Final three-year follow-up analysis of phase I/II study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.

person Katsunori Asai Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan info_outline Katsunori Asai, Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, Yasuhito Terui, Yoshiki Arakawa, Hajime Yonezawa, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Arata Aoi, Ryo Nishikawa

Authors person Katsunori Asai Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan info_outline Katsunori Asai, Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, Yasuhito Terui, Yoshiki Arakawa, Hajime Yonezawa, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Arata Aoi, Ryo Nishikawa Organizations Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan, Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan, Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan, Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan, Department of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan, Department of Neurosurgery, Kagoshima University Hospital, Kagoshima, Japan, Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan, Department of Clinical Oncology & Neuro-oncology Program, Hiroshima University Hospital, Hiroshima, Japan, Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan, Department of Clinical Development, Ono Pharmaceutical Co., LTD., Osaka, Japan Abstract Disclosures Research Funding Pharmaceutical/Biotech Company ONO PHARMACEUTICAL CO., LTD Background: Primary central nervous system lymphoma (PCNSL) is known as an uncommon and extremely aggressive type of non-Hodgkin lymphoma of brain tumors. Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the treatment of relapsed or refractory PCNSL (rrPCNSL) based on the results of phase I/II study in Japan (Trial registration: JapicCTI-173646) in 2020. Methods: In this study, 44 Japanese patients with rrPCNSL received TIR QD at doses of 320 mg (n = 20), 480 mg (n = 7), or 480 mg while fasting (480 mg fasted: n = 17). The International PCNSL Collaborative Group criteria were used to assess the primary endpoint, which was the overall response rate (ORR). We previously reported the interim results with 14.9 (range:1.4–27.7) months of median follow-up in 2020 (Mishima et al., the 25th Society for Neuro-Oncology 2020). The final analysis results with a three-year follow-up are reported here (data cutoff: April 27 th , 2022). Results: For the entire population, the ORR was 63.6% with 36.4% of complete response, the median duration of response was 9.2 months, the median progression-free survival was 2.9 months, and the median overall survival was not reached (median follow-up: 37.1 months). The most frequent adverse events (AEs) were skin and subcutaneous tissue disorders and blood and lymphatic system disorders at any grade, including rash (36.4%) and neutropenia (27.3%), leukopenia (25.0%), lymphopenia (18.2%), and thrombocytopenia (11.4%). Grade ≥3 AEs were neutropenia (9.1%), leukopenia (9.1%), lymphopenia (6.8%), and erythema multiforme (6.8%). One patient with 480 mg had grade 5 AEs (Pneumocystis jirovecii pneumonia and Interstitial lung disease), while neither new grade 5 AEs nor new safety profiles were observed since the last data cutoff. As of the current data cutoff, 15 and 6 of 44 patients had been receiving TIR for more than one and three years, respectively, and 5 of the 6 patients continued receiving TIR, including 4 patients who were receiving 480 mg fasted. Conclusions: In conclusion, TIR showed long-lasting effectiveness in a subset of patients with a tolerable safety profile of rrPCNSL. Clinical trial information: JapicCTI-173646. All(N = 44) 320 mg QD(N = 20) 480 mg QD(N = 7) 480 mg fasted QD(N = 17) ORR (CR + CRu + PR), n (%) [95% CI] 28 (63.6)[47.8–77.6] 12 (60.0)[36.1–80.9] 7 (100.0)[59.0–100.0] 9 (52.9)[27.8–77.0] Complete response (CR + CRu), n (%)[95% CI] 16 (36.4)[22.4–52.2] 5 (25.0)[8.7–49.1] 4 (57.1)[18.4–90.1] 7 (41.2)[18.4–67.1] Median TTR, months[range] 0.9[0.3–1.3] 0.9[0.9–1.3] 0.9[0.3–1.0] 0.9[0.8–1.0] Median DOR, months[range] 9.2[0.6–45.9] 3.7[0.6–45.9] 10.2[0.6–28.8] 12.1[0.9–38.7] Median PFS, months[95% CI] 2.9[1.8–11.1] 2.1[1.8–18.2] 11.1[1.4–22.0] 5.8[1.0–13.0] Median OS, months[95% CI] Not reached[21.0–NE] 37.9[11.2–NE] Not reached[1.4–NE] Not reached[5.5–NE]