Abstract: Background: Bosutinib, a Src/Abl tyrosine kinase inhibitor, is approved at a starting dose of 500 mg once daily (QD) in many countries, including Japan, for patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) after prior therapy. The indication for bosutinib was expanded to patients with newly diagnosed CP CML, at a starting dose of 400 mg QD, in 2017 by the US Food and Drug Administration and in 2018 by the European Medicines Agency. Approval of first-line bosutinib for CP CML was based on data from the global phase 3 BFORE trial, which demonstrated a significantly higher major molecular response (MMR) rate at Month 12 with bosutinib vs imatinib in patients with Ph+ CP CML and e13a2/e14a2 transcripts (primary endpoint; 47.2% vs 36.9%; 2-sided P=0.02). We conducted a phase 2 study to evaluate the efficacy, safety, and pharmacokinetics (PK) of bosutinib in Japanese patients with newly diagnosed CP CML. Methods: In this open-label, single-arm study (NCT03128411), Japanese patients ≥20 years of age with a molecular diagnosis of CP CML within 6 months, Eastern Cooperative Oncology Group performance status 0 or 1, adequate renal and hepatic function, and no prior treatment for CML (hydroxyurea within 6 months permitted) received bosutinib at a starting dose of 400 mg QD. The primary endpoint was MMR at Month 12 in the modified as-treated population, which included patients who were Ph+ and had e13a2/e14a2 transcripts. A total of 60 patients was required in the modified as-treated population for the study to have 〉 82% power to reject the null hypothesis (25% MMR rate at Month 12) and accept the alternative hypothesis (40% MMR rate at Month 12) with a 1-sided ∝-level of 5%. Secondary endpoints included MMR and complete cytogenetic response (CCyR) by Month 12, event-free survival (EFS), overall survival, safety, and PK. Results: In all, 60 Japanese patients with CP CML were treated with bosutinib; all patients were Ph+ and had e13a2/e14a2 transcripts and were included in the modified as-treated population analyzed for efficacy. Median age was 55 years (range 20-83), 60.0% of patients were male, and 45.0%, 43.3%, and 11.7% had low-, intermediate-, and high-risk Sokal scores, respectively. Median duration of follow-up was 16.6 months (range 11.1-21.9), and median duration of bosutinib treatment was 15.3 months (range 0.3-21.9). After 12 months of follow-up, 42 (70.0%) patients remained on bosutinib; 17 (28.3%) discontinued due to adverse events (AEs) and 1 (1.7%) due to physician decision. Median dose intensity was 354.7 mg/day (range 95.3-494.1). The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval [CI] 44.4-65.6); the test of the null hypothesis was rejected (1-sided P 〈 0.0001), and the primary endpoint was met. The MMR rate by Month 12 was 61.7% (90% CI 51.3-72.0), and the CCyR rate by Month 12 was 80.0% (90% CI 71.5-88.5). Deep molecular responses (MR4/MR4.5) were achieved at Months 6, 9, and 12 (Figure). The cumulative incidence of EFS events at Month 12 was 1.7% (90% CI 0.2-6.4). There were no on-treatment transformations to AP/BP CML. No patient died on treatment or within 28 days of the last dose of bosutinib; 1 patient died beyond 28 days of the last dose due to disease progression. The most common treatment-emergent AEs (TEAEs) were diarrhea (86.7%), increased alanine aminotransferase (ALT; 55.0%) and increased aspartate aminotransferase (AST; 46.7%; Table). Grade 3/4 TEAEs reported in ≥10% of patients were increased ALT (33.3%), increased AST (18.3%), diarrhea (15.0%), increased lipase (15.0%), and neutropenia (11.7%). The incidence of cardiac, vascular, and hypertension TEAEs was low (5.0%, 1.7%, and 1.7%, respectively). The average bosutinib plasma trough concentration (mean ± standard deviation of concentrations on Days 28, 56, and 84) was 82.7 ± 48.0 ng/mL, ~1.12-fold higher than that observed in bosutinib-treated patients in the global BFORE trial. Conclusions: The primary objective of this phase 2 study was met, and the MMR rate at Month 12 in Japanese patients with newly diagnosed CP CML was similar to that reported in the bosutinib arm of the multinational BFORE trial. The safety profile of bosutinib was consistent with previous studies. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML. Disclosures Takahashi: Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Chug Pharmaceuticals: Research Funding; Pfizer: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Asahi Kasei Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Bristol-Myers Squibb: Speakers Bureau. Matsumura:Novartis: Speakers Bureau; Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Ishizawa:Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. ONO:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Kyowa Hakko Kirin: Research Funding; ONO Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria. Sekiguchi:Pfizer: Research Funding. Tanetsugu:Pfizer R & D Japan G.K.: Employment. Fukuhara:Pfizer R & D Japan G.K.: Employment. Ohkura:Pfizer R & D Japan G.K.: Employment. Koide:Pfizer R & D Japan G.K.: Employment. Hino:Alexion: Honoraria; Astellas Pharma Inc: Honoraria, Research Funding; Astellas Amgen BioPharma: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding; Daichi-Sankyo: Honoraria, Research Funding; Eisai: Research Funding; Janssen: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee, Research Funding; Mochica Pharmaceutical Co., Ltd: Honoraria; MSD: Honoraria, Research Funding; Mundipharma: Honoraria; Nihon Pharmaceutical Co., Ltd: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ono Pharmaceutical: Honoraria, Other: Consulting fee, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Pfizer Japan Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Shire Japan KK: Honoraria; Sumitomo Dainippon Parma: Honoraria, Research Funding; Taiho Pharama: Research Funding; Takeda Pharmaceutical Co., Ltd: Honoraria, Research Funding; Teijin: Research Funding; Abbott: Research Funding. OffLabel Disclosure: Bosutinib is approved for newly diagnosed patients with chronic phase chronic myeloid leukemia by the US Food and Drug Administration and by the European Medicines Agency, but it is not yet approved for this patient population in Japan, where this study takes place.

Abstract: Abstract 4484 Background: Dasatinib is a highly potent BCR-ABL kinase inhibitor. The previous report from the global DASISION trial showed dasatinib 100 mg once daily resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib; both treatment arms were well-tolerated (N Engl J Med. 2010;362:2260-70). The objective of this subset analysis was to assess the efficacy and safety of dasatinib compared with imatinib in the Japanese population. Methods: Forty-nine Japanese patients (total 519 pts) with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg QD or imatinib 400 mg QD. Confirmed CCyR (cCCyR; CCyR on 2 consecutive assessments at least 28 days apart) was the primary efficacy endpoint with MMR as an important secondary endpoint. The safety profiles were also evaluated. Results: Minimum follow-up time and median treatment duration were 12 months and 15 months, respectively. Twenty-six patients with median age 56 (range, 21–70) years were treated with dasatinib and 23 patients with median age 52 (range, 22–77) years were treated with imatinib. Overall 89% of patients receiving dasatinib and 83% of patients receiving imatinib continue to receive treatment. The cCCyR rate by 12 months (primary endpoint), CCyR rate by 12 months and MMR rate at any time in dasatinib arm were higher than those in imatinib for Japanese patients (96% vs 70%, 96% vs 78%, and 73% vs 48%, respectively). Grade 3/4 cytopenias in dasatinib arm and imatinib arm were as follows: anemia (8% vs 4%), neutropenia (27% vs 39%), and thrombocytopenia (8% vs 9%). Non-hematologic and drug-related adverse events occurring in ≥10% of patients are shown as Table. No deaths were reported in either group. Drug-related serious adverse events were rarely reported and all events were not severe (Grade 1–2, including vomiting, hypoxia and cardiomyopathy in dasatinib arm). Conclusion: Dasatinib showed higher rates of cCCyR and MMR compared with imatinib. Both treatments were well tolerated. Given the predictive value of 12 months cCCyR, dasatinib may improve long-term outcomes in Japanese patients with newly diagnosed CML-CP. Disclosures: Ueda: Bristol-Myers K.K.: Employment. Seriu:Bristol-Myers K.K.: Employment. Bradley-Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment.

Abstract: Bosutinib has been evaluated for treatment of chronic-phase chronic myeloid leukemia (CP-CML) in several clinical studies, including in Japan. This open-label, single-arm, phase 2 study evaluated the efficacy and safety of bosutinib at a starting dose of 400 mg once daily in Japanese patients ( n  = 60) with newly diagnosed CP-CML. The minimum follow-up period was 3 years and median duration of treatment was 35.9 months. At study completion, 60% of patients were still on treatment. Cumulative rates of major molecular response (MMR), molecular response 4 (MR 4 ), and MR 4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively. No patient who achieved MMR or MR 4 had a confirmed loss of response. No patient experienced on-treatment transformation to accelerated/blast phase or died within 28 days of the last bosutinib dose. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% (grade ≥ 3: 81.7%) of patients. The most common TEAEs were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). No new safety signals emerged during the follow-up period. Bosutinib continues to demonstrate a favorable benefit/risk profile and is an important treatment option for Japanese patients with newly diagnosed CP-CML. Optimal management of TEAEs during initial treatment with bosutinib should be prioritized. Trial Registration: ClinicalTrials.gov ID: NCT03128411.

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.