By 2030, one million people will die of liver cancer, which becomes the second leading cause of death after pancreatic cancer from the World Health Organization's annual projections. In fact, over the past 30 years, the incidence of HCC has increased two to threefold in the U.S.[16]. There is no doubt that as the number of HCC patients increasing, there will be a heavy financial burden to the U.S. fiscal expenditure and the medicare reimbursement. Sorafenib is the first-line targeted drug approved for advanced HCC. However, more and more studies have shown that sorafenib has limited survival benefits and associate with severe adverse reactions (SAEs), which damaged patients' quality of life[3]. Recent years, the treatment of advanced HCC has changed dramatically. After 10 years of failed research, there has been an upsurge of targeted therapy and immunotherapy options in both first-line and second-line treatments, changing the way we treated advanced HCC patients. Currently, several cancer immunotherapies targeting the PD-1/PD-L1 pathway were being assessed in patients with advanced HCC[6]. However, some researches demonstrated that PD-1 inhibitors monotherapy did not significantly improve OS. ICIs were not recommended to work alone in patients with HCC. At present, the combination of immunotherapy and antiangiogenic drugs is highly appraised by researchers and clinical physicians[17, 18].
HCC patients were often associated with inflammatory responses, which exacerbated the adverse effects on normal and immune cells. Recent studies have shown that tumor cells have unique neovascular structures that might lead to drug leakage, making it difficult for antitumor drugs and immune cells to reach the tumor site. Anti-VEGF therapies have long been proposed to normalize blood vessels and improve the effectiveness of immunotherapy, which suggested the combination of immunosuppressive and antiangiogenic drugs might have synergistic effects[17]. In the comprehensive NCT03434379 study, the immunotherapy in the Ate plus Beva regimen significantly extended both the OS and PFS[7]. Although the potential use of Ate plus Beva would raise hope for patients, unfortunately, the high price came with a heavy financial burden on healthcare services and society. Obviously, governments and health care systems around the world would have to consider whether part of this therapy’s cost should be borne. The U.S. reimbursement department paid more and more attention to the cost and cost-effectiveness of drug interventions[12]. An economic evaluation is warranted to determine the optimal choices of first-line treatments for HCC patients in terms of both efficacy and cost.
Based on our model, the ICER for Ate plus Beva versus sorafenib was evaluated as $288,663.09/ QALY. The probabilistic sensitivity analyses showed a high likelihood that Ate plus Beva would be considered not cost-effective at a WTP threshold of $150,000/QALY. Currently, there are only two pharmacoeconomic studies about atezolizumab combination with anti-angiogenic therapies. Those showed that atezolizumab plus bevacizumab and chemotherapy was not cost-effective in patients with non-small-cell lung cancer from the perspective of the U.S., which were consistent with our research. Meanwhile, we noted that the price of atezolizumab had the most significant impact on univariate sensitivity analysis results, which suggested that the high cost of ICIs for HCC was an insurmountable problem, especially in a country like the U.S., which lack a powerful governing body to constrain the growth of drug costs[19].
Spending on cancer drugs would be the main reason for an increase in medical insurance expenditure from $36 trillion in 2018 to nearly $60 trillion in 2027, according to the estimate of the U.S. Centers for Medicare and Medicaid Services. As the concept of "financial toxicity" was gradually accepted by the public, the increasing cost of medical care would inevitably impose an economic burden on government departments and society. Meanwhile, we must consider the financial impact on individual patient. Given the high cost of health care, it might lead to lower patient compliance and so that be a risk factor for early mortality[20].
In this study, we sought to explore the possibility of cost-effectiveness of immunotherapy for patients with HCC. First, we conducted a structural sensitivity analysis of second-line treatment regimens after first-line treatment progression for HCC patients. The tyrosine kinase inhibitors, immunotherapy, or chemotherapy regimens were used as the subsequent treatment options in our model, which led to an much higher ICER value than the WTP threshold. When only TKIs were used as second-line therapy, a lower ICER value was produced. Unfortunately, even in this case, Ate plus Beva was not found to be cost-effective. Next, we assumed the price of atezolizumab would decrease to warrant the cost-effectiveness and the affordability of Ate plus Beva regimen. The cost-effectiveness probability of atezolizumab would exceed 50% when the price of atezolizumab decreased by 75% at the WTP of $150,000 per QALY. Finally, biomarker based patient selection might help to maximize the efficacy of ICIs and exclude patients who may not benefit from or even be harmed by ICIs. Several potential biomarkers have been proposed in HCC, including PD-L1 expression, tumor mutation load (TMB) and genome-specific changes[21]. If these biomarkers were employed to select favorable patients, the economics of the Ate plus Beva regimen would likely be improved greatly.
It was worth mentioning that two health economics outcome indicators were evaluated in our study: the ICER and INHB analysis. The INHB studies were used for linear transformations of the ICER analysis. This statistical linear structure made the calculation and interpretation of replacement intervals, hypothesis tests, and acceptable curves easy to understand. Meantime, the INHB analysis was an excellent way to analyze uncertainties in the Markov model, and one of the differences of INHB from the ICER analysis was the inclusion of "patient preferences"[22]. The pharmacoeconomic evaluation results of the combined group were double-verified, which further enhanced the reliability of our results.
As other cost-effectiveness analyses, there were some limitations to this study. First, our study was based on a phase 3 randomized controlled trial, which might not be the best reference to guide real-world patients’ treatments. The actual resources used in disease processes and clinical practice cannot be fully replicated in our model. Drug doses were calculated based on the average body weight of an American, which varied from person to person. The data of registered participants in the NCT03434379 trial were from all over the world, not only from the U.S., but also from Asia[7]. Nonetheless, the sensitivity analyses results demonstrated that body weight was not the main factor and had little impact on ICER. Second, the utility values of this model referred to that of previously published literatures due to the lack of studies about QoL in HCC patients with atezolizumab immunotherapy. The utility values (0.76 for PFS state and 0.68 for PD state) applied in our model were close to a pharmacoeconomic study of another ICI ramucirumab for HCC patients, in which utility scores under PFS state was set to 0.778, and the utility under PD state was 0.688[23], which supported the usability of the utility values in the model. In the routine clinical practice of specific schemes, an EQ-5D questionnaire should be used to investigate the quality of life of patients, so as to make the results more accurate in future studies. Finally, this research ignored the costs of third-line and fourth-line treatments because the number of patients receiving the above treatments was very few in the NCT03434379 trial. Only 3.3% and 0.3% of patients received third-line and fourth-line treatments in Ate plus Beva regimen, 11.5% and 2.4% patients in sorafenib regimen, respectively[7]. In addition, no standard therapy in third-line and fourth-line treatments was recommended in the NCCN Guidelines. Therefore, in the model, it was assumed that these patients received the BSC after disease progression. Although it might cause some bias, the sensitivity analysis demonstrated a minor influence on ICER.