FDA Accepts Tirabrutinib NDA for Relapsed/Refractory PCNSL, Sets December 2026 Action Date

The FDA has accepted a new drug application for tirabrutinib (Velexbru), a second generation Bruton tyrosine kinase inhibitor, for the treatment of patients with relapsed/refractory primary central nervous system lymphoma. The regulatory agency assigned a Prescription Drug User Fee Act target action date of December 18, 2026.

The application was submitted under the accelerated approval pathway and is supported by results from the phase 2 PROSPECT study (NCT04947319). The most recent readout from the trial was presented at the 2025 American Society for Clinical Oncology Annual Meeting.

At a median follow-up of 11.5 months, patients treated with tirabrutinib (n = 48) achieved an overall response rate of 67% (95% CI, 52%-80%), including a 44% (95% CI, 29%-59%) complete response rate. The incidence of partial responses, stable disease, and progressive disease was 23% (95% CI, 12%-37%), 19% (95% CI, 9%-33%), and 13% (95% CI, 5%-25%), respectively. One patient was not evaluable (95% CI, 0%-11%).

The median duration of response with tirabrutinib was 9.3 months (95% CI, 4.6-14.6), and the median time to response was 1 month (range, 0.9-3.7 months). The median progression-free survival was 6 months (95% CI, 5.3-11.1), whereas the median overall survival was not reached (95% CI, 12.5-NE).

Patients 18 years and older with relapsed/refractory PCNSL with a measurable brain lesion more than 1.0 cm in diameter, an ECOG performance status of 0 to 2, a life expectancy of at least 3 months, and prior treatment with at least 1 high-dose methotrexate were eligible for trial enrollment. Those on trial received 480 mg of tirabrutinib as a monotherapy once daily until end of treatment, disease progression, or unacceptable toxicity.

The median age on trial was 65.5 years (range, 34-87), and 44% of patients were male. Moreover, most patients had an ECOG performance score of 1 (63%), a median Karnofsky performance score of 85 (range, 50-100), and received prior rituximab (Rituxan; 90%) or cytarabine (52%). A total of 63% of patients received 1 prior line of treatment for PCNSL. All patients had received prior methotrexate treatments; other prior treatments included radiotherapy (33%) and hematopoietic stem cell transplants (10%). Slightly more patients had refractory disease (48%) at the time of their most recent treatment than relapsed disease (46%).

The primary end point of the trial was overall response rate per International PCNSL Collaborative Group criteria and assessed by independent review committee. Secondary end points included duration of response, time to response, best overall response, and safety, with overall survival and progression-free survival being exploratory end points.

Safety findings from the phase 2 study revealed that 98% of patients experienced at least 1 any-grade treatment-emergent adverse effect, including 56% experiencing grade 3 or higher events. Moreover, 75% and 27% of patients experienced any-grade or grade 3 or higher treatment-related adverse events. Serious treatment-emergent adverse effects occurred in 44% of patients, with 10% experiencing serious treatment-related adverse events.

The most common any-grade treatment-emergent adverse effects included falls, fatigue, anemia, lymphopenia, headache, and diarrhea. The most common grade 3 or higher treatment-emergent adverse effects included neutropenia, falls, confusional state, maculo-papular rash, anemia, and lymphopenia. Treatment-emergent adverse effects leading to dose interruption, reduction, or study withdrawal occurred in 50%, 10%, and 10% of patients.

Tirabrutinib was well-tolerated, with cardiac events occurring in less than 10% of patients, at no higher than grade 2 severity.

If approved, tirabrutinib would become the first Bruton tyrosine kinase inhibitor therapy commercially available in the United States for the treatment of patients with relapsed/refractory PCNSL.

Relapsed or refractory primary central nervous system lymphoma is a rare and aggressive form of non-Hodgkin lymphoma with limited treatment options. PCNSL is confined to the brain, spinal cord, eye or leptomeninges without systemic involvement. It is considered rare, with an annual incidence rate of approximately five cases per one million people in the United States. Rates can be higher among immunocompromised people aged 65 years and older. Despite improvements in outcomes for newly diagnosed patients after induction treatment, approximately 20% to 30% of patients are refractory to initial therapy and up to 60% eventually experience relapse.

A global phase 3 randomized trial is currently recruiting patients with relapsed/refractory PCNSL. This trial is intended to serve as a confirmatory study for the indication.

Tirabrutinib has already received regulatory approvals in other countries. In Japan, it was approved in March 2020 for the treatment of relapsed/refractory PCNSL and launched in May 2020 under the tradename Velexbru. It was subsequently approved in Japan in August 2020 for the treatment of Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma. Tirabrutinib was approved for relapsed/refractory PCNSL in South Korea in November 2021 and in Taiwan in February 2022.