TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of non-Hodgkin lymphoma localized to the brain, cerebrospinal fluid, or eyes. For patients with PCNSL, treatment options are limited, standard of care is not well established, and prognosis is poor, particularly in the relapsed or refractory (r/r) setting. Tirabrutinib, a highly potent selective second-generation Bruton’s tyrosine kinase inhibitor, is approved in Japan, Taiwan, and South Korea based on a phase I/II study that demonstrated clinical activity in Japanese patients with r/r PCNSL. There are no currently approved drug therapies for PCNSL in the US or Europe. Here we report results from the PROSPECT study (NCT04947319) conducted in the US.

Methods: In this open-label phase II study, patients with r/r PCNSL received oral tirabrutinib 480 mg as monotherapy once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by Independent Review Committee. Secondary endpoints included duration of response (DOR), time to response (TTR), best overall response (BOR), and safety. Overall survival (OS) and progression-free survival (PFS) were exploratory endpoints.

Results: Forty-eight patients were enrolled. Median age was 65.5 y (range, 34–87). With a median follow-up of 11.2 mo as of November 1, 2024 (data cut-off), ORR was 66.7% (n = 32), with a complete response rate (CRR), confirmed (CR) + unconfirmed (CRu), of 43.8% (n = 21) and a partial response rate of 22.9% (n = 11). Median DOR was 9.3 mo (range, 0.0–23.5), and median TTR was 0.95 mo (range, 0.9–3.7). Median OS was not reached (range, 1.0–33.0); median PFS was 6.0 mo (range, 0.0–26.0). Overall incidence of any-grade treatment-emergent adverse events (TEAEs) was 97.9% (n = 47) and grade ≥ 3 was 56.3% (n = 27). Any-grade treatment-related adverse events (TRAEs) were experienced by 75.0% (n = 36), most frequently anemia (18.8%), fatigue (14.6%), neutrophil count decreased (14.6%), pruritus (14.6%), rash (14.6%), and maculo-papular rash (14.6%). Grade ≥ 3 TRAEs were experienced by 27.1% (n = 13), most frequently neutrophil count decreased (8.3%) and rash maculo-papular (4.2%). Deaths related to TEAEs occurred in 2 (4.2%) patients: 1 patient died from seizure and pneumonia, and the other from a fall; these grade 5 TEAEs were considered unrelated to study treatment. At data cutoff, 27.1% (n = 13) of patients remain on tirabrutinib treatment. Main reasons for discontinuation were disease progression (54.2%, n = 26) and death (8.3%, n = 4), and 1 (2.1%) patient discontinued due to an AE; deaths included the 2 patients with grade 5 TEAEs.

Conclusions: With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treatment option for patients with r/r PCNSL.

Research funding declaration: ONO Pharmaceutical Co., Ltd.

Encore Abstract: ASCO 2025

Keyword: molecular targeted therapies

Potential sources of conflict of interest:

L. Nayak

Employment or leadership position: Dana Farber Cancer Institute

Consultant or advisory role: Ono, Kite/Gilead, Genmab, Curis, Miltenyi, BraveBio

Honoraria: Ono Pharmaceuticals

Other remuneration: Speakers Bureau—Ono, AstraZeneca; Research Funding—Ono, Merck, AstraZeneca, Kazia; Patents—Wolters Kluwer (UpToDate)

C. Grommes

Consultant or advisory role: Curis, Roche, BTG, Kyowa Kirin

Honoraria: Ono

Educational grants: Ono

Other remuneration: Speakers Bureau—Ono, Research Funding—Bayer, Ono, Pharmacyclics

A. Kallam

Other remuneration: Speakers Bureau—Genmab

D. Peereboom

Consultant or advisory role: Orbus Therapeutics, Novocure, SERVIER, Anheart Therapeutics, Neonc Technologies

Honoraria: Novocure, MJH Life Sciences

Educational grants: Novocure

Other remuneration: Research Funding—Pfizer, Novartis, Neonc Technologies, Orbus Therapeutics, Bristol-Myers Squibb, Genentech/Roche, Pharmacyclics, Bayer, Vigeo Therapeutics, MimiVax, Ono, Nuvation Bio, Curis

P. Ambady

Consultant or advisory role: Servier Pharma, Telix Pharma, Springworks

J. Mendez

Employment or leadership position: Summit Physician Specialists

Consultant or advisory role: Servier Pharmaceuticals

A. Sumrall

Consultant or advisory role: Bayer, SERVIER

Honoraria: Cardinal Health

Other remuneration: Research Funding—Chimerix, Ono, Merck

A. Omuro

Consultant or advisory role: Ono Pharma, Telix, Curevac, Nurix, Servier

Other remuneration: Research Funding—Arcus Biosciences

F. Iwamoto

Consultant or advisory role: Novocure, Regeneron, Tocagen, Alexion Pharmaceuticals, Abbvie, Guidepoint Global, Merck, Kiyatec, PPD, Massive Bio, Medtronic, MimiVax, Gennao Bio, Ono, Anheart, Praesidia Therapeutics, and Xcures

Honoraria: Ono

Educational grants: Ono, Roche

Other remuneration: Research Funding—Merck, Bristol Myers Squibb, Roche, Sapience, Novocure, Forma, Celldex, Northwest Biotherapeutics, ABM Therapeutics, Pfizer, Ono

J. Dietrich

Consultant or advisory role: Novartis, Amgen, Janssen, Johnson & Johnson, Ono Pharmaceuticals

Other remuneration: Patents, Royalties, IP—Wolters Kluwer

Y. Umemura

Consultant or advisory role: Servier

Other remuneration: Speakers Bureau—Servier; Research Funding—Servier, Chimerix, Ono Pharma

S. Prados

Employment or leadership position: Ono Pharma USA, Inc.

A. Takazawa

Employment or leadership position: ONO PHARMA USA, INC.

A. Aoi

Employment or leadership position: ONO PHARMA USA, INC.

T. Batchelor

Other remuneration: Research Funding—Ono Pharmaceutical (Institution)