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Cost-effectiveness of the addition of sintilimab as a first-line therapy for locally advanced or metastatic oesophageal squamous cell carcinoma: a Chinese healthcare system perspective

Health Economics Review volume 15, Article number: 2 (2025) Cite this article

Abstract

Background

The ORIENT-15 double-blind randomized controlled trial demonstrated that the addition of sintilimab to chemotherapy for locally advanced or metastatic oesophageal squamous cell carcinoma (OSCC) resulted in better clinical outcomes. In this analysis, we sought to evaluate the cost-effectiveness of sintilimab as a first-line treatment for locally advanced or metastatic OSCC from a healthcare system perspective in China.

Methods

A partitioned survival model was constructed to perform a cost-effectiveness analysis comparing chemotherapy alone with sintilimab for locally advanced or metastatic OSCC patients. Clinical data were obtained from the ORIENT-15 trial and extrapolated to 10 years. Health state utilities and costs were sourced from the literature and from public healthcare institutions. The primary outcomes included the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). Two different sensitivity analyses, one-way and probabilistic, were performed to assess model uncertainty.

Results

Sintilimab-based chemotherapy was more costly ($31699.21 vs. $20687.42) and more effective (0.74 vs. 0.53) than placebo-based chemotherapy, resulting in an ICER of $51908.19 /QALY, which is greater than the willingness-to-pay (WTP) threshold of China ($38223/QALY). Sensitivity analysis demonstrated that the PFS and cost of sintilimab were the major influencing factors affecting the results.

Conclusions

In patients with locally advanced or metastatic OSCC, sintilimab chemotherapy could improve survival time and health benefits compared with traditional chemotherapy, but the present analysis suggests that sintilimab is not a cost-effective treatment option in China.

Background

Oesophageal cancer is extremely harmful to human health and ranks sixth in mortality worldwide. There are nearly 604,000 new cases of oesophageal cancer each year, resulting in 544,000 deaths. The relative 5-year survival rate for patients with metastatic oesophageal cancer is 8% or less [1,2,3]. Compared to other places, East Asian countries had the highest incidence, with a large proportion in China [4]. Half of the world’s oesophageal cancer cases occur in China, placing a severe economic burden on the Chinese people and government [4, 5]. Oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma are the major histological types of oesophageal cancer. OSCC accounts for approximately 90% of cases and has a different molecular profile than oesophageal adenocarcinoma [6,7,8,9]. The standard first-line treatment for patients with unresectable advanced, relapsed, or metastatic OSCC is fluoropyrimidine and platinum chemotherapy [10,11,12,13]. Although chemotherapy has been used as a first-line therapy for decades, patient outcomes are still poor, with 5-year survival rates of 12.4% in Europe and 20.9% in China [14, 15]. Thus, novel treatment strategies are urgently needed for patients with locally advanced or metastatic OSCC.

Sintilimab, a selective human IgG4 anti-PD-1 monoclonal antibody, has been demonstrated in previously published studies to show single agent activity in patients with OSCC who progress after first-line chemotherapy [16,17,18,19]. Sintilimab has been approved for the treatment of classical hepatocellular carcinoma, non-small cell lung cancer, and Hodgkin’s lymphoma by the National Medical Products Administration of China [20,21,22,23]. A recent ORIENT-15 trial evaluated the efficacy and adverse events of sintilimab chemotherapy compared with those of placebo chemotherapy for the first-line treatment of locally advanced or metastatic OSCC [24]. The results indicated that compared with placebo, sintilimab chemotherapy had a significant effect on OS (16.7 months vs. 12.5 months) and median PFS (7.2 months vs. 5.7 months). In terms of safety, the rate of ≥ 3 treatment-related adverse events in the sintilimab-chemotherapy group was lower than that in the placebo-chemotherapy group (60% vs. 55%). The ORIENT-15 trial suggested that sintilimab combination therapy could be considered a novel standard first-line treatment option for treating locally advanced or metastatic OSCC patients.

Although sintilimab has shown apparent medical benefits in the treatment of locally advanced or metastatic OSCC, the addition of sintilimab could substantially increase treatment costs. Due to limited health resources, clinical effectiveness is not the only consideration; the cost-effectiveness of treatments also needs to be considered to inform decision-making. To the best of our knowledge, no published study has evaluated the cost and effectiveness of sintilimab in the treatment of locally advanced or metastatic OSCC. Here, this study was designed to evaluate the cost-effectiveness of sintilimab chemotherapy as the first-line treatment of locally advanced or metastatic OSCC based on clinical data from the ORIENT-15 trial from a healthcare system perspective. This evidence will provide health policy-makers with timely information on the economic value of sintilimab-based protocols and reimbursement policies to optimize resource utilization.

Methods and methods

Model structure

A partitioned survival model was constructed in Microsoft Excel to compare the cost-effectiveness of sintilimab combined with placebo for first-line treatment of locally advanced or metastatic OSCC patients. In the decision model, three mutually exclusive health states were considered: progression-free survival (PFS), progressive disease (PD) and death (Fig. 1). At the beginning, patients were in an “event-free” state. During each subsequent 3-week model cycle, patients could be in a “PFS” state or randomly transition to a “PD” state or a “death” state if disease progression changed. The time horizon was set at 10 years since the survival rate of patients with OSCC was less than 10%. All future costs and health outcomes were discounted at an annual rate of 5% for Chinese payers according to the China Guidelines for Pharmacoeconomic Evaluations [25]. Based on the local Consumer Price Index, which translates all costs into US dollars, the average exchange rate for the full year of 2023 would be ¥7.29 (Chinese yuan) to $1.

Patients aged ≥ 18 years with advanced or metastatic OSCC who had not received systemic treatment were included. Patients in the initial PFS state were randomly assigned (1:1) to receive placebo or sintilimab (3 mg/kg in patients weighing < 60 kg or 200 mg in patients weighing ≥ 60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The chemotherapy regimen included 93% patients received cisplatin plus paclitaxel or 7% patients received cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on Days 1–5). In ORIENT-15 trial, median duration of the use of sintilimab or placebo in the sintilimab-chemotherapy group was 28.0 weeks and 20.0 weeks in the placebo-chemotherapy group. Here, we assume the duration of the use of sintilimab or placebo was 28.0 weeks and 20.0 weeks, respectively. A cost-effectiveness analysis was performed to evaluate the outcomes of the two strategies and expressed as total cost, life-years, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). The following formula was used to calculate the ICER:

$$\:\text{I}\text{C}\text{E}\text{R}=\frac{\begin{aligned}&\text{C}\text{o}\text{s}\text{t}\:\left(\text{S}\text{i}\text{n}\text{t}\text{i}\text{l}\text{i}\text{m}\text{a}\text{b}\:\text{a}\text{n}\text{d}\:\text{c}\text{h}\text{e}\text{m}\text{o}\text{t}\text{h}\text{e}\text{r}\text{a}\text{p}\text{y}\right)\cr&\quad-\text{C}\text{o}\text{s}\text{t}\:\left(\text{p}\text{l}\text{a}\text{c}\text{e}\text{b}\text{o}\:\text{a}\text{n}\text{d}\:\text{c}\text{h}\text{e}\text{m}\text{o}\text{t}\text{h}\text{e}\text{r}\text{a}\text{p}\text{y}\right)\end{aligned}}{\begin{aligned}&QALY\:\left(Sintilimab\:and\:chemotherapy\right)\cr&\quad-QALY\:(placebo\:and\:chemotherapy\end{aligned}}$$

To improve the accuracy of the results, a half-cycle correction was carried out. As recommended by the World Health Organization, three times the Chinese per capita gross domestic product (GDP) in 2022 ($38,442) was used as the WTP threshold to confirm the cost-effectiveness of treatment options [26,27,28,29].

Our study was a retrospective study of medical records. We developed a health economic model based entirely on previously published literature, and no patient-level data were analysed.

Fig. 1
figure 1

Cost-effectiveness model. (A) 1-year decision tree based on the ORIENT-15 trial; (B) long-term partitioned survival model

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Validation of the model

The PFS and PD curves of patients in the ORIENT-15 trial were satisfactorily fitted by log-normal proportional hazards models (Table 1). The modelled clinical outcomes were similar to those of the ORIENT-15 trial in terms of median PFS and OS (Fig. 2), suggesting that the results were acceptable and could be used for model validation.

