BTK Inhibitor Plus Immunotherapy Shows Durable Responses in Relapsed CNS Lymphoma

Patients whose primary central nervous system lymphoma has returned or stopped responding to treatment have few good options, but a prospective phase II trial now reports that combining the BTK inhibitor orelabrutinib with the PD-1 antibody sintilimab produced substantial and unusually durable responses. In the multicenter, single-arm study, 28 consecutive patients with relapsed or refractory primary central nervous system lymphoma received the combination between March 2021 and October 2023, and the overall response rate after four treatment cycles reached 60.7 percent.

The trial, registered as NCT04899427, enrolled patients whose disease had relapsed or proved refractory, a population with a notoriously poor prognosis and limited effective salvage treatments. Among the 28 evaluable patients, 17 responded after four cycles: eight achieved complete responses, two achieved unconfirmed complete responses, and seven achieved partial responses. That corresponds to 28.6 percent complete responses, 7.1 percent unconfirmed complete responses, and 25.0 percent partial responses.

Durability was the standout feature of the results. The median duration of response was 42.4 months, a notably prolonged figure for a disease where earlier BTK inhibitor approaches showed considerable efficacy but an unsatisfactory duration of effect. The median progression-free survival was 8.4 months, with one-year and two-year progression-free survival rates of 49.7 percent and 40.7 percent respectively.

Overall survival data were similarly encouraging, though still maturing. The median overall survival had not been reached at the time of analysis, with one-year and two-year overall survival rates of 77.4 percent and 73.3 percent. The median age of participants was 61.0 years, and 92.9 percent of them had relapsed disease while 7.1 percent had refractory disease.

The rationale for pairing these two drugs rests on complementary biology. Orelabrutinib is a new, highly selective Bruton tyrosine kinase inhibitor that has demonstrated an improved ability to cross the blood-brain barrier, a critical property for treating tumors confined to the central nervous system. PD-1 inhibitors, meanwhile, have independently shown efficacy in primary central nervous system lymphoma.

According to the study’s background, combining BTK inhibition with PD-1 blockade produces synergistic effects: BTK inhibition suppresses tumor proliferation, promotes T-cell infiltration into the tumor, and reverses T-cell exhaustion, thereby enhancing the effectiveness of PD-1 blockade. The phase II study was designed specifically to evaluate whether this mechanistic synergy would translate into clinical benefit for relapsed or refractory patients.

Safety results supported the combination’s tolerability. Treatment-emergent adverse events of any grade occurred in 75.0 percent of patients, or 21 of 28. Most events were mild to moderate: 71.4 percent of patients, 20 of 28, experienced grade 1-2 events, while 14.3 percent, four of 28, experienced grade 3-4 events. One grade 5 event, a COVID-19 infection, was reported. Notably, no immune-related adverse events occurred, a relevant finding given the inclusion of a PD-1 checkpoint inhibitor in the regimen.

The investigators concluded that the combination provided significant clinical benefit for this challenging population, with high response rates, notably durable responses, and a manageable safety profile that they argue supports the regimen as a valuable treatment option. Nevertheless, for patients whose lymphoma has relapsed or resisted prior therapy in the central nervous system, a regimen delivering a 60.7 percent response rate with responses lasting a median of more than three and a half years represents a meaningful advance against one of the most difficult lymphoma subsets to treat.

Subject of Research: A phase II trial of orelabrutinib plus sintilimab in relapsed or refractory primary central nervous system lymphoma

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

Article References: Zhang, Y., Zhang, Y., Liu, H., Ma, J., Wei, C., Zhao, D., Ruan, J., Zhang, W., & Zhou, D. (2026). 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. https://doi.org/10.1186/s12885-026-17092-x

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17092-x

Keywords: orelabutinib, sintilimab, primary central nervous system lymphoma, BTK inhibitor, PD-1 inhibitor, relapsed refractory lymphoma, phase II trial, progression-free survival, duration of response, immunotherapy, blood-brain barrier, safety