Camrelizumab

This study was guided by the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) updated reporting guidelines (Supplementary Table S1) (Husereau et al., 2022 (link)). This economic evaluation was based on modelling techniques and published literature, and did not require approval of the institutional research ethics board because no real human participants or animals were involved.
A hypothetical cohort of patients, aged at least 18 years, with histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic ESCC with the same characteristics as those patients enrolled in ESCORT-first (Luo et al., 2021 (link)), CheckMate-648 (Doki et al., 2022 (link)), KEYNOTE-590 (Sun et al., 2021 (link)), ASTRUM-007 (Song et al., 2023 (link)), ORIENT-15 (Lu et al., 2022 (link)) and JUPITER-06 (Wang et al., 2022 (link)) clinical trials. Eligible patients received one of seven first-line interventions: (1) Chemotherapy (Cisplatin, 75 mg/m², day 1 plus Paclitaxel, 175 mg/m², day 1 or Fluorouracil, 800 mg/m², days 1 through 5; 3-week); (2) Camrelizumab (200 mg; 3-week) plus chemotherapy; (3) Nivolumab (240 mg; 2-week) plus chemotherapy; (4) Pembrolizumab (200 mg; 3-week) plus chemotherapy; (5) Serplulimab (75 mg/kg; 2-week) plus chemotherapy; (6) Sintilimab (200 mg; 3-week) plus chemotherapy; (7) Toripalimab (240 mg; 3-week) plus chemotherapy (Supplementary). After disease progression, we assumed that the remaining patients would receive subsequent best supportive anti-cancer regimens to accurately capture the cost-effectiveness associated with first-line treatment.

The study only considered direct medical costs, including drug acquisition, follow-up, best supportive treatment, and severe adverse event (SAE) management costs. In accordance with the ESCORT clinical research and guidelines (CSCO, 2020 ; Huang et al., 2020 (link)), 200 mg carrelizumab was administered intravenously on the first day of every 2 weeks, 75 mg/m² docetaxel was provided on the first day of every 3 weeks, and 180 mg/m² of irinotecan was administered intravenously on the first day every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. The cost effectiveness of the two scenarios was discussed to avoid the effect of the course of drugs on the results. In the first scenario, camrelizumab was assumed to be used for six (IQR 4–13) courses, docetaxel for three (2–3) courses, and irinotecan for four (2–5) courses in accordance with the results of ESCORT (Huang et al., 2020 (link)). A shorter time horizon (3, 5 and 7 years) was also considered in this scenario. In the second scenario, both groups continued treatment until the disease progressed. The proportion of patients receiving specific chemotherapy regimens was not defined in the clinical trials. The model assumed that the patients had equal opportunities to receive docetaxel and irinotecan. The average body surface area of the patients in the model was 1.72 m² (1.5–1.9 m²) (Zeng et al., 2013 (link)). After the failure of second-line treatment, the best third-line treatment was not clear, and the specific scheme was not shown in the ESCORT study. Therefore, the best support treatment was regarded as the treatment after progression.
The cost of camrelizumab was derived from the negotiated price of China’s national medical insurance (Nation Healthcare Security Administration, 2020 ). The cost of docetaxel and irinotecan was the median of the bidding price of drugs in different provinces (YaoZH, 2020 ). Only the SAE of grade ≥3 was considered (Guy et al., 2019 (link); Zhang et al., 2020b (link)). The incidence rate of anemia in the camrelizumab group was 3%, while the incidence rates of anemia, decreased neutrophil count, and vomiting in the chemotherapy group were 5.0, 15.0, and 5%, respectively (Huang et al., 2020 (link)). Other costs are shown in Table 1.
The utility value represents the health-related quality of life for each health state. The ESCORT trail did not involve health utility. Thus, the utility in the model was obtained from other public literature (Tan et al., 2018 (link); Zhang et al., 2020b (link); National Institute for Health and Care Excellence, 2021 ), utility values for the PFD and PD health states were taken from EQ-5D data from a global, randomised, placebo-controlled, double-blind, phase 3 study, which recruited adults with advanced gastric cancer or gastro–oesophageal junction adenocarcinoma. The utility of PFD in the two groups was assumed to be consistent, but SAE (grade ≥3) could affect the utility. After disease progression, the utility of all patients in PD state was 0.581 (Zhang et al., 2020b (link); National Institute for Health and Care Excellence, 2021 ). All utility values are shown in Table 1.

Clinical data on the efficacy and safety of tislelizumab and camrelizumab were derived from RATIONALE 302 trial and the published clinical trial ESCORT, respectively [9 ]. Since there is no head-to-head clinical trial of tislelizumab monotherapy versus camrelizumab monotherapy, the anchored matching adjusted indirect comparison (MAIC) method was adopted in the model to adjust the baseline of patient characteristics. In the adjustment process, key baseline demographic and disease characteristics factors, namely age, gender, histological grade, disease metastasis, lymphatic metastasis, PD-L1 expression level, and Eastern Cooperative Oncology Group (ECOG) score, prior therapies (PT) surgery, PT. radiotherapy, PT. platinum-based chemotherapy, which were reported in ESCORT, were included. The results of baseline patient characteristics and clinical efficacy data before and after adjustment are shown in Tables 1 and 2.
Table 1

Baseline characteristics before and after adjustment

	Before adjustment			After adjustment
Adjustment factor	Camrelizumab group [1 ](N = 448)	Tislelizumab group (N = 495)	P value unweighted	Tislelizumab group (ESS = 137)	P value weighted
Age ≤ 60	50%	48%	0.66	50%	1
Male	89%	90%	0.72	89%	1
Histological grade 3(Poorly differentiated)	29%	18%	0	29%	1
Disease metastasis	84%	97%	0	84%	0.91
Lymphatic metastasis	85%	76%	0	85%	1
High PD-L1 expression level (vCPS ≥ 10%)	43%	29%	0	43%	1
ECOG PS = 1	80%	83%	0.29	80%	1
PT. Surgery	49%	45%	0.25	49%	1
PT. Radiotherapy	66%	65%	0.8	66%	1
PT. Platinum-based chemotherapy	95%	98%	0.06	95%	1

Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = performance status; ESS = effective sample size; P.T. = Prior therapies

Table 2

Results of progression-free survival and overall survival after MAIC

Adjustment results	HR-PFS	HR-OS
Tislelizumab monotherapy
Before MAIC	0.85 (0.65–1.10)	0.74 (0.58–0.95)
After MAIC	0.78 (0.55–1.11)	0.68 (0.49–0.94)
Camrelizumab monotherapy	0.69 (0.56–0.86)	0.71 (0.57–0.87)

HR: hazard ratio; PFS: progression-free survival; OS: overall survival; MAIC: matching adjusted indirect comparison

Six parametric distributions, including the exponential, Weibull, Gompertz, log-normal, log-logistic, and gamma distributions, were used to extrapolate the survival curves to capture survival outcomes in lifetime horizon. Since the PFS curves of tislelizumab before and after MAIC adjustment relative to the chemotherapy group and the PFS curves of camrelizumab relative to the chemotherapy group did not meet the PH assumption (Supplementary Figures S1-S2), the MAIC-adjusted HR values were not used to adjust the efficacy. The standard parameters were fitted separately for the camrelizumab monotherapy in ESCORT and the adjusted tislelizumab monotherapy in RATIONALE 302.
The survival curves of the camrelizumab monotherapy were derived from the published literature [9 ] and the IPD was reconstructed using the method of Guyot et al. study [14 ]. The results of the parameter fitting are shown in the Supplementary material table S1. Akaike information criterion (AIC), Bayesian information criterion (BIC), visual inspection, and logic error checking were used to evaluate best-fitting parametric distributions. As a result, the best-fitting distribution for PFS data of tislelizumab monotherapy was log-normal distribution, while the best-fitting parametric distributions for OS data of tislelizumab and PFS along with OS data of camrelizumab monotherapy were log-logistic distributions. The fitting and extrapolation results of PFS and OS curves are shown in Figs. 2 and 3.
Fig. 2

The exploration and fitting of tislelizumab monotherapy OS and PFS

Fig. 3

The exploration and fitting of camrelizumab monotherapy OS and PFS

Only AEs with incidence ≥ 1% and grade ≥ 3 of patients with camrelizumab or tislelizumab were included for this study. AEs to the camrelizumab monotherapy were obtained from ESCORT [9 ], including somasthenia, diarrhea, hyponatraemia, anemia, lymphopenia, and reactive cutaneous capillary endothelial proliferation (RCCEP). Thereinto, hyponatraemia, anemia and lymphopenia were AEs associated with tislelizumab monotherapy only.