Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: Efficacy and safety from the phase II PROSPECT study

Background: 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. Clinical trial information: NCT04947319. Research Sponsor: ONO Pharmaceutical Co., Ltd.