Abstract: Introduction: BOS is approved for patients (pts) with Philadelphia chromosome-positive (Ph+) CML resistant/intolerant to prior therapy and pts with newly diagnosed Ph+ CP CML. Approval of first-line BOS was based on the primary results from the phase 3 BFORE trial, which showed superior efficacy vs imatinib (IMA) in the modified intent-to-treat (ITT) population (pop; Ph+ with e13a2/e14a2 transcripts) after ≥12 mo of follow-up. We report the final efficacy and safety results from the BFORE trial after 5 y of follow-up. Methods: In the open-label BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive BOS (n=268) or IMA (n=268; 3 untreated), both at 400 mg once daily. Efficacy was assessed in the ITT pop (all randomized pts). Long-term secondary endpoints included duration of response (DOR), on-treatment event-free survival (EFS) and overall survival (OS). Safety was assessed in the safety pop (all treated pts). This final analysis was based on an April 17, 2020 last pt last visit (June 12, 2020 database lock), 5 y (240 weeks) after the last enrolled pt. Results: At study completion in BOS and IMA arms, respectively, 59.7% and 57.4% were still on treatment, 86.6% and 86.2% completed 5 y on study. Median duration of treatment and time on study was 55.2 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 394 (39-583) vs 400 (189-765) mg/d. Cumulative major molecular response (MMR) rate by 60 mo was higher with BOS vs IMA (73.9% vs 64.6%), as was cumulative molecular response (MR)4 (58.2% vs 48.1%) and MR4.5 rate (47.4% vs 36.6%; Table). Among evaluable pts, more pts in the BOS arm achieved BCR-ABL1 ≤10% at 3 months (Table); cumulative MMR by 60 mo was higher in pts with transcripts ≤10% vs & gt;10% in both treatment arms (BOS, HR 2.67 [95% CI, 1.90-3.75]; IMA, HR 3.12 [2.19-4.45] ). Pts in the BOS arm achieved responses earlier than pts in the IMA arm; cumulative incidence function for MMR, MR4 and MR4.5 was higher with BOS vs IMA (HR [95% CI]: MMR 1.34 [1.10-1.64] , MR4 1.34 [1.07-1.69], MR4.5 1.41 [1.09-1.83] ). Among responders, duration of MMR was similar for BOS and IMA (Table). Superior MRs with BOS vs IMA were consistent across Sokal risk groups, with the greatest difference seen in pts with high Sokal risk (Table). On-treatment transformations to accelerated/blast phase (AP/BP) occurred in 6 (AP 3; BP 3) BOS- and 7 (AP 6; BP 1) IMA-treated pts. No transformation occurred after the 24-mo follow-up. In all, 18 BOS- vs 25 IMA-treated pts had EFS events. There were no differences in EFS between treatment arms; cumulative incidence of on treatment progression/death at 60 mo was 6.7% for BOS vs 9.3% for IMA (Table). The 60-mo OS rates were similar (94.5% and 94.6%; Table); 14 BOS- and 14 IMA-treated pts died during the study period: 3 and 4 were CML-related, 0 and 1 were due to adverse events (AEs) related to study treatment. The most common reasons for permanent discontinuation were AEs (25.0% vs 12.5%) and lack of efficacy (4.9% vs 16.2%). Treatment-emergent AEs (TEAEs) occurred in 98.9% of pts in each arm; most common ( & gt;30%) were diarrhea (75.0%), nausea (37.3%), thrombocytopenia (35.8%) and increased alanine aminotransferase (ALT; 33.6%) with BOS, and diarrhea (40.4%), nausea (42.3%) and muscle spasms (30.6%) with IMA. Most TEAEs occurred during the first year of treatment. Grade 3/4 TEAEs occurred in 73.5% of BOS- vs 57.0% of IMA-treated pts; most common ( & gt;5%) were increased ALT (20.9%) and lipase (13.4%), thrombocytopenia (14.2%), increased aspartate aminotransferase (10.4%), diarrhea (9.0%) and neutropenia (7.5%) with BOS, and neutropenia (13.6%), thrombocytopenia (6.0%), anemia (5.7%) and increased lipase (5.7%) with IMA. No individual AE led to discontinuation in & gt;5% of pts. The most frequent AEs leading to permanent treatment discontinuation were increased ALT (4.9%) with BOS vs thrombocytopenia (1.5%) with IMA; 1.5% vs 1.1% of pts discontinued due to diarrhea. Conclusions: At 5 y, first-line BOS continued to show superior efficacy vs IMA; BOS-treated pts achieved earlier and deeper molecular response. An improvement in MR with BOS was demonstrated across Sokal risk groups, with the greatest benefit vs IMA observed in Sokal high-risk pts. Long-term AEs were generally manageable, and consistent with previous reports and the known safety profiles of both drugs. These results confirm the use of BOS as a standard of care in pts with newly diagnosed CP CML. Disclosures Brümmendorf: Takeda: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Merck: Consultancy; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding. Cortes:Astellas: Research Funding; Arog: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Immunogen: Research Funding; Telios: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis: Consultancy, Research Funding. Milojkovic:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Clark:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Ariad/Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria. Kota:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria. Lipton:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Rousselot:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Mauro:Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:MSD: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hurtado Monroy:Incyte: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Yver:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Deininger:Gilead Sciences: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Other; SPARC: Research Funding; DisperSol: Consultancy; Pfizer: Honoraria, Other, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galena: Consultancy, Honoraria, Other.

Abstract: Background: Bosutinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. The efficacy and safety of bosutinib by baseline comorbidities in patients with CML resistant/intolerant to prior TKIs were investigated. Methods: The phase 4 BYOND trial (NCT02228382) is further examining efficacy and safety of bosutinib (starting dose 500 mg/day) in patients with CML resistant/intolerant to prior TKIs. Comorbidities were analyzed using the Charlson Comorbidity Index (CCI), a validated measure of the influence of relevant comorbid conditions on mortality. Scores were derived from baseline data and patients grouped by CCI score 2-3, 4-5, and ≥6. This analysis was based on ≥1 year of follow-up and included patients with Ph+ CP CML. Results: 156 patients with Ph+ CP CML (n=42 [26.9%], 48 [30.8%] , and 66 [42.3%] for CCI 2-3, 4-5, and ≥6) received bosutinib. Median treatment duration was 28.9, 23.9, and 20.1 months for CCI 2-3, 4-5, and ≥6; median dose intensity was 366.7, 385.3, and 291.5 mg/day. Across CCI groups, a substantial proportion of patients attained/maintained cytogenetic and molecular responses (Table). Grade 3/4 treatment-emergent adverse events (TEAEs) rates were 64.3%, 72.9%, and 80.3% for CCI 2-3, 4-5, and ≥6. Emerging grade 3/4 TEAEs differed between groups; diarrhea and increased alanine aminotransferase (ALT) were more common for CCI 2-3 (21.4% and 23.8%, respectively) and 4-5 (18.8% and 16.7%) and pleural effusion more common for CCI ≥6 (12.1%). For CCI 2-3, 4-5, and ≥6, 19.0%, 20.8%, and 31.8% of patients discontinued treatment due to AEs and 2.4%, 2.1%, and 9.1% due to insufficient response. Most common AEs leading to discontinuation in the respective groups were increased ALT and aspartate aminotransferase (7.1% each), increased ALT (8.3%), and pleural effusion (3.0%). 10 deaths occurred (n=0 [0%] , 1 [2.1%], and 9 [13.6%] for CCI 2-3, 4-5, and ≥6), 8 due to AEs (none bosutinib-related), 1 CML-related, and 1 of unknown cause. No on-treatment transformations to advanced CML occurred. Conclusions: Across CCI groups, a majority of patients with Ph+ CP CML achieved/maintained cytogenetic and molecular responses, and only 1 CML-related death was reported. Patients with CCI ≥6 showed a trend toward higher rates of TEAEs, discontinuations due to AEs, and death. Results demonstrate efficacy of bosutinib across CCI scores, including patients with important comorbidities. However, CCI stratification may enable identification of patients at higher risk of developing TEAEs who require more careful monitoring. Disclosures Gambacorti-Passerini: Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Gjertsen:Astellas: Consultancy; The Norwegian Cancer Society: Research Funding; BerGenBio: Consultancy; ERA PerMed: Research Funding; ACTII AS: Equity Ownership; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy; Haukeland University Hospital / University of Bergen: Employment; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding; EU Horizon 2020: Research Funding; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Giles:Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy; Actuate Therapeutics Inc: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding.

