Abstract: Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P & lt;0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P & lt;0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

Abstract: Background: In clinical trials of second line and later line therapies for chronic myeloid leukemia (CML), to date only single arm trials have been conducted for the available treatments (i.e. Bosutinib, Dasatinib, Nilotinib and Ponatinib). These trials included heterogeneous patient populations in terms of line of treatment, stage of disease and other patient- and disease baseline characteristics that may impact the outcomes of the treatment. This hampers any direct or indirect comparisons of these second line CML treatments in terms of efficacy measures such as progression-free survival (PFS) and overall survival (OS). In this situation (i.e. lack of common comparator), matching-adjusted indirect treatment comparisons (MAICs) can be applied. Objective: The aim of this research was to compare the efficacy (PFS and OS) of Bosutinib, Dasatinib, Nilotinib and Ponatinib in second line chronic phase CML patients by means of MAICs. Patient data are reweighted such that their medians on demographic and clinical characteristics match those of the aggregated comparator trial, in order to adjust for cross-trial differences in those baseline characteristics. Outcomes of the reweighted patient level dataset are then compared with those of the aggregated comparator trial. Methods: A systematic literature review of second-line or later CML Phase II and Phase III clinical trials identified 2 trials for Bosutinib, 11 trials for Dasatinib, 8 trials for Nilotinib and 2 trials for Ponatinib. For the MAIC, only second line chronic phase trials with three or more years of follow-up (to allow for sufficient differentiation of treatments over time) were considered, resulting in 1 trial for Bosutinib (NCT00261846), 1 trial for Dasatinib (CA180-034), 1 trial for Nilotinib (NCT00109707) and no trials for Ponatinib. To adjust for cross-trial differences, patient data from the Bosutinib trial were subject to the inclusion and exclusion criteria reported in the comparator trials, and were weighted to match all available summary baseline characteristics reported in the 1 Dasatinib trial and the 1 Nilotinib trial. The baseline characteristics considered for reweighing were as follows: age, gender, Imatinib resistant/intolerant, disease duration, and prior stem cell transplantation. After the MAICs, PFS and OS were compared based on hazard ratios (HR) derived by Cox proportional hazard (PH) regressions using the reweighed Bosutinib dataset. The Cox PH assumption was tested with log cumulative hazard plots, Schoenfeld residuals and its corresponding statistical test. In case the PH assumption did not hold, Cox regressions with time varying coefficients were tested and the relative restricted mean survival time (RMST) was estimated. Results: Comparing Bosutinib to Nilotinib resulted in HRs for PFS and OS of 2.0 ( 〈 0.01) and 1.4 (p=0.109) respectively. When compared to Dasatinib, Bosutinib showed a non-significant HR of 1.3 (p=0.30) in favor of Bosutinib for OS and a significant 1.6 HR (p 〈 0.01) for PFS. In the PFS and OS analyses compared to Dasatinib, the PH assumption was violated based on the statistical test or almost violated according to the visual plots. Therefore, we examined the relative restricted mean survival times, which were 1.123 (p=0.02) for PFS and 1.025 (p=0.41) for OS. Discussion: After performing MAICs to adjust for cross-trial differences in baseline characteristics, Bosutinib appeared to have a significantly greater PFS than Nilotinib (p 〈 0.01). Based on the relative RMST analyses, Bosutinib also appeared to have a significantly greater PFS than Dasatinib, at the p 〈 0.05 level. For OS the findings were numerically positive in favor of Bosutinib, but not statistically significant, compared to both. However, qualitatively, Bosutinib appears to be an equally effective second line chronic phase CML therapy. The greater PFS compared to Nilotinib and Dasatinib, especially at the end of the follow up period for Bosutinib, may translate into future OS benefits not yet observed. A limitation of our study is that we could only correct for observed differences between the trials, and not for unobserved ones. Also, the reweighing was performed for all relevant reported baseline characteristics; not all baseline characteristics were reported in all trials. Both limitations could have an impact on the outcomes and therefore the study conclusions. Disclosures Muresan: Ingress-health Nederland BV: Employment. Mamolo:Pfizer Inc: Employment, Equity Ownership. Cappelleri:Pfizer Inc: Employment, Equity Ownership. Shapiro:Pfizer Inc: Employment, Equity Ownership. Crescenzo:Pfizer Inc: Employment. Su:Pfizer: Employment, Equity Ownership; Bristol Myers Squibb: Equity Ownership. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.

