Velexbru (Japan) (tirabrutinib)

No drug is specifically approved in the United States for primary CNS lymphoma. First treatment is high-dose methotrexate with rituximab and other chemotherapy, often followed by a stem cell transplant, and when the disease comes back doctors use ibrutinib, lenalidomide with rituximab, nivolumab or further chemotherapy off label. Tirabrutinib would be the first BTK inhibitor with a US approval in this setting. Tirabrutinib and ibrutinib have not been compared directly, and the accelerated approval would depend on the ongoing Phase 3 trial confirming benefit.

Almost all primary CNS lymphomas are diffuse large B-cell lymphomas that keep themselves alive through a growth signal called the B-cell receptor pathway, often because of changes in the genes MYD88 and CD79B. That pathway runs through an enzyme called Bruton tyrosine kinase, or BTK. Tirabrutinib locks onto BTK permanently and switches the signal off, so the lymphoma cells stop dividing and die. It is a second-generation BTK inhibitor, designed to be more selective for BTK than the first drug in the class, ibrutinib, which can mean fewer off-target effects. Because it is a small molecule taken by mouth, it crosses into the brain, which is essential for a cancer confined to the central nervous system.

In PROSPECT, 56.3% of the 48 patients had a grade 3 or higher treatment-emergent adverse event, and 75.0% had an adverse event of any grade that was considered related to the drug. The most frequent drug-related events were anemia (18.8%), a measles-like rash (16.7%), fatigue (14.6%), low neutrophil counts (14.6%), low lymphocyte counts (14.6%), itching (14.6%) and other rash (14.6%). Two patients died of adverse events judged unrelated to the drug, and 1 patient stopped treatment because of an adverse event. There is no US label yet; approved BTK inhibitors as a class carry warnings about bleeding, infections, low blood counts, heart rhythm problems and second cancers.

PROSPECT (NCT04947319) is a Phase 2 study with 2 parts. Part A enrolled 48 US patients with relapsed or refractory primary CNS lymphoma who took tirabrutinib alone. After a median follow-up of 11.5 months, the overall response rate was 67% and the complete response rate 44%; the median time to response was 1.0 month, the median duration of response 9.3 months, and the median progression-free survival 6.0 months, with median overall survival not reached. Part B is testing tirabrutinib at 320 mg or 480 mg combined with standard methotrexate-based chemotherapy in newly diagnosed patients. A global Phase 3 confirmatory trial in relapsed or refractory disease (NCT07104032) is recruiting.

Tirabrutinib was discovered by Ono Pharmaceutical in Japan. Japan approved it for relapsed or refractory primary CNS lymphoma in March 2020, where it launched as Velexbru in May 2020, and added Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma in August 2020; South Korea approved it for PCNSL in November 2021 and Taiwan in February 2022. The FDA granted Orphan Drug designation in March 2023. Ono presented the PROSPECT results in May 2025 and folded its US operations into Deciphera Pharmaceuticals, which it had acquired, in July 2025. The FDA accepted the new drug application under the accelerated approval pathway with a target action date of December 18, 2026. In June 2026 Ono filed in Japan to extend the drug to central nervous system involvement of other lymphomas.