Dr Batchelor on the Rationale for Investigating Tirabrutinib in PCNSL

Tracy T. Batchelor, MD, MPH, co-leader, Neuro-Oncology Program, Dana-Farber Cancer Institute, Neurologist-in-Chief, Department of Neurology, Brigham and Women’s Hospital, Giovanni Armenise - Harvard Professor of Neurology, member, Center Scientific Council, Harvard Medical School, discusses the rationale for investigating tirabrutinib (Velexbru) for the treatment of patients with primary central nervous system lymphoma (PCNSL).

PCNSL is an uncommon B-cell malignancy characterized by high proliferation contained to the brain and cerebrospinal fluid. Most forms of PCNSL are diffuse large B-cell lymphoma, and thus involve frequent mutations in the B-cell receptor pathway, Batchelor begins. These mutations occur at different nodes and cause hyperactivation of the downstream target NFκB, thereby promoting B-cell proliferation, survival, and migration, he details. Utilizing and/or developing agents that target the B-cell receptor signaling axis could therefore interfere with this process and result in cytotoxicity of malignant B cells, Batchelor explains.

The second-generation BTK inhibitor tirabrutinib is one such option, Batchelor states. In March 2023, the FDA granted tirabrutinib orphan drug designation in PCSNL. Early case reports have shown that BTK inhibitors like ibrutinib (Imbruvica) are active and able to produce radiographic responses in PCNSL, Batchelor notes. Tirabrutinib has good CNS bioavailability and could provide more durable responses when utilized in the relapsed/refractory setting, he says.

Tirabrutinib also demonstrated early activity in patients with relapsed/refractory PCNSL in the large, phase 1/2 ONO-4059-02 trial (JapicCTI-173646). Long-term data from this trial demonstrated that patients who received the regimen had an overall response rate (ORR) of 63.6%, supporting its approval in Japan. Results from this trial also supported initiation of the phase 2 PROSPECT study (NCT04947319) of tirabrutinib plus a high-dose methotrexate, rituximab (Rituxan), and temozolomide in newly diagnosed PCNSL in the United States.