First-Line Atezolizumab Plus Bevacizumab versus Sorafenib in Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

Simple Summary There is a growing body of literature demonstrating high cancer drug costs relative to the benefits provided to patients treated on a large scale. We examined the cost-effectiveness of atezolizumab–bevacizumab for the first-line treatment of patients with unresectable hepatocellular carcinoma, based on the results of the pivotal phase 3 trial IMbrave 150. Our model was most sensitive to the overall survival hazard ratio and body weight. We found that atezolizumab–bevacizumab was cost-effective if we assumed all patients at the end of the IMbrave 150 trial were cured of hepatocellular carcinoma. Otherwise, atezolizumab–bevacizumab was not cost-effective. We concluded that price reduction, duration of therapy capped to ≤12 months, or dosage of bevacizumab reduced to ≤10 mg/kg would favorably influence cost-effectiveness, even if long-term clinical benefits were modest. The long-term effectiveness of atezolizumab–bevacizumab is a critical factor of its cost-effectiveness. Further studies to optimize the duration and dosage of therapy are warranted. Abstract Background: The IMbrave 150 trial revealed that atezolizumab plus bevacizumab (atezo–bev) improves survival in patients with unresectable hepatocellular carcinoma (HCC) (1 year survival rate: 67.2% vs. 54.6%). We assessed the cost-effectiveness of atezo–bev vs. sorafenib as first-line therapy in patients with unresectable HCC from the US payer perspective. Methods: Using data from the IMbrave 150, we developed a Markov model to compare the lifetime cost and efficacy of atezo–bev as first-line systemic therapy in HCC with those of sorafenib. The main outcomes were life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Results: Atezo–bev demonstrated a gain of 0.44 QALYs, with an additional cost of USD 79,074. The ICER of atezo–bev was USD 179,729 per QALY when compared with sorafenib. The model was most sensitive to the overall survival hazard ratio and body weight. If we assumed that all patients at the end of the IMbrave 150 trial were cured of HCC, atezo–bev was cost-effective (ICER USD 53,854 per QALY). However, if all patients followed the Surveillance, Epidemiology, and End Results data, the ICER of atezo–bev was USD 385,857 per QALY. Reducing the price of atezo–bev by 20% and 29% would satisfy the USD 150,000/QALY and 100,000/QALY willingness-to-pay threshold. Moreover, capping the duration of therapy to ≤12 months or reducing the dosage of bev to ≤10 mg/kg would render atezo–bev cost-effective. Conclusions: The long-term effectiveness of atezo–bev is a critical but uncertain determinant of its cost-effectiveness. Price reduction would favorably influence cost-effectiveness, even if long-term clinical outcomes were modest. Further studies to optimize the duration and dosage of therapy are warranted.


Introduction
Background and objectives 3 Provide an explicit statement of the broader context for the study. 5-6 Present the study question and its relevance for health policy or practice decisions. 5-6 Methods Target population and subgroups 4 Describe characteristics of the base case population and subgroups analysed, including why they were chosen. 6 Setting and location 5 State relevant aspects of the system(s) in which the decision(s) need(s) to be made. 6 Study perspective 6 Describe the perspective of the study and relate this to the costs being evaluated. 7 Comparators 7 Describe the interventions or strategies being compared and state why they were chosen. 6 Time horizon 8 State the time horizon(s) over which costs and consequences are being evaluated and say why appropriate. 7 Discount rate 9 Report the choice of discount rate(s) used for costs and outcomes and say why appropriate. 7 Choice of health outcomes 10 Describe what outcomes were used as the measure(s) of benefit in the evaluation and their relevance for the type of analysis performed. 7

Measurement of effectiveness 11a
Single study-based estimates: Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data.

7-8 11b
Synthesis-based estimates: Describe fully the methods used for identification of included studies and synthesis of clinical effectiveness data. Measurement and valuation of preference based outcomes 12 If applicable, describe the population and methods used to elicit preferences for outcomes.
not applicable

Estimating resources and costs 13a
Single study-based economic evaluation:Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

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Model-based economic evaluation: Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

8-9
Currency, price date, and conversion 14 Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate.
9-10 -10Choice of model 15 Describe and give reasons for the specific type of decision-analytical model used.
Providing a figure to show model structure is strongly recommended. 7 Assumptions 16 Describe all structural or other assumptions underpinning the decision-analytical model. 8

Analytical methods 17
Describe all analytical methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (such as half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty.

Study parameters 18
Report the values, ranges, references, and, if used, probability distributions for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended. Table 1 33Incremental costs and outcomes 19 For each intervention, report mean values for the main categories of estimated costs and outcomes of interest, as well as mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios.
10, Table 2 Characterising uncertainty 20a Single study-based economic evaluation:Describe the effects of sampling uncertainty for the estimated incremental cost and incremental effectiveness parameters, together with the impact of methodological assumptions (such as discount rate, study perspective). 20b Model-based economic evaluation: Describe the effects on the results of uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions.

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Characterising heterogeneity 21 If applicable, report differences in costs, outcomes, or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.
11, supplementary Table 4 Discussion Study findings, limitations, generalisability, and current knowledge 22 Summarise key study findings and describe how they support the conclusions reached. Discuss limitations and the generalisability of the findings and how the findings fit with current knowledge.

Source of funding 23
Describe how the study was funded and the role of the funder in the identification, design, conduct, and reporting of the analysis. Describe other non-monetary sources of support. 2

Conflicts of interest 24
Describe any potential for conflict of interest of study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors recommendations.

2
For consistency, the CHEERS statement checklist format is based on the format of the CONSORT statement checklist.

Technical notes 1. Justifying the choice of Markov Modeling Over Partitioned Survival Modeling
The IMbrave 150 trial has reported outcomes as co-primary endpoints of overall survival (OS) and progressionfree survival (PFS) curves. These two curves contain combined information on the rates of three clinical outcomes: disease progression, pre-progression mortality, and post-progression mortality. Notably, accurate oncological modeling depends on accurate identification of time-dependent rates of these three distinct rates from the published survival curves.
The Markov survival model (MSM) and partitioned survival model (PSM) are two commonly used models in oncological modeling. We select the MSM model in this analysis owing to the following reasons. First, PSM assumes constant costs and utilities over time, which is inappropriate for modeling advanced HCC patients. Second, PSM does not accurately model multiple lines of therapy. However, in the IMbrave 150 study, a substantial number of patients received two or more lines of systemic therapies or additional local therapy.   The three main health states are represented by ovals and include 'progression-free', 'disease progression', and "death." Arrows represent possible transitions from one health state to the next.   Cost-effectiveness of Atezo-Bev combination compared with dosage and duration of Bev. The atezo-bev combination costs < $150,000 per QALY when the duration of atezo-bev is capped at 12 months. When the bev dosage is reduced to 10 mg/kg, atezo-bev is consistently cost-effective at frequently accepted thresholds. Abbreviations: Atezo, atezolizumab; Bev, bevacizumab; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; (B). Cost-effectiveness of Atezo-Bev combination compared with duration of Bev and survival estimation; The atezo-bev combination costs < $100,000 per QALY in the optimistic survival estimation; however, the atezo-bev combination costs > $150,000 in most scenarios under the pessimistic survival estimation. Abbreviations: Atezo, atezolizumab; Bev, bevacizumab; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year. #Base case scenario: extrapolated long-term outcome from short-term data of IMbrave 150 study (i.e. 3-year survival rate of 37.7%); Pessimistic scenario: we assumed that survival after 17 months would follow the survival estimates of the US population with advanced HCC obtained from the SEER database (i.e. 3-year survival rate of 27.8%); Optimistic scenario: we assumed that all patients 'alive' at 17 months were 'cured' and the risk of death would be equal to their age-adjusted background mortality rate (i.e. 3-year survival rate of 60.7%); (C) Cost-effectiveness of Atezo-Bev combination compared with bev dosage and survival estimation. The atezo-bev cost < $100,000 per QALY in the optimistic survival estimation, whereas the atezo-bev combination costs > $150,000 in all scenarios under the pessimistic survival estimation. Abbreviations: Atezo, atezolizumab; Bev, bevacizumab; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year. # Base case scenario: extrapolated long-term outcome from short-term data of IMbrave 150 study (i.e. 3-year survival rate of 37.7%); Pessimistic scenario: we assumed that survival after 17 months would follow the survival estimates of the US population with advanced HCC obtained from the SEER database (i.e. 3-year survival rate of 27.8%); Optimistic scenario: we assumed that all patients 'alive' at 17 months were 'cured' and the risk of death would be equal to their age-adjusted background mortality rate (i.e. 3-year survival rate of 60.7%); (D) Two-way sensitivity analyses for utility value of atezo-bev and sorafenib. (E) Two-way analyses for post-progression therapy costs of atezo-bev and sorafenib. Abbreviations: ICER, incremental cost-effectiveness ratio; Atezo, atezolizumab; Bev, bevacizumab; QALY, quality-adjusted life-year; Abbreviations: ICER, incremental cost-effectiveness ratio; Atezo, atezolizumab; Bev, bevacizumab; QALY, quality-adjusted life-year .