https://orcid.org/0000-0002-7188-8989
Figures
Abstract
Background
To evaluate the cost-effectiveness of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma (HCC) from the perspective of the Chinese health service system.
Methods
A lifetime partitioned survival model (PSM) was developed to cost-effectively analyze Tislelizumab vs Sorafenib as the first-line treatment of unresectable HCC. The clinical and safety data were derived from a recently randomized clinical trial (RATIONALE-301). Utilities were collected from the published literature. Costs were obtained from an open-access database (http://www.yaozh.com) and previous studies. The model cycle was 21 days, according to the RATIONALE-301 study, and the simulation period was patients’ lifetime. Long-term direct medical costs and quality-adjusted life-years (QALYs) were determined. The incremental cost-effectiveness ratio (ICER) was used as the evaluation index. one-way sensitivity analysis (OSWA) and probabilistic sensitivity analysis (PSA) were used to analyze the uncertainty of parameters and to adjust and verify the stability of the baseline results.
Results
The Tislelizumab group generated a cost of $39,746.34 and brought health benefits to 2.146 QALYs, while the cost and utility of the Sorafenib group were $26750.95 and 1.578 QALYs, respectively. The Tislelizumab group increased QALYs by 0.568, the incremental cost was $12995.39, and the ICER was $22869.64/QALY, lower than the willingness to pay threshold (WTP). OSWA results showed that the utility of progressed disease (PD), cost of Camrelizumab, and cost of Tislelizumab were the main factors affecting the ICER. PSA results showed that, within 1000 times the Monte Carlo simulation, the cost of the Tislelizumab group was lower than three times the per capita gross domestic product (GDP) of China ($37653/QALY). The cost-effectiveness acceptability curves (CEAC) revealed that when WTP was no less than $12251.00, the Tislelizumab group was the dominant scheme, and the economic advantage grew with an increasing WTP. When WTP ≥ $19000.00, the Tislelizumab group became the absolute economic advantage.
Citation: Chen Q, Sun Q, Zhang J, Li B, Feng Q, Liu J (2024) Cost-effectiveness analysis of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma. PLoS ONE 19(3): e0295090. https://doi.org/10.1371/journal.pone.0295090
Editor: Po-Yao Hsu, Kaohsiung Medical University Hospital, TAIWAN
Received: November 14, 2023; Accepted: February 14, 2024; Published: March 4, 2024
Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The clinical and safety data were derived from a recently randomized clinical trial (RATIONALE-301). Utilities were collected from the published literature included in PubMed, Web of science, Embase Cochrane, CNKI, Wanfang and Weipa. Costs were obtained from an open-access database (http://www.yaozh.com) and previous studies.
Funding: This work was supported by the National Natural Science Foundation of China (GrantNo.82374314).
Competing interests: 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.
Introduction
Primary hepatoma is a malignant tumor of the digestive system and the sixth most common malignancy worldwide [1]. As a significant type of primary hepatoma, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths globally [2] and the fourth leading cause of cancer deaths in China [3]. On the one hand, most HCC patients already have advanced disease at diagnosis [4] and cannot be treated with transplantation, ablation, surgical resection, and radiotherapy [5,6]. On the other hand, the efficacy of tyrosine kinase inhibitors (TKI) as first-line chemotherapy regimens for HCC is minimal [7]. The above two factors lead to the 5-year survival rate remains poor [8].
In recent years, Studies have increasingly shown that programmed death-1 (PD‐1) and programmed death ligand-1(PD-L1) are the most prevalent immune checkpoint inhibitors, which have shown some clinical benefit in late-stage or metastatic HCC, such as Nivolumab, Pembrolizumab and Sintilimab. In the CheckMate 040 study, Nivolumab plus Ipilimumab, compared with Nivolumab, improved efficacy and safety in patients with advanced HCC previously treated with Sorafenib [9]. A recent randomized controlled study (ORIENT-32) indicated that Sintilimab plus a Bevacizumab biosimilar had improved progression-free survival (PFS) and overall survival (OS) in patients with unresectable hepatocellular carcinoma [10]. Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced HCC [11].
Recently, RATIONALE-301 research evaluated for the first time the efficacy and safety of Tislelizumab vs Sorafenib as a first-line Treatment for Unresectable HCC [12]. The results showed that the OS of the Tislelizumab and Sorafenib groups was 15.9 months and 14.1 months, respectively. Patients in the Tislelizumab group also had a higher objective response rate (14.3% vs 5.4%). From a security perspective, the incidence of treatment-related adverse events (TRAE) in Tislelizumab ≥3 was lower (22.2% vs. 53.4%) compared with Sorafenib. In short, it can improve patients’ OS, PFS, and Objective Response Rate (ORR) and is a safe and effective treatment. At present, there is no economic research on Tislelizumab as the first-line treatment of advanced HCC in China. Therefore, from the perspective of the Chinese healthcare system, this study explores the cost-effectiveness of Tislelizumab as the first-line treatment option in patients with advanced HCC by establishing a partitioned survival model (PSM) to provide clinicians with more options.
