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

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.