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Phase 2 Study of Tirabrutinib (ONO/GS-4059), a Second-Generation Bruton's Tyrosine Kinase Inhibitor, Monotherapy in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström Macroglobulinemia

2019; Elsevier BV; Volume: 134; Issue: Supplement_1 Linguagem: Inglês

10.1182/blood-2019-124614

1528-0020

Wataru Munakata, Naohiro Sekiguchi, Shinya Rai, Kenshi Suzuki, Hiroshi Handa, Hirohiko Shibayama, Tomoyuki Endo, Yasuhito Terui, Noriko Iwaki, Noriko Fukuhara, Hiro Tatetsu, Shinsuke Iida, Takayuki Ishikawa, Ryota Shiibashi, Koji Izutsu,

Renal Diseases and Glomerulopathies

BACKGROUND Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma in which bone marrow is infiltrated by immunoglobulin M (IgM)-producing clonal lymphoplasmacytic cells. Tirabrutinib (ONO/GS-4059) is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. We performed a prospective, multicenter phase 2 study of tirabrutinib in patients with treatment-naïve (TN) or relapsed/refractory (R/R) WM. METHODS Patients with TN or R/R WM, serum IgM ≥500 mg/dL, ECOG performance status ≥1, and normal end-organ function were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR, ≥ partial response [PR]) assessed by an independent review committee (IRC) according to the criteria of the VIth International Workshop on Waldenström Macroglobulinemia (IWWM) (Owen RG et al. Br J Haematol. 2013). Secondary endpoints included overall response rate (ORR, ≥ minor response [MR]), time to major response (TTMR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Twenty seven patients (18 TN and 9 R/R) were treated as of July 3, 2019, and the median follow-up duration was 6 months. The median age of patients was 71 years (range 50-83), and 20 patients (74.1%) had ECOG performance status 0. Median serum IgM was 3600 mg/dL (range 730-6930). Median number of prior therapies among R/R patients was 2 (range 1-7), and 8 patients had received prior rituximab monotherapy or rituximab-containing chemotherapy. IRC-assessed MRR was 77.8% (95%CI: 52.4-93.6) in TN and 88.9% (95%CI: 51.8-99.7) in R/R. IRC-assessed ORR was 94.4% (95%CI: 72.7-99.9) in TN and 100% (95%CI: 66.4-100.0) in R/R. Median TTMR was 1.9 months (range 1.0-5.7) in TN and 2.1 months (range 1.0-3.7) in R/R. Median DOR, PFS, and OS were not reached. The most common adverse events (AEs) at any grade were rash (41%), neutropenia (22%), and leukopenia (15%), of which most were grade 1 or 2. Grade ≥3 AEs were neutropenia (7.4%), leukopenia, lymphopenia, atypical mycobacterial infection, rash erythematous, and erythema multiforme (3.7% each); there was no grade 4 or 5 AE. There were 4 bleeding events and all events were grade 1: mouth hemorrhage, petechiae, anal hemorrhage, and hematoma (3.7% each). Rash-related events occurred in 56% of patients and 2 events were grade 3: erythema multiforme and rash erythematous (3.7% each) which were manageable. CONCLUSION Although the follow-up time was relatively short, the results of this phase 2 study showed that tirabrutinib monotherapy is a highly effective treatment option for patients with TN and R/R WM, with a manageable safety profile. Disclosures Munakata: Ono: Research Funding. Sekiguchi:Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme. Otsuka, Pfizer, PPD SNBL, Sumitomo Dainippon Pharma, Daiichi Sankyo Company, Bristol-Myers Squibb: Research Funding. Shinya:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Handa:Ono: Research Funding. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Endo:Ono: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Iwaki:Ono: Research Funding. Fukuhara:AbbVie: Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinkyaku: Honoraria; Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; Gilead: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Bayer: Research Funding; Solasia Pharma: Research Funding. Tatetsu:Ono: Research Funding. Iida:Astellas: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Teijin Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Research Funding. Shiibashi:Ono: Employment. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Celgene: Consultancy; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for WM/LPL.