Post-Hoc Analysis of the Final, Three-Year Follow-up Results of a Phase I/II Study on Tirabrutinib (ONO-4059) in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma
Authors: Fukuhara Noriko , Narita Yoshitaka , Nagane Motoo , Mishima Kazuhiko , Terui Yasuhito , Arakawa Yoshiki , Yonezawa Hajime , Asai Katsunori , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo 
Published: December 2023

[Background]
Tirabrutinib (TIR; ONO-4059) is a second-generation inhibitor of Bruton's tyrosine kinase with high kinase selectivity. Based on the results of study ONO-4059-02 in patients with relapsed or refractory (r/r) primary central nervous system lymphoma (PCNSL) (Phase I/II study, jRCT: 2080223590), TIR was approved in Japan, Korea, and Taiwan. We have reported the results of 3-year follow-up (median follow-up: 37.1 months) of study ONO-4059-02, in which the overall response rate (ORR), the primary endpoint, was 63.6% and median duration of response was 9.2 months. The 3-year PFS and OS rates were 13.9% and 56.7%, respectively (Asai et al. ASCO 2023, Abstract 7548). Several clinical questions still remained to be addressed, including the proportion of patients who received subsequent treatment after discontinuation of TIR, and their treatment types; the characteristics of patients with higher efficacy of TIR; and the impact of long-term TIR treatment on Karnofsky Performance Status (KPS) and the Quality of Life (QoL). Here, we report the results of post-hoc analyses of the 37-month follow-up data of study ONO-4059-02.
[Methods]
In study ONO-4059-02, 44 patients with r/r PCNSL, age ≥20, and KPS≥70 were treated with TIR once daily at doses of 320 mg (n=20), 480 mg (n=7), or 480 mg (n=17) under a fasted condition. TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. We assessed the number of patients who received subsequent treatment after discontinuation of TIR and their treatment types. ORR was assessed in patient subgroups according to their characteristics. In addition, patient characteristics associated with 12-month PFS rates were identified using univariate/multivariate logistic regression analysis. The time course of KPS and QoL during the TIR treatment was also assessed. QoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions.
[Results]
Of the 44 patients, 6 patients were treated for 3 years. At the time of last visit, 2 patients (4.5%) continued the TIR treatment, 10 (22.7%) discontinued the TIR treatment but had not received subsequent treatment, and 32 (72.7%) received subsequent treatment after discontinuation of TIR. The subsequent treatments included systemic therapy, radiotherapy, hematopoietic stem cell transplantation, and surgery. Major subsequent treatments were MTX-based therapy (n=18) and radiotherapy (n=10) with the 3-year OS rate of 61.1% and 40.0%, respectively.
The subgroup analyses of ORR by patient characteristics showed that response to TIR was observed in all patient subgroups; ORR was low in those refractory to the treatment just before TIR (33.3%), those receiving ≥ 4 previous treatments (33.3%), those receiving hematopoietic stem cell transplantation (28.6%), those with high tumor burden (42.9%), and those having mutations in CD79B and MYD88 (40.0%). The univariate/multivariate analyses for the 12-month PFS rate identified that baseline KPS 90-100 was significantly associated with long-term response (odds ratio 5.99, P=0.0289). The median baseline KPS was 80.0 (range: 70~100) and was maintained during the TIR treatment (max: 49 cycles). QoL scores were generally maintained.
[Conclusion]
The majority of patients were able to receive subsequent treatment, including MTX, after TIR. TIR responses were observed in all patient subpopulations, and the baseline KPS was suggested to be associated with long-term response. KPS and QoL were generally maintained during the long-term observation period.