The FDA has accepted a new drug application (NDA) seeking the approval of the BTK inhibitor tirabrutinib (Velexbru) for the treatment of relapsed/refractory primary central nervous system lymphoma (PCNSL).1
The regulatory agency assigned a Prescription Drug User Fee Act target action date of December 18, 2026.
The NDA is based on data from the phase 2 PROSPECT study (NCT04947319) presented at the 2025 ASCO Annual Meeting, which demonstrated high overall response rates (ORR) and complete response (CR) rates, prolonged duration of response (DOR), and manageable safety with tirabrutinib monotherapy in patients with relapsed/refractory PCNSL.2,3
At a median follow-up of 11.5 months, patients treated with tirabrutinib (n = 48) achieved an ORR of 67% (95% CI, 52%-80%), including a 44% (95% CI, 29%-59%) CR 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 (NE; 95% CI, 0%-11%).3
“[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 Pharmaceuticals, said in a 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.”
Take-Home Points: Tirabrutinib in PCNSL
- At a median follow-up of 11.5 months, patients in the PROSPECT trial achieved an ORR of 67% (95% CI, 52%-80%), including a CR rate of 44% (95% CI, 29%-59%) with tirabrutinib monotherapy.
- The agent also produced a median PFS of 6 months (95% CI, 5.3-11.1), a 9.3-month DOR (95% CI, 4.6-14.6) and a median TTR of 1 month (range, 0.9-3.7 months).
- Falling, fatigue, anemia, lymphopenia, headache, and diarrhea were common TEAEs that occurred in at least 15% of patients treated with tirabrutinib.
What was the design of the PROSPECT trial?
The open-label study enrolled patients that were at least 18 years of age who had an ECOG performance status of 2 or less.3 Patients also needed to have a measurable brain lesion with a diameter larger than 1 cm. Relapsed or refractory disease status, prior receipt of one or more lines of HD-MTX-based therapy, and a life expectancy of 3 months or higher were also required for enrollment. Patients with intraocular PCNSL without a brain lesion, non-B cell PCNSL, a systemic presence of lymphoma or prior treatment with BTK inhibitors were not included in the trial.4
Eligible patients received 480 mg of tirabrutinib monotherapy daily until disease progression or unacceptable toxicity. 3
ORR per International PCNSL Collaborative Group (IPCG) criteria as assessed by independent review committee (IRC) was the primary end point of the trial. Secondary end points included DOR, time to response (TTR) and best overall response by IRC. PFS and overall survival (OS) were key exploratory end points.
The median age for all patients was 65.5 years (range, 34-87). Most patients were female (56%), had an ECOG performance status of 1 (63%), and had received 1 (63%) prior treatment for PCNSL. Additionally, patients had a median Karnofsky performance status of 85 (range, 50-100). All patients had received prior methotrexate treatments; other prior treatments included rituximab (Rituxan; 90%), cytarabine (52%), 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%).
What additional safety and efficacy data were reported from PROSPECT?
The median DOR with tirabrutinib was 9.3 months (95% CI, 4.6-14.6), and the median TTR was 1 month (range, 0.9-3.7 months). The median PFS was 6 months (95% CI, 5.3-11.1), whereas the median OS was not reached (95% CI, 12.5-NE).
Regarding safety, nearly all patients experienced any-grade treatment-emergent adverse effects (TEAEs; 98%), 56% of which were grade 3 or higher. Half of patients experienced any-grade TEAEs that led to dose interruption, 31% of which were grade 3 or higher. Thirty-three percent of any-grade TEAEs that led to dose interruption were treatment related, whereas 17% of grade 3 or higher TEAEs were treatment related. Any-grade TEAEs that led to dose reductions occurred in 10% of patients, 6% of which were treatment related. Serious any-grade TEAEs were experienced in 44% of patients; 35% were grade 3 or higher. Common TEAEs that occurred in at least 15% of patients included falling, fatigue, anemia, lymphopenia, headache, and diarrhea. Notably, cardiac events occurred in less than 10% of patients and were all grade 1/2 in severity.
What next steps are planned for tirabrutinib in R/R PCNSL?
Based on these findings, a global, randomized phase 3 trial (NCT07104032) evaluating tirabrutinib vs rituximab and temozolomide (Temodar) in relapsed/ refractory PCNSL is currently recruiting patients and will act as a confirmatory study for this indication.1,5
References
- 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. February 16, 2026. Accessed February 17, 2026. https://www.deciphera.com/news/deciphera-pharmaceuticals-announces-us-food-and-drug-administration-acceptance-filing-new-drug
- ONO PHARMA presents positive results from pivotal trial in U.S. patients with relapsed or refractory PCNSL at 2025 ASCO annual meeting. News Release. Deciphera. May 28, 2025. Accessed February 17, 2026. https://www.deciphera.com/news/ono-pharma-presents-positive-results-pivotal-trial-us-patients-relapsed-or-refractory-pcnsl-0
- 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
- Study of tirabrutinib (ONO-4059) in patients with primary central nervous system lymphoma (PROSPECT Study). ClinicalTrials.gov. Updated October 24, 2025. Accessed February 17, 2026. https://clinicaltrials.gov/study/NCT04947319
- Study of tirabrutinib vs rituximab/temozolomide for relapsed/refractory primary central nervous system lymphoma (PCNSL). Clinicaltrials.gov. Updated February 2, 2026. Accessed February 17, 2026. https://clinicaltrials.gov/study/NCT07104032
