A novel combination therapy featuring the second-generation BTK inhibitor orelabrutinib has demonstrated promising efficacy in treating newly diagnosed primary central nervous system lymphoma (PCNSL), according to results from a prospective phase II trial published in Investigational New Drugs.
The study evaluated orelabrutinib combined with rituximab and high-dose methotrexate (ORM regimen) as induction therapy in 28 patients with newly diagnosed PCNSL. At the end of induction therapy, the overall response rate reached 71.4% (95% CI, 51.3–86.8), including 16 patients (57.1%) achieving complete responses and 4 patients (14.3%) achieving partial responses.
Treatment Protocol and Patient Population
Patients received six cycles of the ORM regimen consisting of 150 mg/day orelabrutinib, 375 mg/m² rituximab, and 3.5 g/m² methotrexate administered every three weeks. The treatment was followed by autologous hematopoietic stem cell transplantation and orelabrutinib maintenance therapy.
The study enrolled patients from October 21, 2020, to October 22, 2024, with all 28 participants evaluated for both efficacy and safety analyses. The primary endpoint was overall response rate at the end of induction therapy, while secondary endpoints included progression-free survival, overall survival, and safety assessments.
Survival Outcomes and Long-term Follow-up
At a median follow-up of 21.6 months, the median progression-free survival was 35.3 months (95% CI, 8.4–not evaluable), and median overall survival was not reached. The survival rates demonstrated sustained benefit, with progression-free survival rates of 64.3% at both 1 and 2 years, declining to 45.9% at 3 years. Overall survival rates remained robust at 96.3% at 1 year, 90.9% at 2 years, and 82.7% at 3 years.
Safety Profile and Tolerability
All 28 patients (100%) experienced treatment-related adverse events of any grade, though the safety profile remained manageable. Grade 3 treatment-related adverse events occurred in seven patients (25.0%), primarily consisting of five cases (17.9%) of leukopenia, one case (3.6%) of thrombocytopenia, and one case (3.6%) of diarrhea.
Notably, the study observed no Bruton's tyrosine kinase inhibitor-related off-target toxicities such as atrial fibrillation or flutter, and no treatment-related deaths occurred during the trial period.
Clinical Significance for PCNSL Treatment
Primary central nervous system lymphoma represents a particularly challenging malignancy due to limited treatment options and the blood-brain barrier's restriction of drug penetration. The current study addresses this unmet medical need by incorporating orelabrutinib, a second-generation BTK inhibitor with enhanced blood-brain barrier permeability compared to first-generation agents.
The researchers noted that orelabrutinib's cerebrospinal fluid concentration reaches 20.10 ± 14.70 ng/mL, substantially higher than ibrutinib's 0.77 ng/mL, potentially contributing to its enhanced therapeutic activity in central nervous system malignancies.
Broader Clinical Context
The trial was registered as NCT05600660 on ClinicalTrials.gov and represents part of ongoing research into BTK inhibitor applications in PCNSL. The study's authors concluded that "the ORM induction regimen showed anti-tumor activity with a favorable safety profile, offering a potential therapeutic strategy for newly diagnosed PCNSL."
These findings contribute to the evolving treatment landscape for PCNSL, where high-dose methotrexate has traditionally served as the cornerstone of therapy. The incorporation of targeted agents like orelabrutinib may offer improved outcomes while maintaining acceptable toxicity profiles for this challenging patient population.