Methods
Data source and the study population
The patient data and treatment plan information used in this study were derived from the RATIONALE-301 study. The target population was consistent with the target patient population of the RATIONALE-301 trial. Inclusion criteria: age 18–75 years; has received no prior systemic therapy for HCC; at least one measurable lesion in the liver according to the mRECIST criteria; ECOG PS score ≤ 1; Child-Pugh class A; normal liver functions. Exclusion criteria: has known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC histology; has tumor thrombus involving main trunk of portal vein or inferior vena cava; has received within 28 days before randomization loco-regional therapy and any prior immunotherapy to the liver; any active immune deficiency or autoimmune disease and/or has a history of any immune deficiency or autoimmune disease that may relapse. A total of 662 patients were included, patients were randomized to Tislelizumab (338), 200 mg intravenously every 3 weeks; or Sorafenib (324), 400 mg orally twice daily, until symptomatic deterioration associated with disease progression. unacceptable toxic effects, or study withdrawal. Camrelizumab in combination with FOLFOX4 regimen was selected as a second-line treatment for all patients with progressive disease in accordance with the CSCO Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022).
Model construction
According to the disease progression of hepatoma, a three-state PSM of PFS, progressed disease (PD), and death was established for cost-effectiveness analysis. It was assumed that all patients entered the model from the PFS state, the model cycle was set to 21 days, and the simulation time was lifetime horizon. According to the “Chinese Pharmacoeconomic Evaluation Guidelines (2020)”, the discount rate of both cost and utility is set to 5%. The main outputs of the model were total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The survival curve fitting of this study was painted using R 4.2.0 software, and the PSM model was constructed with Microsoft Excel 2019 software.
Survival and progression risk estimation
We used the Getdata Graph Digitizer software to extract the survival data of the RATIONALE-301 trial and then reconstructed the pseudo-individual patient data by using the survHE and survival package of R 4.2.0 software. Log-normal, Log-logistic, Weibull, Exponential, Gen.Gamma and Gompertz distributions were selected to calculate the parameters as previously described (Figs 1 and 2). Based on the Akaike information criterion (AIC) and Bayesian information criterion (BIC), the best-fitting parametric distribution curves of both PFS and OS of the two groups was selected (Table 1).
Utility and cost
The utility values of PFS and PD status associated with advanced HCC were 0.76 and 0.68, respectively [20]. From the perspective of China’s healthcare system, only direct medical expenses were considered, including drug costs, follow-up costs, and treatment costs of adverse reactions (AEs) no less than grade 3 according to Chinese standard. The price of drugs was obtained from the latest market bid price in public databases, which were all up to date in 2023. It was assumed that the patient’s average weight and average body surface area (BSA) were 65 kg and 1.72 m2 [21], respectively. Follow-up costs were derived from references. The cost in this article is calculated in RMB. The incidence of AEs was obtained from the RATIONALE-301 trial. Because the RATIONALE-301 trial did not classify AEs, this study could not consider the management costs of serious adverse reactions. To simplify the model, only adverse events with an incidence rate of ≥ 10% were included, including AST level increased, ALT level increased, blood bilirubin level increased, rash/pruritus, platelet count decreased, fatigue, diarrhea, decreased appetite, weight decreased, hypertension, alopecia, palmar-plantar erythrodysesthesia syndrome [12]. The details are given in Table 1.
Sensitivity analysis
We consider that the parameters included in the model may fluctuate within a certain range. The one-way sensitivity analysis (OWSA) was performed to test the robustness of the parameters in the model. In the OWSA, input parameters were adjusted one-by-one to their respective minimum and maximum values, with a range of the 95% confidence intervals reported in the referenced literature or a ± 20% change from the base-case value (the rate of AEs were set over a range of ± 10% of the baseline values), in order to ascertain the variables that significantly influenced the economic outcomes. The results are shown in the form of a cyclone diagram. Probabilistic sensitivity analysis (PSA) can evaluate the variation of multiple parameters and 1000 Monte Carlo simulations to obtain scatter plots and good curves to test the acceptable probability of different optimal strategies at different WTP thresholds.
Scenario analysis
Considering the potential impact of discount on the results of pharmacoeconomics, and according to the requirements of the "China Pharmacoeconomics Evaluation Guide 2020", the discount rate was 0–8%. In this study, 3% and 8% were used as the discount rates in the model for scenario analysis to explore the economics of the two treatment options under different discount rates.
Results
Base-case analysis
The results of base-case analysis are shown in Table 2. The aggregate costs of the Tislelizumab group was $39746.34, and the cumulative health benefit gained was 2.146 QALYs; The aggregate cost and cumulative effect of the Sorafenib group were $26750.95 and 1.578 QALYs, respectively. The incremental cost of the Tislelizumab group was $12995.39, and the incremental effect was 0.568 QALYs. The ICER was $22869.64/QALYs when using 3 times per capita GDP of China in 2022 as the criterion for the willingness to pay (WTP) threshold. The ICER was lower than the WTP threshold.