Abstract: Background: Bosutinib is approved at a starting dose of 500 mg once daily (QD) in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to prior treatment and at a starting dose of 400 mg QD in newly diagnosed patients with chronic phase (CP) CML. Approval of bosutinib after prior therapy was based on a phase 1/2 study in patients previously treated with imatinib ± dasatinib and/or nilotinib. After long-term follow-up (≥4 years), durable responses and maintenance of health-related quality of life (HRQoL) were seen in patients after prior imatinib (CP CML second-line [CP2L] cohort [n=284] ) or prior imatinib + dasatinib and/or nilotinib (CP CML third/fourth-line [CP3L/CP4L] cohort [n=115/4] ). As a post-authorization commitment to the European Medicines Agency, the BYOND study is providing additional safety and efficacy data for bosutinib in patients with CML after failure of prior tyrosine kinase inhibitor (TKI) treatment. Cumulative confirmed major cytogenetic response rate by 1 year (primary endpoint; not powered) in evaluable patients with CP CML was 75.8% after 1 or 2 prior TKIs (n=99) and 62.2% after 3 prior TKIs (n=45). Cumulative complete cytogenetic response rate anytime on treatment was 86.0%, 83.9%, and 73.3% in the CP2L, CP3L, and CP4L cohorts, respectively. Patients had high rates of molecular responses across all lines of treatment. Evaluation of HRQoL through patient-reported outcome (PRO) measures is an exploratory objective of BYOND. Methods: BYOND (NCT02228382) is an ongoing, phase 4, single-arm, open-label study of bosutinib at a starting dose of 500 mg QD in patients with CML and resistance/intolerance to prior treatment. At baseline and during treatment, patients were asked to complete the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu v4) instrument, a 44-item, valid assessment of HRQoL in patients with leukemia. Each item was scored on a scale from 0 to 4, with higher scores indicating better HRQoL. Changes in HRQoL that are clinically meaningful to a patient have been defined as the minimal important difference (MID) for most FACT-Leu domains. We report PRO results at Month 12 of bosutinib treatment in the CP CML cohorts; for comparison, we present PRO data at Month 12 from the CP CML cohorts of the phase 1/2 study of bosutinib in previously treated patients. Results: At baseline, most FACT-Leu scores were similar ( 〈 5% difference) in the CP2L and CP3L cohorts of the BYOND study (Table); social and functional well-being scores were lower and the emotional well-being score was higher in the CP2L cohort. Baseline FACT-Leu scores were lower in the CP4L cohort, with 〉 5% differences seen for physical and emotional well-being compared with the CP2L cohort, and for physical, social, and functional well-being, FACT-General (FACT-G) total, FACT-Leu total, and trial outcome index (TOI) FACT-Leu compared with the CP3L cohort. At Month 12, no mean change in a FACT-Leu domain score met the MID (Figure), indicating preservation of baseline HRQoL across all cohorts. Mean changes in FACT-Leu scores from baseline to Month 12 were similar in the CP2L cohorts of the BYOND study and the phase 1/2 study. HRQoL trends were also generally similar in the CP3L cohort of BYOND and the CP3L/4L cohort of the phase 1/2 study, in which 97% of patients received third-line bosutinib. Conclusions: HRQoL was maintained from baseline in patients with CP CML following 12 months of bosutinib treatment in the BYOND study. HRQoL changes at Month 12 were comparable to those observed in previously treated patients in the initial phase 1/2 study of bosutinib, wherein long-term efficacy and HRQoL stability were subsequently reported. In addition, FACT-G scores in the BYOND study were consistent with those previously reported for general populations as well as patients with various cancers. Maintenance of HRQoL is important for patients with CP CML who potentially will receive lifelong TKI treatment, and the PRO results from BYOND suggest bosutinib is a well-tolerated treatment option, thus providing further support for its use in patients with CP CML resistant/intolerant to prior TKIs. Relationships between molecular response and HRQoL in the BYOND study are being explored. Disclosures Brümmendorf: University Hospital of the RWTH Aachen: Employment; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Watts:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Russell-Smith:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Giles:Actuate Therapeutics Inc: Employment; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy. Hochhaus:MSD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding.

Abstract: Introduction: Tyrosine kinase inhibitor therapy has been associated with cardiovascular (CV) events. BOS is approved for patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) CML and Ph+ CML resistant/intolerant to prior therapy. We analyzed cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) in pts with newly diagnosed CP CML receiving BOS or IMA after 5 yrs follow-up in BFORE. Methods: In the open-label, phase 3 BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive first-line 400 mg once-daily BOS (n=268) or IMA (n=268; 3 untreated). The current analysis included all pts who received ≥1 dose of study drug. TEAEs were monitored from first dose of study drug until 28 d after last dose; monitoring of non-serious adverse events (AE) ended at the start of a new cancer treatment. Prespecified MedDRA terms (cardiac, n=133; vascular, n=502) comprised clusters of investigator-assessed TEAEs (Table). Multivariable proportional subdistribution hazard models predicting time to first TEAE included treatment group; baseline demographic information; history of cardiac events, vascular events, hypertension, diabetes, hyperlipidemia, and tobacco use; as well as hypertension, cardiac (for vascular model) and vascular (for cardiac model) TEAEs. CI excluding 1 was considered predictive of outcome. This analysis was based on 17-Apr-20 last pt last visit (12-Jun-20 database lock), 5 y (240 wks) after last enrolled pt. Results: At study completion, 59.7% of BOS pts and 58.1% of IMA pts were still on treatment. Median duration of treatment was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39-583) vs 400.0 (189-765) mg/d. In the BOS vs IMA arm, 57.8% vs 56.2% of pts had ≥1 CV risk factor at baseline; 20.9% vs 17.7% had ≥3 risk factors, respectively. The most common risk factors were a history of hypertension (BOS, 34.0%; IMA, 30.6%), BMI & gt;30 (BOS, 23.1%; IMA, 21.9%), age ≥65 y (BOS, 19.8%; IMA, 17.4%), and history of hyperlipidemia (BOS, 16.8%; IMA, 18.9%). Rates of cardiac, vascular and hypertension TEAEs; serious adverse events (AEs); AEs leading to treatment withdrawal and drug-related TEAEs (per investigator) were low in both arms (Table). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs were similar between arms (Table). Risk factors for cardiac TEAEs (HR; 95% CI) were age in years (1.04 [1.02-1.07]), race other than Asian or black compared to white ( & lt;0.01 [ & lt;0.01- & lt;0.01]), a history of tobacco use (6.94 [1.89-25.40] ) and cardiac events (3.59 [1.68-7.65]), hypertension (3.07 [1.20-7.84] ) and vascular TEAEs (5.27 [1.53-18.18]). Risk factors for vascular TEAEs (HR [95% CI] ) were black race compared to white ( & lt;0.01 [ & lt;0.01- & lt;0.01]), a history of vascular events (4.65 [1.81-11.97] ) and cardiac TEAEs (7.73 [2.31-25.84]). In multivariable analyses, treatment group was not predictive of time to initial cardiac (HR 0.87 [95% CI 0.45-1.70] ) or vascular (HR 2.17 [95% CI 0.94-45.04) TEAEs. The most common cardiac, vascular, and hypertension TEAEs, respectively, were sinus bradycardia (2.2%), angina pectoris (3.0%) and hypertension (9.7%) with BOS vs electrocardiogram QT prolongation (3.8%), peripheral coldness (1.1%) and hypertension (10.9%) with IMA. One grade 5 cardiac (acute cardiac failure) and one vascular (myocardial ischemia) TEAE were reported with BOS, and one vascular (cerebrovascular accident) TEAE with IMA; none were considered related to study drug. Successful treatment rechallenge was achieved in the majority of pts with dose interruptions due to cardiac (BOS, 85.7%; IMA, 100%) and vascular (BOS, 100%; IMA, not applicable) TEAEs who were readministered study drug. No pts had dose interruptions due to hypertension TEAEs. Cardiac, vascular and hypertension TEAEs resolved in 57.7%, 75.0% and 35.7% of pts receiving BOS and 65.2%, 66.7% and 48.3% receiving IMA. Conclusions: In this final analysis of BFORE, the incidence of cardiac, vascular, and hypertension TEAEs in pts with newly diagnosed CP CML receiving BOS or IMA was low and was similar between treatment groups. These AEs infrequently led to treatment discontinuation. In addition to continued improved efficacy with BOS vs IMA after 5 yrs follow-up (Brümmendorf et al., ASH 2020), these safety results support the use of first-line BOS as a standard of care in pts with CP CML. Disclosures Cortes: Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Telios: Research Funding; Astellas: Research Funding; Sun Pharma: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Hjorth-Hansen:Pfizer: Honoraria, Research Funding; Austrian Orphan Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Kota:Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Pfizer: Consultancy, Honoraria. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Brümmendorf:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding.

Abstract: Introduction: Bosutinib is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and patients with newly diagnosed Ph+ chronic phase (CP) CML. The phase 4 BYOND trial (NCT02228382) further evaluated the efficacy and safety of bosutinib in patients with previously treated CML. We report the final results from BYOND. Methods: Patients with CML resistant/intolerant to previous tyrosine kinase inhibitor therapy received bosutinib 500 mg once daily. This final analysis was based on a November 23, 2020 database lock, after 3 years of follow-up. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML; 4 patients with accelerated phase CML and 3 with Ph−/BCR-ABL1+ CML were analyzed separately. At study completion (median follow-up, 47.8 months), 48.1% of patient with Ph+ CP CML were still receiving treatment, and 68.6% completed the study. Most common primary reason for treatment discontinuation was adverse events (AEs) (26.9% [n=42/156]). Median treatment duration was 40.9 months (range, 0.2−50.1) and median dose intensity 306.4 mg/day (range, 79.7−560.6). Dose interruptions due to AEs occurred in 76.3% of patients and dose reductions in 79.5% of patients. Dose reduction (without further reduction) to 400, 300, or 200 mg/day occurred in 35 (22.4%), 46 (29.5%), and 38 (24.4%) patients, respectively. In evaluable patients with Ph+ CP CML, 81.1% (95% CI: 73.7-87.2), 71.8% (95% CI: 63.9-78.9), 59.7% (95% CI: 51.4-67.7) and 48.3% (95% CI: 40.1−56.6) attained or maintained complete cytogenetic response, major molecular response (MMR), MR 4, and MR 4.5 respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib (Table 1). Among responders, the Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR 4 at 36 months were 87.2% (78.0−92.7) and 80.7% (69.4−88.1), respectively. No patients with Ph+ CP CML progressed to accelerated/blast phase on-treatment. At 48 months, the cumulative incidence of progression free-survival events was 5.1% (95% CI: 2.4-9.4) and the Kaplan-Meier overall survival rate 88.3% (95% CI: 81.8-92.6). There were 17 deaths; 2 were considered CML-related (off-treatment progression to AP/BP, n=1; cardiogenic shock, n=1) and none were considered to be treatment-related by the investigator. In the overall patient population (N=163), any grade treatment-emergent AEs (TEAEs) were reported by 99.4% of patients and grade 3/4 TEAEs were reported by 79.1% of patients (Table 2). Most common (≥10%) TEAEs leading to dose reduction were diarrhea (27.0%) and increased ALT (12.3%) and most common TEAEs leading to temporary dose interruption were diarrhea (30.7%), increased ALT (14.7%), vomiting (13.5%), increased AST (11.0%), and nausea (10.4%). AEs leading to treatment discontinuation in ≥2% of patients were increased ALT (4.9%) and AST (2.5%). Conclusions: After 3 years, bosutinib continued to show efficacy in previously treated patients with Ph+ CP CML. Long-term AEs were generally manageable and consistent with previous reports of bosutinib. These results confirm the use of bosutinib as a standard of care in previously treated patients with CML. Figure 1 Figure 1. Disclosures Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Brümmendorf: Bristol Myers: Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Kelly: Takeda: Consultancy; AstraZeneca: Consultancy; Sanofi-Aventis: Consultancy; Denovo Biopharma: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Berkley Lights: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company; Bayer: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Epizyme: Speakers Bureau; Pharmacyclics: Speakers Bureau; Karyopharm: Speakers Bureau; Gilead: Speakers Bureau. Oehler: OncLive: Honoraria; Takeda: Consultancy; Pfizer: Research Funding; BMS: Consultancy. Garcia-Gutiérrez: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Pfizer: Research Funding. Hjorth-Hansen: Pfizer: Research Funding; Novartis: Research Funding; AOP: Research Funding. Leip: Pfizer: Current Employment, Current equity holder in publicly-traded company. Purcell: Pfizer: Current Employment, Current equity holder in publicly-traded company. Luscan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira: Pfizer: Current Employment, Current equity holder in publicly-traded company. Giles: Novartis: Consultancy; Actutate Therapeutics: Current Employment; Epigene Therapeutics: Consultancy, Current equity holder in publicly-traded company. Hochhaus: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding.