Orelabrutinib Combo Shows Durable Responses in Relapsed/Refractory CNS Lymphoma

The combination of the Bruton tyrosine kinase (BTK) inhibitor orelabrutinib and the anti–PD-1 antibody sintilimab produced high response rates and durable disease control with a manageable safety profile in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), according to results from a phase 2 trial (NCT04899427) published in BMC Cancer.¹

The overall response rate (ORR) after 4 cycles of treatment, the study's primary end point, was 60.7% (n = 17/28). This included complete responses (CRs) in 8 patients (28.6%), unconfirmed CRs in 2 (7.1%), and partial responses in 7 (25.0%). Four patients (14.3%) had stable disease, and 7 (25.0%) had progressive disease.

At a median follow-up of 22.9 months, the median progression-free survival (PFS) in the intention-to-treat population was 8.4 months (95% CI, 4.4-not estimable [NE]), with 1-year and 2-year PFS rates of 49.7% (95% CI, 34.2%-72.3%) and 40.7% (95% CI, 25.5%-64.9%), respectively. In a sensitivity analysis censoring 1 death related to COVID-19, the median PFS increased to 20.5 months (95% CI, 4.6-NE). The median overall survival (OS) was not reached, with 1-year and 2-year OS rates of 77.4% (95% CI, 63.0%-95.1%) and 73.3% (95% CI, 58.2%-92.5%), respectively. Among the 17 responders, the median duration of response (DOR) was 42.4 months.

Treatment-emergent adverse events (TEAEs) of any grade occurred in 75.0% of patients (n = 21/28), with grade 3/4 TEAEs in 14.3% (n = 4/28). One grade 5 event, a COVID-19 infection, was reported. The most common any-grade TEAEs were fatigue (39.3%), bleeding events (35.7%), infection (35.7%), leukopenia (32.1%), neutropenia (28.6%), and gastrointestinal symptoms (28.6%). TEAEs led to treatment discontinuation in 2 patients (7.1%), and no immune-related AEs occurred.

“This prospective phase 2 study shows that the combination of orelabrutinib and sintilimab is an effective and well-tolerated treatment option for patients with [relapsed/refractory] PCNSL, with high response rates and durable disease control. The safety profile was manageable, with no unexpected toxicities, reinforcing the feasibility of this combination,” corresponding authors Wei Zhang and Daobin Zhou, of the Department of Hematology at Peking Union Medical College Hospital in Beijing, China, wrote in the publication with study coinvestigators.¹

The prospective, single-arm, phase 2 study was conducted at 4 centers in China and enrolled 28 patients between March 2021 and October 2023. Eligible patients were 18 to 75 years old and had histologically or cytologically confirmed PCNSL without evidence of systemic lymphoma, at least 1 measurable lesion, and disease that relapsed or progressed after at least 1 prior methotrexate-containing regimen. Patients previously treated with a BTK inhibitor or PD-1 inhibitor were excluded.

Patients received orelabrutinib at 150 mg orally once daily plus sintilimab at 200 mg intravenously on day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or withdrawal. Concurrent radiotherapy was not permitted. Responses were assessed by contrast-enhanced brain MRI per International Primary CNS Lymphoma Collaborative Group criteria.

The median patient age was 61.1 years (range, 48-78), and patients had received a median of 2 prior lines of therapy (range, 1-5). By International Extranodal Lymphoma Study Group risk score, 32.1% of patients were low risk, 39.3% were intermediate risk, and 28.6% were high risk.

The primary end point of the study was ORR after 4 cycles. Secondary end points included 1-year PFS rate, PFS, DOR, OS, and safety.

In exploratory univariate analyses, an ECOG performance status of 2 or higher was associated with worse PFS (HR, 4.56; 95% CI, 1.13-18.41; P = .033); age 65 years or older (HR, 6.86; 95% CI, 1.32-35.57; P = .022) and elevated lactate dehydrogenase (HR, 9.96; 95% CI, 1.19-83.12; P = .034) were associated with worse OS. Among 4 patients who transitioned to orelabrutinib monotherapy after completing the planned combination, 3 later relapsed, which the authors noted may suggest a benefit of continued PD-1 blockade, although the sample was too small to draw conclusions.

The authors acknowledged limitations including the single-arm design without a control group, the small sample size and limited number of events, a high proportion of patients with unclassified molecular subtype, the lack of central pathology review, and cerebrospinal fluid examinations performed only when clinically indicated.

The investigators noted that the observed ORR fell within the 50% to 70% range reported with ibrutinib (Imbruvica) monotherapy in this setting, while the median DOR was longer than typically reported. They also pointed to a phase 2 trial (NCT03770416) of ibrutinib plus nivolumab (Opdivo) in relapsed CNS lymphomas, which reported an ORR of 77.8% and a median PFS of 13.7 months in the PCNSL subset, as supporting a potential class effect for BTK inhibitor plus PD-1 inhibitor combinations that warrants evaluation in larger, randomized trials.²

References

1. Zhang Y, Liu H, Ma J, et al. Efficacy and safety of orelabrutinib combined with sintilimab in patients with relapsed/refractory primary central nervous system lymphoma: a prospective multicenter phase II study. BMC Cancer. Published October 28, 2026. doi:10.1186/s12885-026-17092-x
2. Chihara D, Steiner RE, Nair R, et al. Phase 2 trial of ibrutinib and nivolumab in patients with relapsed CNS lymphomas. Blood Adv. 2025;9(7):1485-1491. doi:10.1182/bloodadvances.2024014635