Abstract: Introduction: In the ongoing phase 3 BFORE trial (NCT02130557), a significantly higher major molecular response rate at Month 12 was seen with bosutinib vs imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML), and bosutinib treatment was accompanied by improvement or maintenance of health-related quality of life (HRQoL), as assessed by the patient-reported Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) instrument. Diarrhea is a common side effect of bosutinib and occurred more frequently in bosutinib- vs imatinib-treated patients in the primary analysis of the BFORE trial (all grades: 70.1% vs 33.6%). Here, the impact of diarrhea, specifically on HRQoL, was assessed in patients receiving bosutinib or imatinib in the BFORE trial. Methods: Patients with CP CML were randomized 1:1 to receive first-line bosutinib or imatinib. HRQoL was analyzed in the modified intent-to-treat (mITT) population, comprised of Philadelphia chromosome-positive patients with typical BCR-ABL transcripts. The FACT-Leu consists of the 27-item FACT-General (FACT-G) scale with 4 domains (physical, social, emotional, and functional well-being) and the 17-item leukemia-specific subscale; higher scores and changes in scores indicate better HRQoL. Patients completed questionnaires at baseline, every 3 months for the first 2 years and every 6 months thereafter while on treatment, and at treatment completion. In this post hoc analysis, FACT-Leu scores from the first 12 months of treatment were analyzed in patients with diarrhea (any event during treatment) or chronic diarrhea (event lasting ≥28 days). Longitudinal analyses were conducted and standardized effect sizes were calculated to characterize the strength of effect on the FACT-Leu scores for the diarrhea and chronic diarrhea subgroups. Standardized effect sizes of approximately 0.1, 0.2, 0.5, and 0.8 (in absolute values) were considered trivial, small, medium, and large, respectively. Results: In the mITT population (bosutinib: n=246; imatinib: n=241), 163 (66.3%) patients in the bosutinib arm and 74 (30.7%) in the imatinib arm had diarrhea and were evaluable for HRQoL; 34 (13.8%) and 20 (8.3%), respectively, had chronic diarrhea (≥28 days). Among patients who developed diarrhea, the FACT-Leu total score and most subscale scores improved from baseline to Month 12 in both treatment arms, although changes were generally not significant (P 〉 0.05) and could be interpreted as small or trivial, based on effect size (Table). For patients with diarrhea in the bosutinib arm, changes from baseline in the leukemia-specific subscale could be characterized as small improvements starting at Month 6 of treatment; in the imatinib arm, an improvement was not seen until Month 12, and all changes could only be characterized as trivial (Figure). Among patients with chronic diarrhea, the changes from baseline at Month 12 were not significant for all FACT-Leu total or subscale scores in the bosutinib arm and could be interpreted as small or trivial; in the imatinib arm, changes from baseline in all FACT-Leu scores were numerically negative and nonsignificant with the exception of the physical well-being domain (P 〈 0.01), which had a large effect size (Table). For patients with chronic diarrhea in the bosutinib arm, improvements in the leukemia-specific subscale at Month 3 through Month 9 could be characterized as small; in the imatinib arm, a deterioration was seen at Month 3 through Month 12, and changes could be considered small at Months 9 and 12 (Figure). Conclusions: In this post hoc analysis of the BFORE trial, HRQoL was not negatively affected by diarrhea or chronic diarrhea in the bosutinib arm. Although the analysis is limited by the small number of patients, chronic diarrhea during treatment with imatinib appeared to have a greater impact on HRQoL than chronic diarrhea during treatment with bosutinib, based on the magnitude of the effect sizes and direction of changes, particularly for physical well-being. These data suggest that patients with CP CML treated with bosutinib can preserve or slightly improve HRQoL during therapy, regardless of the presence of diarrhea or chronic diarrhea. Disclosures Brümmendorf: Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment, Equity Ownership. Bushmakin:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Crescenzo:Pfizer: Employment. DeAnnuntis:Pfizer Inc: Employment, Equity Ownership. Viquiera:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding.

Abstract: Objectives: Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor for adult patients with Philadelphia chromosome−positive chronic myeloid leukemia (Ph+ CML), has a recommended starting dose of 500 mg/d. This analysis evaluates efficacy and safety following BOS dose reduction due to intolerance in patients with Ph+ CML. Methods: Data from 2 studies were analyzed: a phase 1/2 study (NCT00261846) that included patients with chronic phase (CP) CML following resistance/intolerance to imatinib (IM; CP2L) or to IM plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after at least IM (advanced [ADV]); and a phase 3 study (NCT00574873) in CP CML patients treated with BOS or IM as first-line therapy (CP1L). Results: Of 570 CP2L/CP3L/ADV patients receiving BOS (median treatment duration 11 months [range: 0.03−96]), 257 (45%) experienced ≥1 dose reduction (236 patients to 400 mg/d and 95 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 54.5 (range: 4-1875) and 146 days (8-2166), respectively; median duration of dose reduction was 3.6 (0.03-87.7) and 4.2 months (0.03-60.5), respectively. In CP1L, 248 patients received BOS (median treatment duration: 55.4 months [0.03−76] ), of whom 111 (45%) experienced ≥1 dose reduction (103 to 400 mg/d and 56 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 64.0 (2-1714) and 139 days (20-1778), respectively; median duration of dose reduction was 2.6 (0.03-66.1) and 8.9 months (0.03-71.2), respectively. Patients achieved anew or maintained a previously achieved complete cytogenetic response following BOS dose reduction to 400 mg/d (achieved: 29% [CP2L/CP3L/ADV], 40% [CP1L] ; maintained: 13% [CP2L/CP3L/ADV], 26% [CP1L] ) and to 300 mg/d (achieved: 14% [CP2L/CP3L/ADV], 18% [CP1L] ; maintained: 24% [CP2L/CP3L/ADV], 45% [CP1L] ; Table 1). Treatment-emergent adverse events (TEAEs) were generally similar in incidence, type, and severity before vs after BOS dose reduction. However, incidences of certain gastrointestinal TEAEs were lower and of similar severity following BOS dose reduction to 400 mg/d (diarrhea: 84% vs 50% [CP2L/CP3L/ADV], 70% vs 41% [CP1L] ; nausea: 45% vs 23% [CP2L/CP3L/ADV], 34% vs 21% [CP1L] ; vomiting: 33% vs 21% [CP2L/CP3L/ADV], 28% vs 22% [CP1L] ) or to 300 mg/d (diarrhea: 85% vs 31% [CP2L/CP3L/ADV], 75% vs 38% [CP1L] ; nausea: 43% vs 14% [CP2L/CP3L/ADV], 43% vs 21% [CP1L] ; vomiting: 34% vs 11% [CP2L/CP3L/ADV], 34% vs 18% [CP1L] ). Conclusions: CP2L/CP3L/ADV and CP1L CML patients who required BOS dose reduction due to AEs were still able to achieve or maintain cytogenetic responses and appeared to experience fewer gastrointestinal AEs. Disclosures Kota: Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Lipton:Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. An:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Crescenzo:Pfizer Inc: Employment. Woloj:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Khoury:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees.