ALBERT

Description: 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

Description: 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 (

Description: Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment paradigm for chronic myeloid leukemia (CML). Although not curative, TKIs have increased the life expectancy of patients with CML to approximately that of the general population. There are currently 5 TKIs (imatinib, bosutinib, dasatinib, nilotinib, and ponatinib) approved in the United States to treat CML. Bosutinib was initially approved in September 2012 for the treatment of patients with Philadelphia chromosome-positive (Ph+) CML intolerant or resistant to prior therapy; the indication was expanded in December 2017 to patients with newly diagnosed chronic phase (CP) CML, based on data from the phase 3 BFORE trial demonstrating superior efficacy vs imatinib in this population. A budget impact model was developed to estimate the change in cost to US commercial payers following the addition of first-line (1L) bosutinib to the drug formulary for newly diagnosed Ph+ CP CML. As the introduction of bosutinib in the 1L setting is expected to have a halo effect on treatment pathways and utilization in subsequent treatment lines, the model also captured second- and third-line (2L and 3L) treatments for CML. Methods: The model estimated the 5-year budget impact of introducing bosutinib for the treatment of newly diagnosed patients with Ph+ CP CML by comparing costs for a hypothetical US health plan with 1 million members in settings with and without 1L bosutinib, and was built with data for TKI costs and medical resource use, including routine follow-ups and management of adverse events (AEs). The model population was comprised of adult patients with Ph+ CP CML without the T315I mutation, which carries a poor prognosis, who were receiving 1L, 2L, or 3L TKI treatment, and was calculated from published incidence and prevalence data. In the setting with 1L bosutinib, the model assumed bosutinib would take shares equally from other TKIs, excluding generic imatinib, for 1L use; for 2L and 3L use, where bosutinib was already indicated, changes in bosutinib shares, due to the halo effect of 1L use, were also taken equally from other TKIs. Costs and medical resource use data were obtained from claims data and public sources, and grade 3/4 AE rates (reported in ≥5% of patients) were obtained from the BFORE trial and package inserts for individual TKIs. Treatment response, based on major molecular response (MMR), was also factored and assumed to impact medical resource use. In each year of the model, it was assumed that patients received a full year of assigned treatment, based on US observational data showing median duration of TKI treatment of 〉1 year for patients with CML. Scenario analyses were conducted to identify the key drivers of budget impact. Results: Base-case results of the model indicated that the addition of bosutinib as a 1L treatment option for Ph+ CP CML would result in a total budget increase of 0.77% (from $223,234,271 to $224,943,605; Figure) for a hypothetical health plan over 5 years, which translated to total increases of $1.71 per member and $6,465 per treated member. Increases in total annual costs ($47,100 increment in Year 1 to $762,930 increment in Year 5) were mostly due to 1L drug costs, with low-cost increases per member per year ($0.05 in Year 1 to $0.76 in Year 5) and per member per month (

Description: Introduction: Gemtuzumab ozogamicin (GO; MylotargTM) was approved by the US Food and Drug Administration in 2017 and the European Medicines Agency in 2018 in combination with standard of care (SOC) chemotherapy (daunorubicin/cytarabine) for the treatment of de novo acute myeloid leukemia (AML). Although initial remission rates for de novo AML are high, overall survival (OS) is low; however, a proportion of patients experience long-term remission (〉5 years) and can be considered cured. Statistically cured populations can be estimated by fitting mixture cure models (MCMs) to survival data, a method that takes into account background survival rates. The objective of this research was to assess and compare the statistical cure rates with GO plus SOC vs SOC alone among adult patients with de novo AML. Methods: MCMs (Weibull, lognormal, and gamma) were fitted to patient-level data from the phase 3 ALFA-0701 trial on event-free survival (EFS) and OS of patients with remission (GO plus SOC: n=100; SOC alone: n=96), and OS of all patients (with remission and refractory; GO plus SOC: n=135; SOC alone: n=136). As refractory patients do not experience remission, this methodology would not provide clinically meaningful results since they are unlikely to experience a cure. Analyses for the subgroup excluding patients with adverse cytogenetics were also explored. For the GO plus SOC arm, P values

Description: Introduction Several randomized controlled trials (RCTs) compare second generation tyrosine kinase inhibitors (TKIs) with imatinib (IM) for the first-line (1L) treatment of chronic phase chronic myeloid leukemia (CP-CML). However, an examination indicated cross-trial heterogeneity in terms of disease and patient characteristics (baseline risk score, age, trial region, and post-baseline IM dose escalation) and outcomes reported (type and time of evaluation). For this reason, a matching adjusted indirect treatment comparison (MAIC) can be used to assess comparative efficacy. The objective of this study was to compare the efficacy of bosutinib (BOS) with nilotinib (NIL) and dasatinib (DAS) in 1L CP-CML via unanchored MAICs. Methods As well as heterogeneity in baseline characteristics, differences in the amount of IM dose escalations in earlier clinical pivotal trials (ENESTnd: 15.9% at 12 months; DASISION 20% at 24 months) relative to more recent ones (BFORE: 27.5% and 30.9% at 12 and 24 months, respectively) were observed. Because differences in IM dose-escalation regimens are trial design matters, they cannot be adjusted for using anchored MAICs. Therefore, an unanchored MAIC (which dismisses the common comparator arm, in this case IM) was used. Unanchored MAICs comparing BOS with NIL and DAS were performed to match the summary statistics in the BFORE trial to the reported summary statistics in the ENESTnd (NIL) and the DASISION (DAS) trials. Outcomes assessed included major molecular response (MMR) at 12 months and at any time after 12 months, complete cytogenetic response (CCyR) by 12 months, and deep molecular response (MR4) at 12 months. Statistical significance was assessed based on confidence intervals (CI; significant when CI excludes 1). The sample size of the matching-adjusted BOS population was estimated using the effective sample size (ESS). No adjustments for multiple comparisons were made. Results The MAICs showed an MMR at 12 months of 49.32% (vs 47.13% before the MAIC, N=244, ESS=186) for BOS vs 44% for NIL (OR 1.24, 95% CI [0.87-1.77], N=282) and an MMR at any time of 58.09% (vs 57.79% before MAIC, N=244, ESS=142) for BOS vs 57% for NIL (OR 1.05, 95% CI [0.72-1.5], N=282), and 58.52% (vs 58.16% before MAIC, N=239, ESS=192) for BOS vs 52% for DAS (OR 1.3, 95% CI [0.9-1.88], N=259). BOS had a CCyR by 12 months of 82.59% (vs 82.38% before MAIC, N=244) vs 80% for NIL (OR 1.19, 95% CI [0.75-1.87], N=282, ESS=195) and 80.47% (vs 82.01% before MAIC, N=239, ESS=185) vs 83% for DAS (OR 0.84, 95% CI [0.53-1.35], N=259). MR4 at 12 months was 20.34% (vs 20.49% before MAIC, N=244, ESS=185) for BOS vs 12% for NIL (OR 1.87, 95% CI [1.15-3.05], N=282). MMR and MR4 at month 12 were not reported for DAS. Discussion The general MAIC limitations (impact of having access to only marginal covariate distribution, choice of scale for indirect comparisons, choice of target population and sampling variation in the target population) apply to our analyses as well. Nevertheless, indirect comparisons using unanchored MAICs were conducted because cross-trial heterogeneity in patient baseline characteristics could bias the results of a naïve comparison and increases in IM dose escalation over time could bias the results of an anchored MAIC. The unanchored MAICs indicated that BOS was numerically higher than NIL for all response rates examined, however, except for MR4, none were statistically significant. BOS had a numerically higher MMR at any time and a numerically lower CCyR by 12 months compared with DAS, however, neither were statistically significant. BOS therefore seems to be an equally effective TKI as NIL and DAS in the 1L CP-CML setting. These findings, based on statistical methods, should be confirmed by clinical research. Disclosures Muresan: Ingress-health Nederland BV: Employment. Mamolo:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Crescenzo:Pfizer: Employment. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.

Description: Introduction: Tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with chronic-phase chronic myeloid leukemia (CP-CML). The emergence and availability of second-generation TKIs (dasatinib, nilotinib and bosutinib) has led to increased choice for patients and physicians, with data from randomized clinical trials indicating improved efficacy of such therapies compared to the first-generation TKI (imatinib). Differences in the efficacy of second-generation TKIs are negligible; however, all have distinct dosing instructions and safety profiles. Understanding the patient perspective is invaluable for optimizing healthcare decisions, with interest in information regarding patient preferences growing among a wide variety of stakeholders, including regulatory agencies, reimbursement bodies and prescribers. However, evidence is lacking regarding treatment preferences and priorities for patients with CP-CML. The aim of this study was to explore attributes of currently-licensed TKI therapies that are relevant and important to patients with CP-CML. This research represents the first step in the conduct of a discrete choice experiment (DCE), or conjoint analysis, to explore treatment preferences more broadly among CP-CML patients. Patient-guided design is crucial to ensuring attributes of investigation are meaningful. Hence the qualitative insights will advise and validate attribute and level selection for inclusion in the forthcoming DCE. Methods: In-depth qualitative interviews were conducted with 12 US-based patients with a clinician-confirmed diagnosis of CP-CML. The sample included 10 females and 2 males (median age 46 years) who were diagnosed 2 years (n=3), 4-7 years (n=5), 10-12 years (n=3) and 16.5 years (n=1) prior to interview. Ten patients had received a second-generation TKI. Current treatments were dasatinib (n=8), bosutinib (n=1) and imatinib (n=3). Previous treatments included imatinib (n=6), nilotinib (n=3) and dasatinib (n=1). The interviews utilized concept elicitation techniques to capture attributes of importance in both TKI treatment experience and TKI treatment selection. Transcripts were thematically analyzed using Atlas.ti. Results: Open-ended questioning elicited an array of attributes related to TKI treatments. It was important to all patients to ensure that a CP-CML treatment was effective. Treatment efficacy was conveyed with multiple descriptors; most commonly "BCR-ABL" (n=7) or major molecular response "MMR", polymerase chain reaction "PCR" and "remission" (each n=3). Eight patients discussed the importance of dose frequency, specifically the burden of scheduling self-administration of oral tablets (n=5). Seven patients conveyed the difficulty of taking a TKI with specific meal requirements, most notably when fasting is required prior to and post-administration (n=4). A multitude of important treatment side effects were elicited at investigation into the patient TKI treatment experience. Fatigue was reported by 11 patients (n=10 spontaneous) and considered by most patients (n=8/11) to be directly attributable to treatment versus the CML itself. Four patients considered fatigue an inevitable component of TKI treatment. Nausea was elicited by 7 patients (n=5 spontaneous) and some patients (n=5/9) considered it to be influential in treatment selection. Muscle pain was reported by 6 patients (n=4 spontaneous), while skin rash was reported by 5 patients and bone pain by 4 patients (all spontaneous). Diarrhea was reported by 4 patients (n=3 spontaneous). Additional symptoms reported by ≤2 patients are presented in Figure 1. Spontaneously elicited concepts were ranked by importance. All patients considered efficacy within the top three most important attributes. Six patients considered fatigue to be either of second or third most-importance. The rankings in Figure 2 serve to portray the varied perspectives and experiences of patients on TKI treatments. Conclusions: The TKI treatment experience for CP-CML patients is multifaceted. This type of study - the first that we know of - supplies valuable insight into the patient perspectives of TKI treatment to establish a foundation to better inform relevant decisions in the field. The qualitative findings will provide the input necessary to inform attribute and level selection to characterize treatment profiles ahead of an upcoming patient-preference DCE. Disclosures Mason: Adelphi Values: Employment; Pfizer: Consultancy. Mamolo:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Viqueira:Pfizer Inc: Employment, Equity Ownership. Gater:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Russell-Smith:Pfizer: Employment, Equity Ownership. Tatlock:Adelphi Values: Employment. Shah:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership.