Challenges for Measuring Cost-effectiveness of Immunotherapy in Unresectable Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a significant and growing cause of cancer-related death in the United States.¹ HCC prognosis markedly differs by tumor stage at diagnosis.² Patients with advanced tumor burden usually have a poor prognosis, with median survival of 1 to 2 years.¹ Evidence-based treatments are limited for advanced HCC, but recent advances have resulted in an increase in the use of immunotherapeutic agents. Among these are atezolizumab and bevacizumab, fully humanized monoclonal antibodies selectively targeting programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor, respectively.

Zhang et al³ evaluated the cost-effectiveness of this combination therapy vs sorafenib (an oral multikinase inhibitor) as a first-line treatment for advanced HCC from a US payer perspective. Progression-free and overall survival data were drawn from the IMBRAVE150 trial,⁴ which showed a significant survival benefit in patients with unresectable or metastatic HCC treated with atezolizumab and bevacizumab compared with sorafenib only. Despite this survival benefit, Zhang and colleagues³ found that atezolizumab plus bevacizumab combination therapy was not likely to be cost-effective compared with current treatments for advanced HCC, with an incremental cost-effectiveness ratio of $322 500 per quality-adjusted life-year gained.³ A threshold analysis showed that prices for atezolizumab and bevacizumab would have to be reduced by 37% and 47%, respectively, to be considered a cost-effective alternative at common willingness-to-pay thresholds of $150 000 or $100 000. The authors demonstrated the robustness of these findings through 1-way and probabilistic sensitivity analyses, showing that their conclusions held across of a variety of subgroups and for most tested model input combinations.

This analysis provides new and important insight for decision-makers with as much nuance as the available data will allow. However, this study also highlights the challenges of conducting cost-effectiveness analysis for a disease as complex as advanced HCC. Zhang et al³ generated many of their key model inputs from the IMBRAVE150 trial data,⁴ which included disproportionate representation from patients with well-preserved liver function (Child-Pugh class A) and good performance status (Eastern Cooperative Oncology group scores 0-1). It is unclear how these results generalize to the benefits and/or risks, and therefore the cost-effectiveness, of the drug in clinical practice, where patients have comparatively more severe disease. With the lack of clarity regarding the predictive value of PD-L1 status and how it affects progression-free survival in HCC, it remains unclear whether a subset of patients who are likely to have a better response to atezolizumab plus bevacizumab combination therapy could be identified through biomarker analyses.⁴

Additionally, HCC is a disease characterized by profound racial and ethnic disparities in the United States. Higher age-specific incidence and mortality rates are seen among Asian, Black, and Hispanic individuals compared with non-Hispanic White individuals.⁵ Black and Hispanic patients tend to present with more advanced tumor burden and have worse survival compared with non-Hispanic White patients.⁶ The participants of the IMBRAVE150 trial⁴ were recruited across 17 countries, and while more than 50% of participants identified as Asian, only 10 participants (2%) across both treatment and control groups identified as Black, and no data were reported for individuals with Hispanic ethnicity. Without decision models that reflect the clinical and demographic characteristics of the population for which a decision is being made, we lack crucial information to guide clinical care. Given the well-documented racial and ethnic disparities in the receipt of immunotherapy,⁷ it is likely that introducing atezolizumab plus bevacizumab as a treatment for advanced HCC will only increase the existing disparities in HCC mortality.

HCC incidence and mortality in the United States have increased markedly over the past decades and are predicted to continue rising for many subgroups.¹ Zhang et al³ provide novel insight through conducting a cost-effectiveness analysis of a newer immunotherapy—atezolizumab plus bevacizumab combination therapy—in a disease with few promising treatment alternatives. As the authors discuss, the finding that this treatment is not cost-effective at standard willingness-to-pay thresholds is unlikely to stop it from being incorporated into clinical practice, nor do they suggest this should be the case. However, they underscore the importance of prioritizing HCC interventions that have been shown to be a high-value use of resources, including surveillance among patients with known risk factors. We further contend that efficient allocation of resources for a disease that disproportionately affects individuals from marginalized racial and ethnic groups requires a dedication to equity at every step of the process, including in data collection and model development.

Published: April 7, 2021. doi:10.1001/jamanetworkopen.2021.5476

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wagle NS et al. JAMA Network Open.

Corresponding Author: Jennifer C. Spencer, PhD, Center for Health Decision Sciences, Harvard T.H. Chan School of Public Health, 718 Huntington Ave, Boston, MA 02115-5924 (jspencer@hsph.harvard.edu).

Conflict of Interest Disclosures: None reported.