BACKGROUND: In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. METHODS: Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre-and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model. RESULTS: Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. CONCLUSIONS: Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm.

BackgroundRibociclib (RIBO) and palbociclib (PALBO), combined with letrozole (LET), have been evaluated as treatments for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in separate Phase III randomized controlled trials (RCTs), but not head-to-head. Population differences can lead to biased results by classical indirect treatment comparison (ITC). Matching-adjusted indirect comparison (MAIC) aims to correct these differences. We compared RIBO and PALBO in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer using MAIC.MethodsPatient-level data were available for RIBO (MONALEESA-2), while only published summary data were available for PALBO (PALOMA-2). Weights were assigned to MONALEESA-2 patient data such that mean baseline characteristics matched those reported for PALOMA-2; the resulting matched cohort was used in comparisons. Limited by the results reported in PALOMA-2, progression-free survival (PFS) was the primary comparison. Cox regression models were used to calculate adjusted hazard ratios (HRs) for PFS, before indirect treatment comparison (ITC) was performed with 95% confidence intervals. An exploratory analysis was performed similarly for overall survival using earlier PALBO data (PALOMA-1). Grade 3/4 adverse events were also compared.ResultsRacial characteristics, prior chemotherapy setting, and the extent of metastasis were the most imbalanced baseline characteristics. The unadjusted PFS HRs were 0.556 (0.429, 0.721) for RIBO+LET versus LET alone and 0.580 (0.460, 0.720) for PALBO+LET versus LET alone. MAIC adjustment resulted in an HR of 0.524 (0.406, 0.676) for RIBO+LET versus LET. PFS ITC using unadjusted trial data produced an HR of 0.959 (0.681, 1.350) for RIBO versus PALBO, or 0.904 (0.644, 1.268) with MAIC. Unadjusted overall survival HR of RIBO versus PALBO was 0.918 (0.492, 1.710); while exploratory MAIC was 0.839 (0.440, 1.598). ITC of grade 3/4 adverse events yielded a risk ratio of 0.806 (0.604, 1.076).ConclusionMAIC was performed for RIBO and PALBO in the absence of a head-to-head trial: though not statistically significant, the results favored RIBO.

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BackgroundImmune thrombocytopenia (ITP) is an auto-immune disorder characterized by enhanced platelet destruction and, subsequently, the potential for increased bleeding. Thrombopoietin receptor (TPO-R) agonists have recently emerged as promising therapies for ITP patients who are refractory to other treatments. While eltrombopag (EPAG) is the only TPO-R agonist US Food and Drug Administration approved for use in pediatric patients, romiplostin (ROMI) has been used in Phase III clinical studies.MethodsA cost-consequence model (CCM) was developed to evaluate the costs of EPAG, ROMI, and watch-and-rescue (W&R) in relation to their respective treatment outcomes in previously-treated pediatric chronic ITP (cITP) over a 26-week time horizon. The costs of drugs, administration, routine care, rescue medications, adverse events, and mortality were included. Data on platelet count response rate, bleeding events, and adverse events were derived from all relevant identified Phase III-registered clinical trials, health outcomes were compared via indirect treatment comparison.ResultsThe overall estimated cost of EPAG per patient was US$66,550, compared to US$101,056 for ROMI and US$32,720 for W&R. EPAG’s lower cost compared to ROMI was largely due to lower drug costs (US$62,202 vs US$84,396), administration costs (US$0 vs US$1,955), and significantly lower costs due to severe bleeding (US$354 vs US$10,191). When assessing cost per severe bleeding event avoided, EPAG was dominant over ROMI (less expensive and more effective). EPAG was again dominant over ROMI when assessing the cost per responder and per bleeding event (any grade). Sensitivity analysis was consistent with the base case findings.ConclusionEPAG was the preferred TPO-R agonist to treat cITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs.

Background: Trial data often does not cover a sufficiently long period of time to truly capture time-toevent endpoints, however, Health Technology Assessment (HTA) bodies often require overall survival (OS) and progression-free survival (PFS) estimates. Often, significant survival effects are found beyond the time period observed in clinical trials, thus, extrapolation of trial results is required for health economic and HTA evaluations. Objectives: This paper looks at different techniques that can be used to extrapolate trial data, as well as criteria that should be used to select the most appropriate technique. Using these insights a formal decisionmaking criteria will be established, allowing users to follow a systematic approach to extrapolating survival estimates. The techniques are then applied to a metastatic breast cancer (MBC) example. Methods: A criterion-based guide was devised to allow the accurate extrapolation and justification of survival estimates in a MBC study comparing eribulin (Halaven) monotherapy with treatment of their (patient’s) physician’s choice (TPC). Parametric and piecewise models are used to extrapolate survival estimates, and statistical as well as visual tests are used to decide the most appropriate modelling technique. Results: In the case study presented, the optimal model was identified as the Accelerated Failure Time (AFT) Parametric model using a Gamma distribution with a treatment covariate for OS, and the Kaplan-Meier survival estimates for PFS. Conclusions: Survival estimates must be extrapolated to a time point such that the benefits of a therapy can be clearly demonstrated. A systematic approach combined with a formal decision-making structure should be used to minimize the potential for bias as well as making the process transparent.

BackgroundThrombopoietin-receptor agonists eltrombopag (EPAG) and romiplostim (ROMI) are treatment options for adults with chronic immune thrombocytopenia (cITP) who have had an insufficient response to corticosteroids or immunoglobulins.MethodsA cost-consequence model was developed to evaluate the costs relative to treatment success of EPAG, ROMI, and watch and rescue (W&R) in previously treated patients. The primary endpoint assessed was severe bleeding, derived from all identified phase III registered clinical trials. Health outcomes were compared via indirect treatment comparison. Costs incorporated in the model included drug and administration, routine care, rescue medications, bleeding-related adverse events, other adverse events, and mortality costs. A trial (26-week) time horizon was used, as certain endpoints used in the model were bound to within-trial results.ResultsIn the intent-to-treat (ITT) population, the overall estimated cost per patient for EPAG was US$66,560 compared to US$91,039 for ROMI and US$30,099 for W&R. Compared to the ITT population, the difference in cost between EPAG and ROMI was slightly greater in splenectomized patients (US$65,998 for EPAG compared to US$91,485 for ROMI) and slightly less in non-splenectomized patients (US$67,151 for EPAG compared to US$91,455 for ROMI), though the overall trend remained the same. When assessing cost per severe bleeding event avoided in the ITT population, EPAG dominated (less expensive, more effective) ROMI. Sensitivity analyses confirmed these results.ConclusionEPAG was preferred over ROMI in the treatment of cITP, largely driven by the reduction in severe bleeding events associated with its use.

BackgroundCost-utility analyses for acute myeloid leukemia (AML) require health state utility values (HSUVs) in order to calculate quality-adjusted life-years (QALYs) for each health state.AimThis study reviewed AML-related HSUVs that could be used in economic evaluation studies.Materials and methodsEMBASE, MEDLINE, and Cochrane databases were searched from January 2000 to November 2016 for relevant studies that reported quality of life (QoL) and HSUVs in AML. Identified relevant European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 values were mapped to HSUVs. HSUVs for each health state in the AML treatment pathway were then collated.ResultsTen relevant studies were identified. Six were cost-effectiveness analyses utilizing HSUVs for calculation of QALYs, one was an effectiveness analysis (incremental QALY), and two were QoL studies reporting AML-specific utilities. An additional study reported QoL for patients undergoing stem cell transplantation (SCT). Since no study reported HSUVs for relapse, values from a study of secondary AML patients who failed prior treatment for myelodysplastic syndrome were used. Where multiple HSUVs were available, collected values were given priority over assumed values. AML treatment (induction, consolidation, or SCT) was associated with decreased HSUV, while post-treatment complete remission led to increased HSUV.ConclusionThere are some methodologically robust HSUVs that can be directly used in economic evaluations for AML. Careful interpretation is advised considering significant differences in methodologies and patient population (inclusion, size). We need to develop HSUVs with larger-sized studies, making greater use of condition-specific data.

Objectives: The objective of this evaluation was to assess cost-effectiveness of pegfilgrastim compared to filgrastim when used as prophylaxis in subsequent chemotherapy cycles for patients who experience a neutropenic event (NE; absolute neutrophil count < 500/m3), consistent with Turkish regulatory indication. Pegfilgrastim was compared to filgrastim (5 days) for reducing incidence of FN events in patients receiving cytotoxic chemotherapy for solid tumors in Turkey. MethOds: An economic model was developed to assess cost-effectiveness of pegfilgrastim compared to filgrastim given for 5 days per cycle (short course based on Turkish clinical practice) in breast cancer patients receiving highly myelotoxic (≥ 20% FN risk) or moderately myelotoxic (10-20% FN risk) chemotherapy regimens. A Markov cycle tree was modeled comprising two components: a decision tree that tracks initial chemotherapy cycle and associated NE events, and a Markov model consisting of two phases. Phase 1 tracks FN events in subsequent chemotherapy cycles following an NE, while Phase 2 tracks long-term cancer-related survival. All analyses were performed from the payer perspective and included direct health care costs only. A lifetime time horizon was considered. Deterministic sensitivity analyses were conducted on key model parameters. Results: The average cost of treating an FN episode for a solid tumor was calculated as TRY8900[$4070] based upon consultation with Turkish clinicians. For highly myelotoxic regimens, switching to prophylaxis with pegfilgrastim after an NE was a dominant strategy (incremental cost: TRY-99 [$-45], incremental QALY: 0.03). ICER for medium myelotoxic regimens was TRY7920[$3622] (incremental cost: TRY55[$25], incremental QALY: 0.01); highly cost-effective based on WHO-recommended ICER threshold (GDP per capita = TRY22718[$10390]). Cost-effectiveness results were robust to deterministic changes in key model parameters (e.g. risk of FN in subsequent cycles, cost of FN). cOnclusiOns: Prophylaxis with pegfilgrastim for reducing incidence of FN after a first NE is either dominant or cost-effective compared to filgrastim (5 days).Objectives: Considering the increasing number of treatment options for metastatic breast cancer (MBC), it is important to develop high-quality methods to assess the cost-effectiveness of new anticancer drugs. This study aims to develop a global economic model that could be used as a benchmark for the economic evaluation of new therapies for MBC. MethOds: The Global Pharmacoeconomics of Metastatic Breast Cancer (GPMBC) model is a Markov model that was constructed to estimate the incremental cost per quality-adjusted life years (QALY) of new treatments for MBC from a Canadian healthcare system perspective over a lifetime horizon. Specific parameters included in the model are cost of drug acquisition, survival outcomes, and incidence of treatment-related adverse events (AEs) whereas global parameters are patient characteristics, health states utilities, disutilities and costs associated with treatmen...