Within-trial hospitalization resource utilization and budget impact analysis for darolutamide in metastatic hormone-sensitive prostate cancer using ARASENS.

BACKGROUND: ARASENS was a randomized, double-blind, phase 3 trial comparing darolutamide + docetaxel + androgen deprivation therapy (ADT) with placebo + docetaxel + ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC). OBJECTIVE: To use clinical trial data from ARASENS to understand whether the addition of darolutamide to docetaxel + ADT leads to increased hospitalizations and to estimate the budget impact on the US health care system. METHODS: We used mixed-effects negative binomial regression to estimate hospitalization and intensive care unit (ICU) admission rates and length of hospital stay (LoHS) counts. Hospitalization rates were estimated per treatment arm for the period during and after administration of docetaxel. Based on these estimates, a budget impact analysis evaluated the hospitalization costs (including ICU admissions) and standalone ICU hospitalization costs for the totality of the US population over a 5-year time horizon. The analysis compared a scenario without darolutamide vs one with darolutamide included in the US payer formulary. Hospitalization estimates were varied in a one-way sensitivity analysis. RESULTS: The first 4 months of treatment (when patients were receiving docetaxel) were associated with increased hospitalizations across both arms. The addition of darolutamide was associated with a numerical reduction in the rate of hospitalization (per year) due to any reason both during docetaxel treatment (1.01 visits per year [95% CI = 0.82-1.20] vs 1.18 visits per year [95% CI = 0.96-1.41]) and after docetaxel treatment (0.28 visits per year [95% CI = 0.23-0.34] vs 0.33 visits per year [95% CI = 0.27-0.40]). Darolutamide was associated with a marginally longer LoHS per hospitalization compared with placebo (+1.90 days per year) both during and after docetaxel treatment. ICU admissions were low in the ARASENS data; admission rates were assumed to be the same during and after docetaxel treatment. ICU admission rate estimates were equivalent across arms (0.02 visits per year [95% CI = 0.01-0.03]). The budget impact per treated member per month represents a cost-neutral option after Year 5 with a cumulative budget impact of -$9.71. CONCLUSIONS: The addition of darolutamide to docetaxel + ADT was associated with a numerically lower rate of hospitalization but marginally longer LoHS compared with docetaxel + ADT alone. Darolutamide represents a cost-neutral alternative per treated member per month compared with docetaxel + ADT with regard to hospitalizations at the end of a 5-year time horizon.

Prognostic Value of Neurotrophic Tyrosine Receptor Kinase Gene Fusions in Solid Tumors for Overall Survival: A Systematic Review and Meta-Analysis.

PURPOSE: Evidence suggests that neurotrophic tyrosine receptor kinase (NTRK) gene fusions in solid tumors are predictive biomarkers for targeted inhibition across a number of adult and pediatric tumor types. However, despite robust clinical response to tyrosine receptor kinase (TRK) inhibitors, the natural history and prognostic implications of NTRK fusions in solid tumors are poorly understood. It is important to evaluate their prognostic significance on survival to provide some context to the clinical effectiveness observed in clinical trials of TRK-targeted therapies. METHODS: A systematic literature review was conducted in Medline, Embase, Cochrane, and PubMed to identify studies comparing the overall survival (OS) of patients with NTRK fusion-positive (NTRK+) versus NTRK fusion-negative (NTRK-) tumors. Five retrospective matched case-control studies published before 11 August 2022 were assessed for inclusion, and three were selected for the meta-analysis (sample size: 69 NTRK+, 444 NTRK-). Risk of bias was assessed using the Risk of Bias Assessment tool for Non-randomized Studies tool. The pooled hazard ratio (HR) was estimated using a Bayesian random-effects model. RESULTS: In the meta-analysis, the median follow-up ranged from 2 to 14 years and the median OS was between 10.1 and 12.7 months (where reported). Comparing patients with tumors NTRK+ and NTRK-, the pooled HR estimate for OS was 1.51 (95% credible interval, 1.01 to 2.29). The patients analyzed had no previous or current exposure to TRK inhibitors. CONCLUSION: In patients not treated with TRK inhibitor therapies, those with NTRK+ solid tumors have a 50% increased risk of mortality within 10 years from diagnosis or the start of standard therapy compared with those with NTRK- status. Although this is the most robust estimate of the comparative survival rate to date, further studies are required to reduce uncertainty.

Supporting Biomarker-Driven Therapies in Oncology: A Genomic Testing Cost Calculator.

BACKGROUND: Adoption of high-throughput, gene panel-based, next-generation sequencing (NGS) into routine cancer care is widely supported, but hampered by concerns about cost. To inform policies regarding genomic testing strategies, we propose a simple metric, cost per correctly identified patient (CCIP), that compares sequential single-gene testing (SGT) vs. multiplex NGS in different tumor types. MATERIALS AND METHODS: A genomic testing cost calculator was developed based on clinically actionable genomic alterations identified in the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets. Using sensitivity/specificity data for SGTs (immunohistochemistry, polymerase chain reaction, and fluorescence in situ hybridization) and NGS and marker prevalence, the number needed to predict metric was monetarized to estimate CCIP. RESULTS: At base case, CCIP was lower with NGS than sequential SGT for advanced/metastatic non-squamous non-small cell lung cancer (NSCLC), breast, colorectal, gastric cancers, and cholangiocarcinoma. CCIP with NGS was also favorable for squamous NSCLC, pancreatic, and hepatic cancers, but with overlapping confidence intervals. CCIP favored SGT for prostate cancer. Alternate scenarios using different price estimates for each test showed similar trends, but with incremental changes in the magnitude of difference between NGS and SGT, depending on price estimates for each test. CONCLUSIONS: The cost to correctly identify clinically actionable genomic alterations was lower for NGS than sequential SGT in most cancer types evaluated. Decreasing price estimates for NGS and the rapid expansion of targeted therapies and accompanying biomarkers are anticipated to further support NGS as a preferred diagnostic standard for precision oncology.

Survival Outcomes of Patients With Tropomyosin Receptor Kinase Fusion-Positive Cancer Receiving Larotrectinib Versus Standard of Care: A Matching-Adjusted Indirect Comparison Using Real-World Data.

PURPOSE: Larotrectinib, a highly specific tropomyosin receptor kinase (TRK) inhibitor, previously demonstrated high response rates in single-arm trials of patients with TRK fusion-positive cancer, but there are limited data on comparative effectiveness against standard-of-care (SoC) regimens used in routine health care practice, before widespread adoption of TRK inhibitors as SoC for TRK fusion-positive cancers. Matching-adjusted indirect comparison, a validated methodology that balances population characteristics to facilitate cross-trial comparisons, was used to compare the overall survival (OS) of larotrectinib versus non-TRK-inhibitor SoC. MATERIALS AND METHODS: Individual patient data from three larotrectinib trials (ClinicalTrials.gov identifiers: NCT02122913, NCT02637687, and NCT02576431) were compared with published aggregate real-world data from patients with locally advanced/metastatic TRK fusion-positive cancer identified in the Flatiron Health/Foundation Medicine database. OS was defined as the time from advanced/metastatic disease diagnosis to death. After matching population characteristics, the analyses included (1) a log-rank test of equality to test whether the two groups were similar before larotrectinib initiation; and (2) estimation of treatment effect of larotrectinib versus non-TRK-inhibitor SoC. These analyses are limited to prognostic variables available in real-world data. RESULTS: Eighty-five larotrectinib patients and 28 non-TRK-inhibitor SoC patients were included in the analyses. After matching, log-rank testing showed no difference in baseline characteristics between the two groups (P = .31). After matching, larotrectinib was associated with a 78% lower risk of death, compared with non-TRK-inhibitor SoC (adjusted hazard ratio, 0.22 [95% CI, 0.09 to 0.52]; P = .001); median OS was 39.7 months (95% CI: 16.4, NE [not estimable]) for larotrectinib and 10.2 months (95% CI: 7.2, 14.1) for SoC. CONCLUSION: Matching-adjusted indirect comparison analyses suggest longer OS with larotrectinib, compared with non-TRK-inhibitor SoC, in adult patients with TRK fusion-positive cancer.

Comparison of Alternative Methods to Assess the Cost-Effectiveness of Tumor-Agnostic Therapies: A Triangulation Approach Using Larotrectinib as a Case Study.