Fig. 2
figure 2

(A) progression-free survival (PFS) for patients in the ORIENT-15 trial; (B) progression-free survival (PFS) for the model-estimated data; (C) OS for patients in the ORIENT-15 trial; (D) overall survival (OS) for the model-estimated data; (E) in terms of the median OS and PFS, the simulated results were consistent with the empirical data from the ORIENT-15 trial; Sin-Che, sintilimab-chemotherapy; Pla-Che, placebo-chemotherapy; OS, overall survival; PFS, progression-free survival

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Clinical data

PFS and OS data from the placebo-chemotherapy arm and sintilimab-chemotherapy arm were derived from the ORIENT-15 trial [24], and the PFS and OS curve data points were obtained using Getdata Graph Digitizer software version 2.26. The software obtain the data by setting the coordinate axis and scale size to extract the coordinate points on the picture. The four most commonly used statistical distributions, Weibull, exponential, log-normal and log-logistic [30] were fitted to different parametric survival functions to explore the survival probabilities over the model time horizon with R statistical software. The Akaike information criterion [23] and Bayesian information criterion (BIC) were used to measure the fitting distribution. The lowest values of the AIC and BIC were considered the most suitable [31]. As shown in Table 1, the log-normal distribution was the best match to the data for the PFS, and the Weibull distribution was the best match to the data for the OS curves. According to the characteristics of the log-normal distribution, the formula S(t) = exp(-λt^γ) was used to calculate the probability of survival.

Table 1 Parameters of the various function distribution types
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Costs and utilities

Based on data from the ORIENT-15 trial, the direct medical costs of each strategy were estimated from the perspective of Chinese payers. In the PFS state, the direct costs included drug costs, follow-up, laboratory tests, radiological examinations and serious adverse event (SAE) (grades 3–4) management. Once the disease progressed, patients received supportive care and salvage chemotherapy. All costs were obtained from published sources and are shown in Table 2 [1, 7, 8]. The dosage of chemotherapeutic agents was calculated based on the patient’s body weight. Here, we assumed that a typical patient was 65 kg in weight, 1.64 m in height and had a body surface area (BSA) of 1.72 m [2, 32].

The cost of sintilimab, cisplatin, paclitaxel and 5-fluorouracil was the median of the different provincial drug bidding prices. Only SAEs of grade ≥ 3 were considered in the ORIENT-15 trial [32, 33]. In this study, the costs of a decrease in neutrophil count, a decrease in white blood cell count, anaemia, nausea and vomiting were calculated. We calculated the expected costs of SAEs by summing the unit cost of each SAE multiplied by its probability.

Because of the lack of data on the quality-of-life (QOL) utility for locally advanced or metastatic OSCC patients in China, the utility values of PFS, PD health states and adverse events were obtained from the published literature [2, 6, 10], which reported that the utility values were all evaluated for the health-related QOL of patients using the EuroQol instrument (EuroQoL − 5 Dimension).

Table 2 Model input parameters
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Sensitivity analyses

To account for the uncertainties in parameter estimates, one-way and probabilistic sensitivity analyses were carried out. High/low ranges and various distributions were fitted for each key parameter (Table 2). In the one-way sensitivity analysis, the relevant parameters were changed to their upper and lower boundaries one by one, and the range was ± 20% of the base case value to measure the influence of different factors on the economic results. The results are presented in a Tornado diagram [34, 35]. Probabilistic sensitivity analyses were carried out using a Monte Carlo simulation to evaluate the impact of uncertainty in multiple variables on the results [36], in which 10,000 iterations were generated by sampling with an appropriate pattern of statistical distribution. All costs were assumed to follow γ distributions, whereas β distributions were used for clinical probabilities, quality-of-life utilities and discount rates.

Scenario analyses

Two scenarios were assumed. In the first scenario, the price of sintilimab was assumed to be reduced to 80%, 60%, 40%, 20% or 10% of the current price. OSCC is a malignant disease with short survival [37], with 1, 2, 3 and 5 year survival rates of 71.00%, 46.00%, 38.00% and 20%, respectively [38, 39]. Hence, the scenario analysis in a shorter time horizon, 1, 2, 5 and 8 years, could fully evaluate the cost-effectiveness of sintilimab and provide medication guidance to patients with OSCC.

Results

Base case analysis

The results of the base case analysis are given in Table 3. Over the lifetime horizon of 10 years, the sintilimab-chemotherapy group gained 0.74 QALYs at a cost of $31,699.21. However, the effectiveness was 0.53 QALYs, and the cost was $20,687.42 in the placebo-chemotherapy group, resulting from an incremental gain of 0.21 QALYs and an incremental cost of $11011.80. The ICER ($51908.20/QALY) was greater than the Chinese cost-effectiveness WTP threshold of $38,223/QALY, suggesting that sintilimab-based chemotherapy was not a cost-effective strategy compared with placebo-based chemotherapy.

Table 3 The results of base-case analysis at the 10-year horizon
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Sensitivity analyses

The results of the one-way sensitivity analysis are shown in the tornado diagram (Fig. 3), revealing that the utility of PFS, the price of sintilimab and the cost of laboratory tests and radiological examinations were the key drivers of model outcomes, while they did not change the final outcome and did not lead to an ICER below the WTP threshold in our study. The utility of PFS was the most influential variable, with the ICER decreasing to $68990.00/QALY when the PFS was reduced to 80% of baseline (0.54) and the ICER increasing to $41606.48QALY when the PFS was increased to 120% (0.82) of baseline. Regarding the other two sensitive parameters, the price of sintilimab and the cost of laboratory tests and radiological examinations, the lower and upper limits were used, and the ICERs were adjusted to 47451.94-56364.43 USD and 49723.35-54093.02 USD, respectively. In general, none of the variables could change the final results, indicating that our model was robust.

Fig. 3
figure 3

One-way sensitivity analyses of sintilimab-chemotherapy versus placebo-chemotherapy strategies. The influence parameters are listed in descending order according to the influence of the change in each parameter on the ICER; ICERs, incremental cost-effectiveness ratios; PD, progressive disease; PFS, progression-free survival

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Probabilistic sensitivity analysis results

As shown in Fig. 4, each point presented a simulated ICER value from each of the 10,000 Monte Carlo simulations. The scattered points were mostly distributed in the first quadrant, which indicated that compared with the placebo-chemotherapy group, the sintilimab-chemotherapy group exhibited greater cost and effectiveness. Sintilimab chemotherapy was not an economical option for the first-line treatment of patients with locally advanced or metastatic OSCC, with most scattered points lying above the WTP threshold and exceeding the threshold.

The cost-effectiveness acceptability curves are shown in Fig. 5. At a WTP of 3 GDP per capita ($38,223) in China, the probability of sintilimab-chemotherapy being cost-effective was 3.80%, with a threshold of > $70,000, and the probability of the sintilimab-chemotherapy group being an economical option exceeded 50%.

Fig. 4
figure 4

Results of the probabilistic sensitivity analysis on the cost-effectiveness plane Each dot represents the ICER for each simulation; dots below the ICER threshold represent cost-effective simulations; ICERs, incremental cost-effectiveness ratios

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Fig. 5
figure 5

Cost-effectiveness acceptability curves. The results showed the likelihood that strategies within the willing-to-pay threshold would be considered cost-effective

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Scenario analyses

In scenario 1, when the cost of sintilimab was reduced by 80%, 60%, 40%, 20% and 10%, the ICERs were $47452.54, $42996.90, $38541.25, $34085.61 and $31857.78 per QALY gained, respectively. When the cost of sintilimab was reduced above 20%, the ICER was less than the WTP threshold ($38223/QALY). In scenario 2, the time horizon was changed to 1, 2, 5 and 8 years, ICER changed to 70541.13, 55235.95, 51287.25 and 51756.22 per QALY gained, respectively. Sintilimab-chemotherapy was not economical in assumed years, suggesting the only effective way was to lower the price of sintilimab.

Discussion

To the best of our knowledge, this study was the first modelling analysis to compare the cost-effectiveness of sintilimab-chemotherapy and placebo-chemotherapy as first-line treatments for locally advanced or metastatic OSCC patients from a Chinese healthcare system perspective. The results confirmed that sintilimab-chemotherapy therapy resulted in higher health outcome cost expenditures, with an ICER higher than the WTP threshold based on the GDP of 2022 in China. Sensitivity analyses confirmed the robustness of the model results.

According to the latest reported data from the ORIENT-15 trial, compared with traditional chemotherapy, sintilimab significantly prolonged the median OS and median PFS. However, the high price of sintilimab significantly increases medical expenditures, which makes it necessary to evaluate whether it is cost-effective. Here, our analysis revealed that for first-line treatment of locally advanced or metastatic OSCC in China, the ICER of sintilimab-chemotherapy ($51908.20/QALY) was greater than the WTP threshold ($38,223/QALY), indicating that compared with placebo-chemotherapy, sintilimab-chemotherapy was not an economical treatment option. Similar to our findings, a recent cost-effectiveness analysis revealed that camrelizumab chemotherapy was not an economical treatment option compared with traditional chemotherapy in patients with advanced or metastatic OSCC [40]. Another recent study confirmed that nivolumab-ipilimumab was unlikely to be cost-effective compared with nivolumab-chemotherapy for first-line treatment of advanced OSCC in China [3]. Yang et al. reported that compared with traditional chemotherapy, camrelizumab was not economical for patients with advanced or metastatic OSCC and was used as a second-line treatment for advanced OSCC [41]. These results suggest that although the addition of new drugs can improve treatment efficacy, it also increases costs and worsens economy. According to Chen et al. [42], compared with pembrolizumab plus chemotherapy, sintilimab plus chemotherapy is more cost effective as a first-line treatment for Chinese patients with locally advanced or metastatic squamous NSCLC. In addition, Rui et al. [43] confirmed that sintilimab plus chemotherapy was a more cost-effective option than camrelizumab plus chemotherapy as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in China. Thus, it is necessary to reduce drug costs to reduce the financial burden on the Chinese government and provide more access to Chinese patients.

In our study, compared with traditional chemotherapy, sintilimab-based chemotherapy as a first-line treatment for locally advanced or metastatic OSCC yielded greater QALYs (0.74 vs. 0.53). Although it is not economical, as a first-line treatment for advanced or metastatic OSCC, the ICER value ($39390.61/QALY) was lower than that of other treatment strategies [3, 40]. The primary reason for this difference was that the cost of sintilimab per 100 mg decreased by 60% from 2020 to 2021 through China’s drug price negotiation mechanism. In China, medical insurance policies should constantly improve, causing the prices of anticarcinogens to further decrease, which could help OSCC patients receive first-line and second-line treatments that are safer and more economical than traditional strategies.

The results of one-way sensitivity analysis showed that the PFS and the cost of sintilimab per 100 mg were the most influential factors for the ICER. Probabilistic sensitivity analysis with 10,000 Monte Carlo simulations showed that at the WTP threshold of $38,223 per QALY, the addition of sintilimab was 3.80% cost-effective. Due to the uneven economic development of China’s domestic economy, in some developed provinces and cities of China, sintilimab-chemotherapy regimens might be the optimal treatment option, including in Beijing (WTP = $78,226.75/QALY), Jiangsu (WTP = $59,454.73/QALY), Shanghai (WTP = $73,827.57/QALY), and Fujian (WTP = $52,199.59/QALY).

Our study has several limitations. The first limitation was that our clinical data were based primarily on the ORIENT-15 trial, which lacks long-term survival data in the real world. Here, the survival data beyond the follow-up time horizon were extrapolated with a log-normal survival model, which may not be an accurate reflection of the real-world situation [44]. Second, the actual costs of therapy were not consistent nationally, not to mention internationally. Other relevant costs were not included in this analysis, including facility fees and premeditations. These costs were not expected to change the overall conclusions of the model, as they were likely to be equal between the two therapeutic regimens.

Conclusions

In summary, compared with traditional chemotherapy, sintilimab-chemotherapy was not cost-effective as a first-line treatment for patients with locally advanced or metastatic OSCC in the Chinese healthcare system. When the price of sintilimab decreases by 80%, sintilimab chemotherapy is a reasonable treatment option for patients with locally advanced or metastatic OSCC in China. These findings might be helpful for healthcare system decision-makers, and further studies should be performed to verify the economics of the two regimens with real-world data.

Data availability

No datasets were generated or analysed during the current study.

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Funding

This work was supported by the National Natural Science Foundation of China (52273308).

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Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China

    Cuicui Yu, Yingqi Wu, Yadi Geng, Hui Yan, Pengli Zhu, Peng Ji, Fei Wu, Lijuan Ning, Yubin Feng & Aizong Shen

  2. Technology of China/Anhui Technology Center for Clinical Comprehensive Evaluation of Drugs, Hefei, 230001, China

    Cuicui Yu, Yingqi Wu, Yadi Geng, Hui Yan, Pengli Zhu, Peng Ji, Fei Wu, Lijuan Ning, Yubin Feng & Aizong Shen

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Contributions

Conceptualization, C.Y. and A.S.; methodology, C.Y. and Y.W.; software, C.Y., H.Y. and Y.W.; validation, Y.G., H.Y. and P.Z.; formal analysis, C.Y., Y.G. and P.J.; investigation F.W., L.N. and A.S.; data curation, C.Y., Y.W., Y.G., L.N. and A.S.; writing—original draft preparation, C.Y.; writing—review and editing, C.Y. and Y.W; visualization, Y.F.; supervision, A.S. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Aizong Shen.

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Yu, C., Wu, Y., Geng, Y. et al. Cost-effectiveness of the addition of sintilimab as a first-line therapy for locally advanced or metastatic oesophageal squamous cell carcinoma: a Chinese healthcare system perspective. Health Econ Rev 15, 2 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13561-024-00588-2

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Keywords

Health Economics Review

ISSN: 2191-1991

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