Esophageal cancer is a highly lethal malignancy, with 604,100 new cases and 544,076 deaths in 2020 (1). The incidence of esophageal cancer in Eastern Asia is higher when compared to the world (1, 2). China was a high-incidence area of esophageal cancer and accounted for about half of the global morbidity and mortality (3). The prognosis of esophageal cancer is improving but remains poor, with an overall 5-year survival rate of about 20% (4, 5). Approximately 39% of esophageal cancer with distant metastases at initial diagnosis and the 5-year relative survival for these esophageal cancers is about 5% (6). Although targeted drugs have demonstrated efficacy in many cancers, no targeted drugs are approved for esophageal squamous cell carcinoma. Until immune checkpoint inhibitors were approved for esophageal cancer, the treatment after first-line was limited. The goal of second-line treatment for metastatic esophageal cancer was to palliate symptoms. Unresectable, locally advanced, or metastatic esophageal cancer are not curable. Esophageal cancer contributed to a massive burden on public health care systems in China (7).

Esophageal squamous cell carcinoma is the predominant histology in China. The superiority of pembrolizumab over chemotherapy for second-line therapy in patients with metastatic esophageal squamous cell carcinoma, as well as with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10 tumors, was shown in the KEYNOTE-181 study. Based on the KEYNOTE-181 study, National Medical Products Administration and the US Food and Drug Administration approved pembrolizumab for patients with locally advanced or metastatic esophageal squamous cell carcinoma that express PD-L1 (CPS ≥ 10) after one prior line in China and the USA. And the National Comprehensive Cancer Network (NCCN) recommended pembrolizumab for second-line therapy for esophageal squamous cell carcinoma with PD-L1 CPS ≥ 10 (8).

Although the KEYNOTE-181 study demonstrated a survival advantage and better tolerability for pembrolizumab, pembrolizumab is dramatically expensive for patients and insurance payers. As such, we sought to evaluate the cost-effectiveness of pembrolizumab for advanced esophageal cancer from the Chinese society perspective.

In this study, we found that pembrolizumab was not cost-effective for advanced or metastatic esophageal cancer compared with chemotherapy. The price of pembrolizumab had the highest impact on the ICER when pembrolizumab was administered in patients with squamous cell carcinoma or PD-L1 CPS ≥ 10. Because of the assistance programs for esophageal cancer, patients with squamous cell carcinoma and PD-L1 CPS ≥ 10 can buy two cycles of pembrolizumab and obtain two cycles of pembrolizumab free. When we calculated the cost of pembrolizumab according to the donation plan, the ICER dropped to $65,122.91 per QALY and $53,955.88 per QALY in patients with PD-L1 CPS ≥ 10 and squamous cell carcinoma, respectively. Although pembrolizumab provided the greatest clinical benefit in QALYs for patients with PD-L1 CPS ≥ 10, the cost of PFS state was less in the esophageal squamous cell carcinoma due to the shorter PFS compared with the PD-L1 CPS ≥ 10. The KEYNOTE181 study showed that the greatest survival benefit was observed in patients with squamous cell carcinoma and PD-L1 CPS ≥ 10. But the Supplementary Appendix of the KEYNOTE-181 study only provided the OS curve, not the PFS curve in patients with squamous cell carcinoma PD-L1 CPS ≥ 10 tumors, we cannot estimate the probability of being in each state based on the PFS and OS curves. We did not conduct the Markov model to assess the cost-effectiveness of pembrolizumab in patients with squamous cell carcinoma PD-L1 CPS ≥ 10 tumors.

PD-1 and PD-L1 inhibitors have become an effective treatment strategy for advanced esophageal cancer (18–21), and have been increasingly used after first-line therapies in advanced esophageal cancer (22). Pembrolizumab prolonged survival in patients with many solid cancers (23), but due to the high price of pembrolizumab, the economics of pembrolizumab is controversial (24). Factors including clinical effectiveness, safety, and drug price had an impact on the results of the pharmacoeconomic evaluation. Treatment options are limited for metastatic esophageal cancer, especially after first-line treatment. The survival benefit of Chemotherapy is modest and the side effects of chemotherapy reduce the quality of life. Immunotherapy using immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and camrelizumab, has resulted in survival benefits and fewer side effects for patients with metastatic esophageal cancer. The study performed a Markov model to assess the cost-effectiveness of nivolumab vs. chemotherapy in the second-line treatment for advanced esophageal squamous cell carcinoma based on the ATTRACTION-3 trial. The results of the study showed that nivolumab was not a cost-effective treatment option compared with chemotherapy from the Chinese society perspective (25). Because of the sharp price reduction of camrelizumab, the pharmacoeconomic research results of camrelizumab as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma were inconsistent (14, 15, 26), Yang et al. (14) showed camrelizumab was not cost-effective as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma compared with chemotherapy in China. The cost of camrelizumab in Yang et al. was $2,802 per 200 mg. Both Lin et al. (26) and Cai et al. (15) showed camrelizumab was cost-effective compared with chemotherapy for advanced or metastatic esophageal squamous cell carcinoma (15, 26). The price of camrelizumab was only $452.87 per 200 mg and $432 per 200 mg in Lin et al. (26) and Cai et al. (15), respectively. Up to date, there has been no cost-effectiveness analysis of pembrolizumab as second-line therapy for advanced esophageal cancer.

WTP is a critical parameter to determine whether the intervention is cost-effective. If the ICER was lower than the WTP, the intervention is considered to be favorably cost-effective. The WTP was set as 1–3 times GDP per capita according to the WHO guidelines that were widely referenced in the last decade (27). But some studies suggest that three times of GDP per capita as WTP is too high and the WTP threshold is below 1 × GDP per capita (28, 29). The National Institute of Health and Clinical Excellence (NICE) proposed that the cost-effectiveness threshold of life-extending treatments for patients with terminally ill patients could increase to £50,000/QALY (30, 31) The WTP threshold used in Greek cost-effectiveness studies showed that the median WTP threshold used in oncology studies [€51,000 (€50,000–57,000)] was higher than in non-oncology studies [€34,000 (€30,000–€35,000); p-value < 0.001] (32). There is no established standard in China for the WTP. According to the guidelines and literature, 1 × GDP per capita was set as WTP in our study. The research has certain limitations associated with model-based cost-effectiveness analyses. We primarily relied on the data from a phase III trial rather than real-world experience. Occasionally, real-world experience may deviate from that seen in trials. In addition, detailed data on the clinical and economic burden of treatment-related adverse events remain limited. First, the KEYNOTE181 study only reported the OS and PFS in patients with PD-L1 CPS ≥ 10 tumors, squamous cell carcinoma, and in all patients, respectively, but reported the adverse events in all patients. We hypothesized that the incidences of AEs were similar between different subgroups and estimated the cost of AEs according to the safety outcomes in the total population. Second, the cost data in the model were obtained from official or published prices, but the cost of drugs and tests varied across different regions in China. Third, nutrition support plays an important part in the management of esophageal cancer. As this part of the information was not mentioned in the KEYNOTE-048 trial, these costs were not considered. Besides, due to the lack of utility data in China, the utility values were obtained from Western countries. Imprecise estimates and assumptions were necessary and this uncertainty was evaluated using sensitivity analysis. The results of sensitivity analyses with a range of ± 20% of variation showed that the results were stable.

China has launched national reforms on centralizing drug procurement to contain drug costs. A series of Chinese domestic PD-1 inhibitors including camrelizumab, sintilimab, toripalimab, tislelizumab were included in medical insurance with a price reduction of more than 64%. With the development of the drug industry, more and more PD-1 inhibitors will emerge, which might provide an alternative for patients with esophageal squamous cell carcinoma in China and promote the price reduction of pembrolizumab. With the price adjustment of PD-1 inhibitors, the economy of these drugs will be improved.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

MZ participated in research design, data processing, and manuscript writing, TX and HZ in data processing. ZH participated in research design and manuscript revising. All authors contributed to the article and approved the submitted version.

This work was supported by the 1.3.5 project for disciplines of excellence-clinical research incubation project, West China Hospital, Sichuan University (2021HXFH064).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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