OBJECTIVES: The study objective was to investigate the economic value of tumor-agnostic therapies when only single-arm effectiveness data are available at launch by applying multiple methodologies to establish comparative effectiveness. METHODS: In the absence of direct comparative data, 3 methods were used to estimate the counterfactual: (1) a historical control based on a systematic literature review for each tumor site from the larotrectinib trials, (2) an intracohort comparison using the previous line of therapy time to progression from larotrectinib trials, and (3) a nonresponder control that applied outcomes for larotrectinib nonresponders. Cost-effectiveness was modeled using the partitioned survival approach. Stochastic parameter uncertainty was assessed in a probabilistic sensitivity analysis (PSA). A triangulated estimate of the mean cost-effectiveness result was generated combining all 3 counterfactual estimates. RESULTS: Incremental cost-effectiveness ratios were similar across the 3 methodologies in the deterministic analysis ranging from £83 868 (95% uncertainty interval [UI] £65 698-£107 668) to £104 922 per quality-adjusted life-year (95% UI £80 132-£139 658). PSA results for each method substantially overlapped when plotted on the cost-effectiveness plane. Weighting PSA results for each method equally in the triangulation method produced an incremental cost-effectiveness ratios of £95 587 per quality-adjusted life-year gained (95% UI £70 449-£137 431). CONCLUSIONS: In the absence of direct comparative data, different methods of estimating a counterfactual are possible, each with strengths and limitations. Triangulating results across the methods provides a composite view of the total uncertainty and a more consistent estimation of the cost-effectiveness of the tumor-agnostic intervention compared with choosing a single method.

Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers.

Information regarding the comparative efficacy of first-generation receptor tyrosine kinase inhibitors is limited. This matching-adjusted indirect comparison (MAIC) evaluated differences in efficacy and safety across larotrectinib and entrectinib trials. Data from clinical trials for larotrectinib (LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)) and entrectinib (ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)) were used. Adults (≥18 years) across trials were matched on available baseline characteristics. Outcomes evaluated included overall response rate (ORR), complete response (CR) rate, duration of response (DoR), overall survival (OS), progression-free survival (PFS), any serious treatment-related adverse events of grade ≥ 3 (TRAEs), and TRAEs leading to treatment discontinuation. The MAIC included 74 patients from entrectinib trials and 117 and 147 patients for the larotrectinib efficacy and safety populations, respectively. Post-matching, larotrectinib was associated with a significantly longer median duration of OS than entrectinib (p < 0.05) and a numerically longer median PFS (p = 0.07). ORR was similar for both agents (p = 0.63). The CR rate was higher (p < 0.05) and the DoR was longer for larotrectinib (p < 0.05). Safety outcomes were comparable and low for both treatments. Results were consistent in sensitivity analyses. These findings suggest favorable efficacy for larotrectinib and comparable safety profiles versus entrectinib in treating tropomyosin receptor kinase fusion cancer.

Preferences and Utilities for Treatment Attributes in Type 2 and Non-ambulatory Type 3 Spinal Muscular Atrophy in the United Kingdom.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disease that affects motor neurons, resulting in progressive skeletal muscle weakness and atrophy. OBJECTIVE: The aim was to understand the value patients with SMA and caregivers place on treatment attributes and to estimate health utilities for SMA treatment outcomes from a general public sample. METHODS: Two discrete choice experiments were designed to elicit treatment preferences and health utilities, respectively. Patients with Type 2 and non-ambulatory Type 3 SMA, caregivers of patients with SMA and a general public sample in the UK completed the surveys. Patients and caregiver participants were recruited through patient associations. General public participants were recruited via a survey recruitment panel. Attributes included motor function, breathing function, treatment administration, treatment reactions, eyesight monitoring, contraception (patients only) and overall survival (general public only). Clustered conditional logit models were used to estimate treatment preferences, and marginal rates of substitution were used to estimate disutilities. RESULTS: Adult patients (n = 84) were twice as likely to choose a treatment with improved (vs. stable) motor and breathing function and four to five times less likely to choose a treatment with deteriorated (vs. stable) motor and breathing function as a treatment outcome. Caregivers (n = 83) were three to nine times more likely to choose improved and two to four times less likely to choose deteriorated (vs. stable) motor and breathing function. Both patients and caregivers preferred oral over intrathecal treatment. Treatment reactions, eyesight monitoring or contraception had no significant effect on patient choices. Conversely, caregivers preferred avoidance of treatment reactions. General public data (n = 506) yielded disutilities for unable to sit (- 0.408), need for > 16 h daily mechanical breathing support (- 0.304) and intrathecal therapy (- 0.071). CONCLUSIONS: Study results show the importance of motor and breathing function to patients and caregivers, and an oral treatment preference. Disutilities (decrements to utility) were substantial for SMA disease outcomes and care aspects.

Systematic Literature Review to Assess Economic Evaluations in Spinal Muscular Atrophy (SMA).

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease that affects individuals with a broad age range. SMA is typically characterised by symmetrical muscle weakness but is also associated with cardiac defects, life-limiting impairments in respiratory function and bulbar function defects that affect swallowing and speech. Despite the advent of three innovative disease-modifying therapies (DMTs) for SMA, the cost of DMTs in addition to the costs of standard of care can be a barrier to treatment access for patients. Health Technology Assessment (HTA) decision makers evaluate the cost effectiveness of a new treatment before making a reimbursement decision. OBJECTIVE: The primary objective was to conduct a systematic literature review (SLR) to identify the modelling approaches used in economic evaluations that assess current approved treatments in SMA, with a secondary objective to widen the scope and identify economic evaluations assessing other (non-SMA) neuromuscular disorders. METHODS: An SLR was performed to identify available economic evaluations associated with any type of SMA (Type 1, 2, 3 and/or 4). Economic evaluations associated with other (non-SMA) neuromuscular disorders were identified but not further analysed. Electronic searches were conducted in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform in August 2019, and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites and other relevant sources). Eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full publications was conducted with reference to a published checklist. RESULTS: Nine publications covering eight unique studies met all eligibility criteria for inclusion in the SLR, including four conference abstracts, two peer-reviewed original research articles and three HTA submissions (conducted in Canada, the US and the UK). Evaluations considered patients with early infantile-onset (most likely to develop Type 1 or Type 2 SMA), later-onset SMA and both infantile- and later-onset SMA. Data for the identified economic models were collected from literature reviews and relatively short-term clinical trials. Several intent-to-treat clinical trial populations were used in the studies, which resulted in variation in cycle length and different outcome measures to determine clinical efficacy. The results of the quality assessment on the five full-text, peer-reviewed publications found that they generally provided clear descriptions of objectives, modelling methods and results. However, key decisions, such as choice of economic evaluation, model type and choice of variables for sensitivity analysis, were often not adequately justified. CONCLUSIONS: This SLR highlights the need for economic evaluations in SMA to better align in modelling approaches with respect to (i) consistency in model structure and use of motor function milestones as health states; (ii) consensus on measuring quality of life to estimate utilities; (iii) consistency in data collection by registries; and (iv) consensus on SMA-type classification and endpoints that determine intervention efficacy. Future economic evaluations should also incorporate the review group critiques of previous HTA submissions relating to data inputs and approaches to modelling and should include patient data reflective of the SMA population being modelled. Economic evaluations would also be improved with inclusion of long-term efficacy and safety data from clinical trials and valid patient and caregiver utility data.

Estimating Treatment-Switching Bias in a Randomized Clinical Trial of Ovarian Cancer Treatment: Combining Causal Inference with Decision-Analytic Modeling.

BACKGROUND: Bevacizumab is efficacious in delaying ovarian cancer progression and controlling ascites. The ICON7 trial showed a significant benefit in overall survival for bevacizumab, whereas the GOG-218 trial did not. GOG-218 allowed control group patients to switch to bevacizumab upon progression, which may have biased the results. Lack of data on switching behavior prevented the application of g-methods to adjust for switching. The objective of this study was to apply decision-analytic modeling to estimate the impact of switching bias on causal treatment-effect estimates. METHODS: We developed a causal decision-analytic Markov model (CDAMM) to emulate the GOG-218 trial and estimate overall survival. CDAMM input parameters were based on data from randomized clinical trials and the published literature. Overall switching proportion was based on GOG-218 trial information, whereas the proportion switching with and without ascites was estimated using calibration. We estimated the counterfactual treatment effect that would have been observed had no switching occurred by denying switching in the CDAMM. RESULTS: The survival curves generated by the CDAMM matched well with the ones reported in the GOG-218 trial. The survival curve correcting for switching showed an estimated bias such that 79% of the true treatment effect could not be observed in the GOG-218 trial. Results were most sensitive to changes in the proportion progressing with severe ascites and mortality. LIMITATIONS: We used a simplified model structure and based model parameters on published data and assumptions. Robustness of the CDAMM was tested and model assumptions transparently reported. CONCLUSIONS: Medical-decision science methods may be merged with empirical methods of causal inference to integrate data from other sources where empirical data are not sufficient. We recommend collecting sufficient information on switching behavior when switching cannot be avoided.

Systematic Literature Review to Assess the Cost and Resource Use Associated with Spinal Muscular Atrophy Management.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe neuromuscular disease that is inherited in an autosomal recessive manner with an estimated incidence of 1 in 10,000 live births. The traditional classification of SMA includes five types (Types 0-4 SMA) based on patient age at disease onset and the highest motor milestone achieved. Spinal muscular atrophy leads to progressive muscle denervation, skeletal muscle atrophy and loss of motor function and ambulation, though phenotypes vary along a disease continuum. Regardless of disease severity, or access to treatment, a multidisciplinary approach to care is required to ease the burden of disease. To date, limited global data exist regarding the cost and resource use associated with SMA management. OBJECTIVE: We planned to perform a systematic literature review to identify studies on cost and healthcare resource use associated with SMA. METHODS: A comprehensive search was conducted in 2019 using several electronic databases in addition to supplementary sources and updated in 2021 in order to capture recently published studies. Electronic searches performed in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform were supplemented by searches of the grey literature (reference lists, conference proceedings, global Health Technology Assessment body websites and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full-text publications was evaluated with reference to a published checklist. To accommodate heterogeneity across studies including countries, currencies, populations, time units and methods of reporting used, costs were reported in Euros in 2019. RESULTS: A total of 51 publications, comprising 49 unique studies of patients with SMA that met all eligibility criteria were included in the final selection. The publications comprised data from 14 countries and seven additional studies that reported multi-national data. Because of the heterogeneity between the different types of SMA, data were frequently reported separately for individuals with Type 1 or early-onset SMA and for Types 2, 3, and 4 SMA or later-onset SMA. Generally, direct medical costs and resource use were reported to be highest for patients with Type 1 SMA, decreasing incrementally for patients with Type 2 and Type 3 disease. Where cost categories were similar, direct costs were much lower in Europe than in the USA. Indirect costs were primarily associated with informal care, which was a substantial burden on patients and families in terms of both cost and time. Cost drivers were generally found to be dependent on SMA type. CONCLUSIONS: Long-term robust studies are required to fully elucidate the economic burden of SMA. Considering that motor function can vary broadly, especially in Type 2 SMA, it would be beneficial to understand how costs and resource use are affected by different degrees of ambulation. Reporting data in terms of achieved motor function could also mitigate the challenges of comparing global data studies of small populations. Global, regional, and/or local data collection platforms and disease registry networks could play an important role in helping to address current data gaps.

Systematic Literature Review to Identify Utility Values in Patients with Spinal Muscular Atrophy (SMA) and Their Caregivers.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder that has a substantial impact on health-related quality of life for patients with SMA and their caregivers. Utility values ('utilities') are used in health economic analyses to incorporate individual or societal perspectives regarding the desirability of health outcomes such as a certain health state or change in health states over time. OBJECTIVES: The primary objective of this systematic literature review (SLR) was to identify published utilities associated with patients with SMA and their caregivers and to determine the extent to which Health Technology Assessment (HTA) requirements of methods used to generate utilities are met. A secondary objective was to broaden the scope to identify utilities associated with other (non-SMA) neuromuscular disorders. METHODS: A comprehensive search to capture published utilities associated with patients with SMA and their caregivers was performed in 2019 and updated in 2021 using several electronic databases in addition to supplementary sources. As we anticipated that few published utilities associated with SMA would be identified, the search also captured utilities for other (non-SMA) neuromuscular disorders that may serve as useful surrogate values for studies of SMA and other rare diseases. Electronic searches were performed in Embase, MEDLINE, Evidence-Based Medicine Reviews, and EconLit via the Ovid platform and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites, and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators, and outcomes (PICO) framework. The quality of the full-text publications was assessed using a checklist based on UK National Institute for Health and Care Excellence technical support documents. RESULTS: In total, 14 publications that reported SMA-related patient or caregiver utilities or disutilities met the eligibility criteria to be included in the SLR; the included studies demonstrate the substantial health-related quality-of-life burden of SMA on both patients with SMA and their caregivers. A variety of preference-based measures were used to derive utilities for patients with SMA and their caregivers. Different methods for collecting utility data included patient and proxy assessment of health states using questionnaires, vignette methodologies, structured forms of expert elicitation, and mapped data from results of clinical trials. A range of utilities was reported from both patient- and proxy-reported data, which reflects the degree of disability associated with early- and later-onset SMA. Methods for deriving utilities were assessed with respect to three reference cases from HTA bodies in the UK, the USA, and Canada. None of the 14 publications met the requirements of all three HTA bodies because of differing tariff requirements between countries; one study met the requirements of HTA bodies in Canada and the UK. Also, six studies did not report the method of valuation, which precluded analysis with respect to the HTA reference cases. CONCLUSIONS: This SLR provides a comprehensive repository of the currently available utilities relevant to patients with SMA and their caregivers. This SLR provides recommendations for establishing consensus on the approach to generating utility values for the SMA patient population and their caregivers for health economic decisions.

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study.

BACKGROUND: Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion. OBJECTIVES: We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial. METHODS: Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves. RESULTS: A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively. CONCLUSION: Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate.

Mixture Cure Models in Oncology: A Tutorial and Practical Guidance.

Novel cancer therapies are associated with survival patterns that differ from established therapies, which may include survival curves that plateau after a certain follow-up time point. A fraction of the patient population is then considered statistically cured and subject to the same mortality experience as the cancer-free general population. Mixture cure models have been developed to account for this characteristic. As compared to standard survival analysis, mixture cure models can often lead to profoundly different estimates of long-term survival, required for health economic evaluations. This tutorial is designed as a practical introduction to mixture cure models. Step-by-step instructions are provided for the entire implementation workflow, i.e., from gathering and combining data from different sources to fitting models using maximum likelihood estimation and model results interpretation. Two mixture cure models were developed to illustrate (1) an "uninformed" approach where the cure fraction is estimated from trial data and (2) an "informed" approach where the cure fraction is obtained from an external source (e.g., real-world data) used as an input to the model. These models were implemented in the statistical software R, with the freely available code on GitHub. The cure fraction can be estimated as an output from ("uninformed" approach) or used as an input to ("informed" approach) a mixture cure model. Mixture cure models suggest presumed estimates of long-term survival proportions, especially in instances where some fraction of patients is expected to be statistically cured. While this type of model may initially seem complex, it is straightforward to use and interpret. Mixture cure models have the potential to improve the accuracy of survival estimates for treatments associated with statistical cure, and the present tutorial outlines the interpretation and implementation of mixture cure models in R. This type of model will likely become more widely used in health economic analyses as novel cancer therapies enter the market.

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

PURPOSE: In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). METHODS: Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. RESULTS: The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. CONCLUSIONS: The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Cost-effectiveness of atezolizumab versus docetaxel and nivolumab in the treatment of non-small cell lung cancer as a second line in France.

Aim: To estimate the cost-effectiveness of atezolizumab compared with docetaxel and nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC), as a second-line treatment, in a French setting.Materials and methods: A three-state partitioned-survival model was developed (progression-free survival, post-progression survival, death) based on the phase IIIOAK trial on a 10-year time horizon. The comparison between nivolumab and atezolizumab came from a network meta-analysis. Utilities were estimated from the OAK trial EQ-5D applying the French utility tariffs. Overall survival (OS), progression-free survival (PFS), and treatment duration were estimated using parametric models selected using Akaike and Bayesian information criterion. Extrapolation beyond the trial duration followed NICE DSU TSD 14. Economic perspective was the one of all payers, discount rate fixed at 4% on benefits and costs. This analysis was aligned with French Haute Autorité de Santé recommendations. Results were expressed in total cost (2019) and €/QALY (Quality Adjusted Life Year). Model robustness was checked through sensitivity analyses, and a probabilistic sensitivity analysis was conducted.Results: In comparison to docetaxel, atezolizumab costs 49,429€ more and increased life expectancy by 8 months, generating 0.47 QALY. Incremental cost-effectiveness ratio was estimated at 104,835€/QALY. When comparing nivolumab to atezolizumab, a cost minimization analysis was conducted since no clear evidence supporting a difference in terms of survival benefit was reported. Using list price, and the Market Access Authorization regimens, atezolizumab saved approximately 6,000€, 9.5% of its total costs. Sensitivity analyses confirmed the robustness of our findings.Conclusion: Atezolizumab is more efficient and more costly than docetaxel in the second-line treatment of NSCLC of stage IIIB or IV, in France, with results consistent to previous French authorities' evaluation of immunotherapies in similar indication. Lastly, atezolizumab is a cost saving alternative to nivolumab, based on list price.

Cost-effectiveness of second-line atezolizumab in Canada for advanced non-small cell lung cancer (NSCLC).

Aim: To assess the cost-effectiveness in Canada of atezolizumab compared with docetaxel or nivolumab for the treatment of advanced NSCLC after first-line platinum-doublet chemotherapy. Materials and methods: A three-state partitioned-survival model was developed. Clinical inputs were obtained from the phase III OAK trial comparing atezolizumab with docetaxel in patients with advanced NSCLC who progressed after first-line platinum-doublet chemotherapy. Overall survival (OS) and progression-free survival (PFS) were extrapolated beyond the trial period using parametric models. A cure model assuming a 1% cure fraction was fitted to the OS data for atezolizumab. Outcomes for nivolumab were informed by a network meta-analysis (NMA) vs atezolizumab. Resource use and costs were informed by clinical expert opinion and published Canadian sources. Utility values were obtained from the OAK trial. The perspective of the analysis was that of the Canadian publicly-funded healthcare system. The base case time horizon was 10 years, and the discount rate was 1.5% annually for both costs and effects. Scenario analyses were performed to test the robustness of the results and all analyses were performed probabilistically. Results: Atezolizumab demonstrated a quality-adjusted life-year (QALY) gain of 0.60 compared with docetaxel at an incremental cost of $85,073, resulting in an incremental cost-effectiveness ratio (ICER) of $142,074/QALY. Atezolizumab dominated nivolumab (regardless of dosing regimen), based on modest differences in both QALYs and costs. Docetaxel was most likely to be cost effective at willingness-to-pay (WTP) thresholds below $125,000/QALY gained, while atezolizumab was most likely to be cost effective beyond this WTP threshold. In most scenario analyses, the results remained robust to changes in parameters. A reduced time horizon and alternative approaches to the NMA had the greatest impact on cost-effectiveness results. Conclusion: Atezolizumab represents a cost-effective therapeutic option in Canada for the treatment of patients with advanced NSCLC who progress after first-line platinum doublet chemotherapy.

Systematic review of health state utility values in metastatic non-small cell lung cancer with a focus on previously treated patients.

BACKGROUND: Health state utility values (HSUVs) are an important input to economic evaluations and the choice of HSUV can affect the estimate of relative cost-effectiveness between interventions. This systematic review identified utility scores for patients with metastatic non-small cell lung cancer (mNSCLC), as well as disutilities or utility decrements relevant to the experience of patients with mNSCLC, by treatment line and health state. METHODS: The MEDLINE®, Embase and Cochrane Library databases were systematically searched (September 2016) for publications describing HSUVs in mNSCLC in any treatment line. The EQ-5D website, the School of Health and Related Research Health Utilities Database (ScHARRHUD) and major pharmacoeconomic and clinical conferences in 2015-2016 were also queried. Studies in adults with previously treated mNSCLC were selected for further analysis. The information extracted included study design, description of treatment and health state, respondent details, instrument and tariff, HSUV or (dis) utility decrement estimates, quality of study, and appropriateness for use in economic evaluations. RESULTS: Of 1883 references identified, 36 publications of 34 studies were included: 19 reported EQ-5D scores; eight reported HSUVs from valuations of vignettes made by members of the public using standard gamble (SG) or time trade-off (TTO); two reported SG or TTO directly elicited from patients; two reported EQ-5D visual analogue scale scores only; one reported Assessment of Quality of Life instrument scores; one reported HSUVs for caregivers to patients with mNSCLC using the 12-item Short-Form Health Survey; and one estimated HSUVs based on expert opinion. The range of HSUVs identified for comparable health states showed how differences in study type, tariff, health state and the measures used can drive variation in HSUV estimates. CONCLUSIONS: This systematic review provides a set of published HSUVs that are relevant to the experience of adult patients previously treated for mNSCLC. Our review begins to address the challenge of identifying reliable estimates of utility values in mNSCLC that are suitable for use in economic evaluations, and also highlights how varying estimates result from differences in methodology.

Accounting for Uncertainty in Decision Analytic Models Using Rank Preserving Structural Failure Time Modeling: Application to Parametric Survival Models.

OBJECTIVES: Rank Preserving Structural Failure Time models are one of the most commonly used statistical methods to adjust for treatment switching in oncology clinical trials. The method is often applied in a decision analytic model without appropriately accounting for additional uncertainty when determining the allocation of health care resources. The aim of the study is to describe novel approaches to adequately account for uncertainty when using a Rank Preserving Structural Failure Time model in a decision analytic model. METHODS: Using two examples, we tested and compared the performance of the novel Test-based method with the resampling bootstrap method and with the conventional approach of no adjustment. In the first example, we simulated life expectancy using a simple decision analytic model based on a hypothetical oncology trial with treatment switching. In the second example, we applied the adjustment method on published data when no individual patient data were available. RESULTS: Mean estimates of overall and incremental life expectancy were similar across methods. However, the bootstrapped and test-based estimates consistently produced greater estimates of uncertainty compared with the estimate without any adjustment applied. Similar results were observed when using the test based approach on a published data showing that failing to adjust for uncertainty led to smaller confidence intervals. CONCLUSIONS: Both the bootstrapping and test-based approaches provide a solution to appropriately incorporate uncertainty, with the benefit that the latter can implemented by researchers in the absence of individual patient data.

Analyzing Health-Related Quality of Life Data to Estimate Parameters for Cost-Effectiveness Models: An Example Using Longitudinal EQ-5D Data from the SHIFT Randomized Controlled Trial.

INTRODUCTION: The aim of this article is to discuss methods used to analyze health-related quality of life (HRQoL) data from randomized controlled trials (RCTs) for decision analytic models. The analysis presented in this paper was used to provide HRQoL data for the ivabradine health technology assessment (HTA) submission in chronic heart failure. METHODS: We have used a large, longitudinal EuroQol five-dimension questionnaire (EQ-5D) dataset from the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) (clinicaltrials.gov: NCT02441218) to illustrate issues and methods. HRQoL weights (utility values) were estimated from a mixed regression model developed using SHIFT EQ-5D data (n = 5313 patients). The regression model was used to predict HRQoL outcomes according to treatment, patient characteristics, and key clinical outcomes for patients with a heart rate ≥75 bpm. RESULTS: Ivabradine was associated with an HRQoL weight gain of 0.01. HRQoL weights differed according to New York Heart Association (NYHA) class (NYHA I-IV, no hospitalization: standard care 0.82-0.46; ivabradine 0.84-0.47). A reduction in HRQoL weight was associated with hospitalizations within 30 days of an HRQoL assessment visit, with this reduction varying by NYHA class [-0.07 (NYHA I) to -0.21 (NYHA IV)]. CONCLUSION: The mixed model explained variation in EQ-5D data according to key clinical outcomes and patient characteristics, providing essential information for long-term predictions of patient HRQoL in the cost-effectiveness model. This model was also used to estimate the loss in HRQoL associated with hospitalizations. In SHIFT many hospitalizations did not occur close to EQ-5D visits; hence, any temporary changes in HRQoL associated with such events would not be captured fully in observed RCT evidence, but could be predicted in our cost-effectiveness analysis using the mixed model. Given the large reduction in hospitalizations associated with ivabradine this was an important feature of the analysis. FUNDING: The Servier Research Group.