FDA Accepts Tirabrutinib Application for Relapsed Primary CNS Lymphoma

The FDA accepted filing for a new drug application for tirabrutinib for the treatment of adults with relapsed or refractory primary central nervous system lymphoma (R/R PCNSL). The agency is reviewing the application under accelerated approval and has assigned a Prescription Drug User Fee Act target action date of December 18, 2026.

If approved in the U.S. for R/R PCNSL, tirabrutinib would become the first BTK inhibitor commercially available in the U.S. for this patient population and the third commercial therapy for the Ono group available in the country. Tirabrutinib, marketed internationally under the brand name Velexbru, was developed by Ono Pharmaceutical and is an oral Bruton's tyrosine kinase inhibitor used to treat specific blood cancers.

The NDA submission is supported by results from part A of the phase 2 PROSPECT trial, which evaluated tirabrutinib monotherapy in adult patients with R/R PCNSL. Forty-eight participants received tirabrutinib 480mg daily, until disease progression or clinically unacceptable toxicity. The primary endpoint was overall response rate.

Interim results, presented at the American Society for Clinical Oncology 2025 meeting, demonstrated that after a median follow-up of 11.5 months, the overall response rate was 67%, with a complete response rate of 44%. Furthermore, median duration of response was 9.3 months, and median time-to-response was 1 month.

Any-grade treatment-emergent adverse events were experienced by 75.0%; these included anemia (18.8%), rash maculo-papular (16.7%), fatigue (14.6%), decreased neutrophil count (14.6%), decreased lymphocyte count (14.6%), pruritus (14.6%), and rash (14.6%). Two patients died of treatment-emergent adverse events, but these were considered unrelated to study treatment.

R/R PCNSL is a rare and aggressive form of non-Hodgkin lymphoma that is around the brain, spinal cord, or eyes without systemic involvement. The disease has an annual incidence rate of about five cases per 1 million people in the U.S., and incidence increases among immunocompromised individuals aged 65 years and older.

Patients with PCNSL usually present symptoms that vary based on the location of the lesion in the central nervous system. These may include cranial neuropathy, neuropsychiatric symptoms, increased intracranial pressure, seizures, ocular symptoms, headache, dysmotility and radiculopathy.

Although there are advances in induction treatment for newly diagnosed patients, outcomes remain challenging. Roughly 20% to 30% of patients are refractory to initial treatment and up to 60% will eventually relapse, highlighting the high unmet need for additional therapies.

The application is being reviewed under the accelerated approval pathway, which allows earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint.

Tirabrutinib targets BTK, a key component in the B-cell receptor pathway, which helps control how B cells grow, activate and survive. It also plays a crucial role in several B-cell cancers, including PCNSL.

Tirabrutinib has already received approvals in countries outside the U.S., including Japan, which was approved in March 2020 for the treatment of R/R PCNSL and was launched under the tradename Velexbru in May 2020. It was later approved in Japan for Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma in August 2020. Tirabrutinib was also approved for R/R PCNSL in South Korea in November 2021 and in Taiwan in February 2022.