported for ibrutinib monotherapy in this setting, while the median duration of response was longer than typically reported. CancerNetwork’s summary did not give this study’s own response rate.
They also cited a phase 2 trial of ibrutinib plus nivolumab in relapsed CNS lymphomas (NCT03770416), which reported a 77.8% response rate and median progression-free survival of 13.7 months in its PCNSL subset. The authors said that supports a possible class effect for BTK-plus-PD-1 combinations, one that warrants testing in larger, randomized trials.
Orelabrutinib Also Tested in Untreated DLBCL
A different study, in Frontiers in Oncology, tested orelabrutinib with R-CDOP as first-line therapy in untreated diffuse large B-cell lymphoma with CNS-IPI of 4 or higher. That single-arm phase II trial (NCT06290817) ran at four Chinese centers. Patients got six 21-day cycles with orelabrutinib at 150 mg daily. Its authors described orelabrutinib as a next-generation BTK inhibitor with excellent blood-brain barrier penetration, and reported no atrial fibrillation, major bleeding or invasive fungal infections, toxicities associated with ibrutinib.