Interim Analysis Data from Multi-Center Retrospective Observational Study of Effectiveness, Safety, and Treatment Status of Tirabrutinib in 161 Japanese Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma: Rosetta Study

Background: Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive B-cell lymphoma that develops in the brain. Recently, chemotherapy, particularly high-dose (HD) methotrexate (MTX)-based therapy followed by consolidation therapy with either whole brain radiation therapy (WBRT) or autologous stem cell transplantation (ASCT), has been chosen as first-line treatment. However, treatment outcomes remain poor, with almost 50% of patients experiencing relapse after HD-MTX-based chemotherapy and an effective standard treatment for PCNSL recurrence has yet to be established. Bruton’s tyrosine kinase (BTK) is a key kinase of the B cell signaling pathway and BTK inhibitors are promising candidates for PCNSL treatment apart from MTX. Tirabrutinib (TIR), a second-generation oral Bruton's tyrosine kinase inhibitor, was approved in 2020 based on the results of a Japanese phase I/II study (jRCT2080223590) for relapsed or refractory PCNSL (r/r PCNSL). Because, only 44 patients were enrolled, investigation of treatment results of TIR in a larger cohort is warranted. Therefore, we conducted a retrospective cohort study to evaluate the treatment patterns, effectiveness and safety of TIR monotherapy in a real-world setting in Japan (The ROSETTA study [jRCT1021230006]). Here we report the 17-month follow-up results of this study.

Methods: ROSETTA is multi-center retrospective cohort study. The information was collected from patients’ medical charts through November 1, 2020 to April 30, 2023. The study outcomes were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). ORR was assessed by local investigators. TRAEs were coded according to MedDRA version 25.1.

Results: One hundred sixty-one patients with r/r PCNSL from 51 centers in Japan were enrolled in this study. The median follow-up period was 17.2 (range, 0.9-29.8) months. The median age was 71.0 years (range, 38–89), 93 (57.8%) patients were male, and the median Karnofsky performance status was 70 (range, 20-100). Twelve (7.5%) had intraocular disease and 3 (1.9%) had other diseases apart from CNS and intraocular disorders. The histological types were DLBCL in 112 patients (69.6%), other B-cell lymphoma in 20 patients (12.4%), with no cases of T-cell lymphoma, and unknown type in 29 patients (18.0%). The median number of prior therapies was 1.0 (range, 1-6). One hundred fifty-four (95.7 %) patients had received HD-MTX-based therapy, and 55 (34.2%) and 7 (4.3%) of the patients had received WBRT and ASCT, respectively. The median duration of treatment was 256.0 (range, 4–893) days. Major reasons for treatment discontinuation were disease progression, including death (56 patients; 34.8%), and AEs (32 patients; 19.9%). The ORR and complete response/unconfirmed complete response (CR/CRu) rates were 77.4% and 55.5%, respectively. The median DOR was 12.5 (95% confidence interval [CI], 7.9–18.2) months. The median PFS was 11.8 (95% CI, 8.4–18.2) months, and the 1-year PFS rate was 49.5%. The median OS was not reached (95% CI, 27.6–not reached), and the 1-year OS rate was 76.9%.
TRAEs of any grade were observed in 92 (57.1%) patients, and TRAEs of grade ≥ 3 were observed in 40 (24.8%) patients. The most common TRAEs were rash (n=16, 9.9%), neutrophil count decreased (n=14, 8.7%), and lymphocyte count decreased (n=13, 8.1%). No Grade 5 AEs were observed in this study.

Conclusion: These data demonstrate the effectiveness and safety of tirabrutinib in a large number of patients in clinical practice, and the findings are consistent with previous reports. These data indicate that tirabrutinib is a promising treatment option for r/r PCNSL.