Tirabrutinib NDA Cleared by the FDA in Relapsed/Refractory PCNSL

The FDA has accepted a new drug application (NDA) for tirabrutinib (Velexbru), a second generation Bruton tyrosine kinase inhibitor, for the treatment of patients with relapsed/refractory central nervous system lymphoma (PCNSL), according to a news release from the developer, Deciphera Pharmaceuticals.¹

Supporting the regulatory decision are findings from the phase 2 PROSPECT study (NCT07104032), the most recent readout having been given at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.² Efficacy findings from the trial revealed an objective response rate (ORR) of 67% (95% CI, 52%-80%), with a complete response (CR) rate of 44% (95% CI, 29%-59%) among 48 patients treated with the agent. Moreover, the median progression-free survival (PFS) per independent review committee was 6.0 months (95% CI, 5.3-11.1) and the median overall survival (OS) was not reached (NR; 95% CI, 12.5-not available [NA]).

Based on these findings and a manageable safety profile, the FDA has set a Prescription Drug User Fee Act (PDUFA) date of December 18, 2026.

“[Relapsed/refractory] PCNSL is a rare and aggressive form of non-Hodgkin lymphoma with particularly poor clinical outcomes. Patients often experience difficulty and delay in diagnosis, and once they are diagnosed, there is a high unmet need for a treatment with a favorable safety profile,” Matthew L. Sherman, MD, chief medical officer of Deciphera, stated in the news release.¹ “The FDA’s acceptance of tirabrutinib’s NDA for filing is an exciting milestone as it brings us one step closer to our goal of providing patients with [relapsed/refractory] PCNSL an important new treatment option.”

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.

The primary end point of the trial was ORR per International PCNSL Collaborative Group (IPCG) criteria and assessed by IRC. Secondary end points included duration of response, time to response, best overall response, and safety, with OS and PFS 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 (TEAE), including 56% experiencing grade 3 or higher events. Moreover, 75% and 27% of patients experienced any-grade or grade 3 or higher treatment-related AEs (TRAEs). Serious TEAEs occurred in 44% of patients, with 10% experiencing serious treatment-related TEAEs.

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

The investigators noted that tirabrutinib was well-tolerated, with cardiac events occurring in less than 10% of patients, at no higher than grade 2 severity.

“We are very pleased that the NDA for tirabrutinib has been accepted for filing,” Toichi Takino, president and chief operating officer of Ono Pharmaceutical Co., Ltd, said in the news release.¹ “Tirabrutinib’s potential to address unmet patient needs embodies our corporate philosophy and we will continue to focus on developing and delivering innovative medicines to benefit patients worldwide.”

References

1. Deciphera Pharmaceuticals announces U.S. Food and Drug Administration acceptance for filing of new drug application for tirabrutinib in patients with relapsed or refractory PCNSL. News release. Deciphera Pharmaceuticals. February 17, 2026. Accessed February 18, 2026. https://tinyurl.com/327tx4bm
2. Nayak L, Grommes C, Kallam A, et al. Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: efficacy and safety from the phase II PROSPECT study. J Clin Oncol. 2025;43(suppl 16):2019. doi:10.1200/JCO.2025.43.16_suppl.2019