Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial

Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL. This phase 2 study evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the US. In the open-label PROSPECT study, adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate-based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR), and secondary endpoints included complete response (CR) rate, duration of response (DOR), and time to response (TTR), as assessed by independent review committee. Safety was assessed by frequency and severity of treatment-emergent adverse events (TEAEs). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median DOR was 9.3 months (95% CI, 4.6-14.6), and median TTR was 1.0 month (range, 0.9-3.7). Treatment-related TEAEs occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment related. In patients with R/R PCNSL, once-daily oral tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04947319.

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Journal
Blood
Published
2026-10-01
DOI
https://doi.org/10.1182/blood.2026034926
Primary Topic
CNS Lymphoma Diagnosis and Treatment
Type
article
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article

Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial

Prakash Ambady, Christian Grommes, Neel K. Gupta, Joe Sammy Mendez et al.
Blood
CNS Lymphoma Diagnosis and Treatment
article

Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial

Prakash Ambady, Christian Grommes, Neel K. Gupta, Joe Sammy Mendez, Lauren R. Schaff, Lakshmi Nayak, Andrew Ip, Yoshie Umemura, Antonio M. P. Omuro, Akira Takazawa, Avyakta Kallam, Reinhold Munker, Jörg Dietrich, Ugonma Nnenna Chukwueke, Arata Aoi, Dawit Gebremichael Aregawi, Tracy T. Batchelor, Katherine B. Peters, David M. Peereboom, FABIO MASSAITI IWAMOTO, Ashley Love Sumrall, Jan Drappatz, Ryan T. Merrell, Ka-wai Grace Ho, Vyshak A Venur, Sergio Prados
article en

Abstract

Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL. This phase 2 study evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the US. In the open-label PROSPECT study, adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate-based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR), and secondary endpoints included complete response (CR) rate, duration of response (DOR), and time to response (TTR), as assessed by independent review committee. Safety was assessed by frequency and severity of treatment-emergent adverse events (TEAEs). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median DOR was 9.3 months (95% CI, 4.6-14.6), and median TTR was 1.0 month (range, 0.9-3.7). Treatment-related TEAEs occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment related. In patients with R/R PCNSL, once-daily oral tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04947319.

Blood
Brigham and Women's Hospital (US), City Of Hope National Medical Center (US), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Hackensack University Medical Center (US), Memorial Sloan Kettering Cancer Center (US), Harvard University (US), University of Kentucky (US), University of Washington (US), University of Michigan (US), Columbia University Irving Medical Center (US), Huntsman Cancer Institute (US), Markey Cancer Center (US), Yale University (US), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Levine Cancer Institute (US), City of Hope (US), Ono Pharmaceutical (Japan) (JP), Dana-Farber Cancer Institute (US), Duke Medical Center (US), Deciphera Pharmaceuticals (United States) (US), UPMC Hillman Cancer Center (US), University of Pittsburgh Medical Center (US), Penn State Cancer Institute (US), Vanderbilt University Medical Center (US), Stanford University (US)
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Openalex Percentile: Top 12%
CNS Lymphoma Diagnosis and Treatment
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