Efficacy and Safety of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: Final 3-Year Results of a Phase 2 Study
Authors: Ono Takaaki , Hino Masayuki , Matsumura Itaru , Fujisawa Shin , Ishizawa Kenichi , Sakaida Emiko , Sekiguchi Naohiro , Ono Chiho , Aizawa Mana , Tanetsugu Yusuke , Koide Yuichiro , Takahashi Naoto 
Published: November 2021

Abstract
Introduction : Bosutinib is approved in Japan for patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and Ph+ CML resistant/intolerant to prior therapy. In the primary report of a phase 2 study of first-line bosutinib in Japanese patients with CP CML (NCT03128411), the major molecular response (MMR) rate at 12 months was 55.0% and adverse events (AEs) were manageable and consistent with the known safety profile of bosutinib. Here we report the final 3-year efficacy and safety results of this phase 2 study.
Methods : Japanese patients with newly diagnosed CP CML received bosutinib 400 mg once daily (QD). Dose escalation to a maximum of bosutinib 600 mg QD was permitted for unsatisfactory response. The bosutinib dose could be reduced to 300 mg QD for toxicity; following sponsor approval, dose reduction to bosutinib 200 mg QD was permitted for 4 weeks maximum. Long-term secondary endpoints of the study included duration of response, event-free survival, and overall survival (OS). This final analysis was based on ≥3 years of follow-up.
Results: A total of 60 patients were treated with bosutinib. Median age was 55 years (range 20-83), 60.0% of patients were male, and 46.7%, 41.7%, and 11.7% had low-, intermediate-, and high-risk Sokal scores, respectively. Median duration of follow-up was 39.2 months (range 13.2-45.1), and median duration of treatment was 35.9 months (range 0.3-44.2). At study completion, 36 (60.0%) patients were still on treatment. The most common reason for treatment discontinuation was AEs (35.0%). Median dose intensity was 357.4 mg/day (range 95.3-548.1), with 400 mg QD being the most commonly utilized dose (&gt;50% of ongoing patients across the treatment period). Dose reductions or interruptions due to AEs occurred in 36 (60.0%) and 50 (83.3%) patients, respectively; dose escalations due to insufficient response occurred in 10 (16.7%) patients.
Cumulative rates of MMR, MR 4, and MR 4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively (Table 1). Among patients who achieved MMR or MR 4, none had a confirmed loss of response. Cumulative rates of MMR at any time in patients with low-, intermediate-, and high-risk Sokal scores were 57.1%, 88.0%, and 57.1%, respectively. In patients with dose reductions to 300 (n=36) and 200 (n=9) mg QD, 63.9% (n=23) and 33.3% (n=3) newly achieved MMR or maintained a previously attained MMR after dose reduction. No patient progressed to accelerated/blast phase while on treatment. The cumulative incidence of progression or death adjusting for competing risk of treatment discontinuation at 3 years (90% CI) was 1.7% (0.2-6.4). Two (3.3%) patients died on study, 1 due to disease progression and 1 due to an AE considered unrelated to treatment. The 3-year Kaplan-Meier OS estimate (90% CI) was 96.7% (89.7-98.9). No evaluable patient had an emergent mutation while on treatment or at treatment completion.
Any grade treatment-emergent AEs (TEAEs) occurred in 100% of patients and grade ≥3 TEAEs in 81.7% of patients. The most common TEAEs are shown in Table 2. There were no deaths on treatment. The most common (≥10%) TEAEs leading to dose reduction were alanine aminotransferase (ALT) increased (21.7%) and aspartate aminotransferase (AST) increased (13.3%), and the most common (≥10%) TEAEs leading to dose interruption were ALT increased (28.3%), AST increased (16.7%), diarrhea (11.7%), and liver disorder (10.0%). TEAEs leading to treatment discontinuation in ≥2% of patients were ALT increased (10.0%), AST increased (8.3%), lipase increased (3.3%), drug eruption (3.3%), and erythema multiforme (3.3%).
Conclusions: After ≥3 years of follow-up, bosutinib continued to show clinical benefit, with approximately half of patients achieving deep molecular responses. The overall efficacy results were consistent with the global BFORE trial of first-line bosutinib. No new safety signals emerged with this longer follow-up. Bosutinib continues to demonstrate a favorable risk/benefit profile and is an important treatment option in Japanese patients with newly diagnosed CP CML.
Figure 1 Figure 1.

Disclosures
Ono: Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Hino: TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Abbott: Research Funding; Asahi Kasei Corporation:: Research Funding; ARKRAY: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb　Comapany: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; CSL Behring: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding. Matsumura: MSD: Research Funding; Nippon Shinyaku: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Addvie: Research Funding; Eli Lilly Japan: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Speakers Bureau; Asahi Kasei: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Ishizawa: Otsuka: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Research Funding; SymBio: Honoraria, Research Funding; Kyowa Kirin: Consultancy; Pfizer: Research Funding; Bristol Myers Squibb: Speakers Bureau; IQVIA: Research Funding; Eisai: Honoraria; Chugai: Honoraria; Ono: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bayer: Research Funding; AbbVie: Research Funding. Sakaida: Kyowa Kirin: Research Funding; Ono: Research Funding; Chugai: Research Funding; Bristol Myers Squibb: Research Funding. Sekiguchi: Ono: Research Funding; A2 Healthcare: Research Funding; Astellas: Research Funding; Janssen: Research Funding; Merck Sharp & Dohme: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; PPD-SNBL: Research Funding; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding; Bristol Myers Squibb: Research Funding. Ono: Pfizer: Current Employment, Current equity holder in publicly-traded company. Aizawa: Pfizer: Current Employment. Tanetsugu: Pfizer: Current Employment. Koide: Pfizer: Current Employment. Takahashi: Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ono: Research Funding; Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding.