Globally, primary liver cancer is the sixth most prevalent malignancy and the third leading cause of cancer-related deaths (1). Hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancers, is characterized by high aggressiveness, rapid progression, and a poor prognosis (2). China reports a disproportionately high incidence of HCC, contributing to nearly half of the world’s new cases each year (3). The overall prognosis for patients with HCC remains poor, with a 5-year survival rate of only 19.6% (4). Additionally, the majority of HCC cases are diagnosed at advanced stages, with these patients having a 5-year survival rate of under 10% (5, 6). Over the last decade, targeted therapies based on lenvatinib and sorafenib have become the standard first-line treatments for advanced HCC. Although these therapies have improved patient outcomes, they have only extended the median overall survival (OS) to 10–15 months (7, 8). This highlights the urgent need for more effective treatment strategies for advanced HCC.

Numerous clinical trials have demonstrated that immune checkpoint inhibitors (ICIs), in combination with anti-angiogenic agents such as bevacizumab, outperform sorafenib in prolonging progression-free survival (PFS) and OS in patients with advanced HCC (9–11). The recently completed phase III HEPATORCH trial investigated the efficacy and safety of toripalimab (an ICI) plus bevacizumab (TOR-BEV) as a first-line treatment for advanced HCC. The trial found that TOR-BEV significantly improved the median PFS to 5.8 months, compared to 4.0 months with sorafenib, and increased the median OS to 20.0 months, compared to 14.5 months with sorafenib. Both treatment regimens exhibited comparable safety profiles (12). Thus, TOR-BEV represents a promising new option for the treatment of advanced HCC.

Since 2018, the National Healthcare Security Administration of China has formally incorporated pharmacoeconomic evaluation into the negotiation process for dynamic adjustments to the National Reimbursement Drug List, establishing it as a critical tool for determining whether high-value innovative medicines can be included in the list. This mechanism ensures clinical accessibility while achieving a balance between healthcare fund sustainability and patient benefits. Given the constraints on medical resources in China (13), policymakers and clinicians must carefully consider the cost-effectiveness of treatment options to ensure optimal resource allocation. This is particularly critical in cancer care, which is associated with high treatment costs (14). While TOR-BEV offers superior survival benefits compared to sorafenib, it also incurs significantly higher treatment costs. Therefore, evaluating whether TOR-BEV is cost-effective as a first-line treatment for advanced HCC is essential. To date, no economic evaluations of TOR-BEV as a first-line treatment for advanced HCC have been conducted. This study aims to fill this gap by assessing the cost-effectiveness of TOR-BEV, in comparison to sorafenib, from the perspective of China’s healthcare system.

This study was conducted following the updated Consolidated Health Economic Evaluation Reporting Standards guidelines (2022 version, Supplementary Table 1) (15).

To our knowledge, this study is the first to assess and compare the cost-effectiveness of TOR-BEV and sorafenib as first-line treatments for advanced HCC from the perspective of China’s healthcare system, based on the latest clinical evidence. This represents a key innovation of the study. Our analysis shows that compared to sorafenib, TOR-BEV increases QALYs by 0.45, with an additional cost of $31,037.71, resulting in an ICER of $69,231.90 per QALY, which exceeds the predefined WTP threshold. As a result, from the perspective of China’s healthcare system, TOR-BEV is not considered cost-effective when compared to sorafenib. This may be due to several challenges faced by novel anti-tumor drugs, including lengthy development timelines, high costs, low success rates, and patent protections, all of which contribute to high market prices (37). Consequently, the costs of toripalimab and bevacizumab are significantly higher than sorafenib, making the treatment cost per cycle for the TOR-BEV regimen more expensive without delivering sufficient incremental survival benefits. The one-way sensitivity analysis highlights that, aside from utility values, key factors influencing the model’s outcomes include patient weight (used to calculate the bevacizumab dose) and the costs of bevacizumab and toripalimab, which supports the previous conclusion. Since its establishment in 2018, China’s National Healthcare Security Administration has been actively promoting national procurement strategies and conducting multiple rounds of price negotiations with pharmaceutical companies. These efforts aim to improve the accessibility of anti-cancer drugs and significantly reduce the financial burden on society and cancer patients. As a result, the prices of many anti-cancer drugs have dropped significantly, with reductions ranging from 30 to 70% (38). Given this, the potential price reductions of toripalimab and bevacizumab that would make TOR-BEV cost-effective were explored. These findings suggest that TOR-BEV could become cost-effective if the prices of both drugs were reduced to below 50.1% of their current prices. This provides valuable economic insights for future price negotiations and medical insurance discussions for these drugs. This threshold provides valuable economic insights for future price negotiations, particularly for the National Healthcare Security Administration. Notably, it serves as a concrete, evidence-based target in drug reimbursement decision-making, facilitating sustainable access to innovative oncology therapies while ensuring healthcare fund affordability.

One-way sensitivity analysis indicates that the model outcomes remain stable when the values of model parameters are varied within a specified range. The probabilistic sensitivity analysis further demonstrates that, when used as a first-line treatment for advanced HCC, the probability of TOR-BEV being cost-effective compared to sorafenib is only 1.5%. These findings provide evidence of the model’s robustness from different analytical perspectives. The Scenario 1 analysis reveals that as the model duration increases, the ICER for TOR-BEV compared to sorafenib decreases, suggesting that TOR-BEV becomes more cost-effective with longer treatment durations. This trend may improve patient adherence to long-term treatment, thus having a positive ethical impact. Scenario 2 highlights that TOR-BEV is cost-effective in economically advanced regions, such as Beijing, but not in moderately developed areas like Inner Mongolia or underdeveloped regions like Gansu. This underscores the importance of considering local economic conditions and the availability of medical resources in drug policy and resource allocation decisions, aiming to achieve cost-effective distribution, promote medical equity, and enhance the overall quality and efficiency of healthcare services. Subgroup analysis suggests that only the Eastern Cooperative Oncology Group performance status score of 1 subgroup is cost-effective, while the Barcelona Clinic Liver Cancer stage B and no macrovascular invasion or extrahepatic spread subgroups are nearly cost-effective. This suggests that personalized treatment plans, tailored to individual patient characteristics, could optimize cost-effectiveness, providing valuable guidance for healthcare policymakers in establishing appropriate reimbursement criteria. To the best of our knowledge, several pharmacoeconomic analyses of ICIs combined with bevacizumab for advanced HCC treatment have been conducted, primarily focusing on atezolizumab and sintilimab. Studies by Hou et al. (39), Wen et al. (40), Su et al. (19), and Liu et al. (24) concluded that atezolizumab plus bevacizumab is unlikely to be a cost-effective first-line option for patients with advanced HCC compared to sorafenib, which aligns with our findings. In contrast, Ye et al. (41) and Zhou et al. (42) considered sintilimab combined with bevacizumab biosimilars a cost-effective first-line therapy for advanced HCC, contradicting our results. The choice of comparator is a critical step in cost-effectiveness analysis. According to the 2024 Chinese Clinical Guidelines for Primary Liver Cancer, first-line systemic therapies for advanced HCC include—not only sorafenib—but also regimens such as atezolizumab plus bevacizumab and sintilimab plus bevacizumab. However, no head-to-head trial data are available comparing TOR-BEV with these immune-combination regimens. Therefore, we selected sorafenib as the comparator, which has direct phase III evidence (HEPATORCH trial) and is concurrently recommended by the guidelines, to ensure consistent efficacy inputs and to keep uncertainty manageable.

It should be noted that this study employs a partitioned survival model based on the following assumptions: patients are partitioned into three mutually exclusive and irreversible health states (PFS, PD, and dead); the state proportions are derived from independently fitted PFS and OS curves; and the relative treatment effect observed during follow-up is assumed to remain constant over the extrapolation period. These assumptions impose inherent limitations: the model cannot capture repeated progression or backward transitions; the absence of structural constraints between PFS and OS may produce structural inconsistency (i.e., the proportion alive and progression-free exceeding the proportion alive) if extrapolation is misspecified; and long-term survival probabilities are highly sensitive to the chosen parametric functional form. Insufficient follow-up coupled with minor mis-specification can substantially inflate the uncertainty in cost-effectiveness analysis results and may alter the cost-effectiveness conclusion.

This study has several key strengths. First, it incorporates the latest HEPATORCH trial data, which directly compares the efficacy of TOR-BEV and sorafenib, providing cutting-edge cost-effectiveness evidence. Second, as all participants in the HEPATORCH trial are Asian patients, with 96.3% from mainland China, the trial’s results are highly applicable to cost-effectiveness analyses in the Chinese population. Finally, the detailed subgroup and scenario analyses offer valuable economic insights for various patient groups and treatment settings, serving as an important resource for physicians, patients, and policymakers when selecting personalized treatment plans and making informed decisions.

However, this study has several limitations. First, to simplify the model, only grade 3 or higher adverse reactions with an incidence rate of ≥5% were included, which may underestimate treatment costs. Nonetheless, the one-way sensitivity analysis indicates that adverse reaction management costs do not significantly affect the model’s results. Second, the HEPATORCH trial does not provide quality-of-life data, so survival utility values from Chinese literature were used, which may introduce bias. However, one-way sensitivity analysis suggests this does not alter the model’s outcomes. Third, due to the ongoing nature of the HEPATORCH trial, long-term survival data are unavailable. Extrapolation of survival data beyond the follow-up period using survival models may not fully reflect actual outcomes. The study will be updated once long-term data are available. Fourth, the HEPATORCH trial does not provide detailed information on treatments after PD. The assumption that patients receive regorafenib or best supportive care as second-line treatment may not fully capture real-world clinical practices. Fifth, the subgroup analysis used subgroup-specific hazard ratios to proportionally shift the survival curves, assuming time-invariant treatment effects. If the true efficacy declines over time, this assumption will over-extrapolate tail survival and may systematically inflate lifetime QALYs and ICERs. Coupled with limited sample sizes in each subgroup, these factors warrant cautious interpretation of the subgroup findings. Despite these limitations, the study offers valuable economic insights for policymakers, healthcare providers, and patients.

From the perspective of the Chinese healthcare system, TOR-BEV is unlikely to be cost-effective as a first-line treatment for advanced HCC compared to sorafenib unless the prices of both toripalimab and bevacizumab are reduced to below 50.1% of their current prices. However, this regimen was cost-effective in the subgroup of patients with an Eastern Cooperative Oncology Group performance status score of 1, and economic viability is also expected in highly developed regions such as Beijing.