Sensitivity analysis
One-way sensitivity analysis.
The results of the OWSA are shown in Fig 3, utility of PD, cost of Camrelizumab and cost of Tislelizumab were the primary factors that had a major impact on the results. The incidence of AEs and treatment costs of AEs had little effect on ICER. All parameters fluctuated within a limited range. The ICER value of the model results did not exceed 3 times the GDP per capita with a change in all uncertain parameters, and the results were consistent with the basic analysis results.
Probabilistic sensitivity analysis.
As shown in Fig 4, if the WTP is equal to 1 time the GDP per capita, all the scattered points are above the WTP line, and the Tislelizumab group is not economically efficient. When WTP is equal to 3 times the GDP per capita, the Tislelizumab group is more economical than the Sorafenib group. The CEAC (Fig 5) shows that the economical effectiveness of Tislelizumab as the first-line treatment of HCC increased with an increase in the WTP. When WTP < $12251.00, the Sorafenib group was more economical. If WTP ≥ $19000.00, the economic probability of Tislelizumab was 100%. The CEAC shows that the economical effectiveness of Tislelizumab as the first-line treatment of HCC increased with a growing WTP. When WTP < $12251.00, the Sorafenib group was more economical. If WTP ≥ $19000.00, the probability that Tislelizumab was economical was 100%.
Discussion
HCC is a common invasive malignant tumor that lacks effective treatment options, leading to poor survival and prognosis [22]. In recent years, the application of new drugs, such as immunomodulatory drugs, has significantly improved the treatment efficacy and prolonged survival of HCC patients [23]. Tislelizumab is a fully humanized monoclonal antibody against the PD-1 receptor, which blocks the interaction between PD-1 and its ligand, PD-L1, which unleashes the anti-tumor immune response [24]. Tislelizumab has achieved good efficacy and safety in the treatment of advanced or metastatic esophageal squamous cell carcinoma [25], recurrent or metastatic nasopharyngeal cancer [26], and advanced solid tumors [27]. The results of RATIONALE-301 research indicate that Tirelizumab monotherapy exhibits excellent efficacy, safety, and health-related quality of life [12]. Tirelizumab monotherapy enriches the choices for first-line treatment of advanced HCC and has been recommended by clinical guidelines both domestically and internationally. However, no relevant studies have evaluated the economics of Tislelizumab as a first-line treatment of unresectable HCC. Therefore, this is the first analysis by building a 3-state partitioned survival model to assess the efficacy and cost-effectiveness of Tislelizumab as the first-line therapy for patients with unresectable HCC from the perspective of the Chinese healthcare system, which may provide a reference for the formulation of related health insurance policies and clinical decision-making.
According to primary analysis results, the Tislelizumab group was associated with 0.568 more QALYs than the Sorafenib group, but the cost also increased by $12,995.39. The ICER was $22,869.64, which was lower than three times the per capita GDP of China in 2022. This study showed that Tislelizumab was a cost-effective first-line therapy for patients with unresectable HCC. The results of OWSA showed that the utility of PD, the cost of Camrelizumab and, the cost of Tislelizumab had a more significant impact on ICER. When the discount rate was adjusted to 3%, ICER was $22,657.06/QALY. If the discount rate was adjusted to 8%, ICER was $23,218.77/QALY. Under the condition that the WTP threshold is three times China’s GDP per capita in 2022, the Tislelizumab scheme is economical. Based on the above results, it can be concluded that the Tislelizumab regimen currently has a cost-effectiveness advantage over the Sorafenib regimen.
Although the model can simulate the natural development of the disease and evaluate the economics of the above two treatments for liver cancer under limited medical resources, there are some limitations. First, the survival curve fitting of this model was based on a large-scale phase III clinical trial with strict restrictions on patient conditions. Patients had explicit inclusion and exclusion criteria and high compliance. However, in clinical practice, disease regression and survival status are affected by many factors. Therefore, there may be differences between the various disease outcomes of patients in this study and those in the actual clinical situation. Second, there is a lack of utility values for patients with primary HCC in China. According to “the Guidelines for Pharmacoeconomic Evaluation 2020”, we obtained health utility values from published studies by conducting a literature search. Although the disease progression of patients with HCC was the same, the utility values may not precisely match the clinical reality of our patients due to ethnic differences, and the results of their analysis may be somewhat biased. Third, the treatment regimen of PFS in this study was centered around Tislelizumab and Sorafenib, while for PD, it revolved around Camrelizumab combined with FOLFOX4. In practical clinical practice, doctors can choose different treatment regimens depending on the patients’ individual situation.
Conclusions
Under the current economic conditions in China, the Tislelizumab therapeutic scheme is more cost-effective than the Sorafenib therapeutic scheme for treating patients with unresectable HCC.
Acknowledgments
The authors thank all the local participants for their support and hard work in launching and implementing this study.
References
- 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–249. pmid:33538338
- 2. Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer. 2015;15(11):653–667. pmid:26493646
- 3. Wang C, Cao Y, Yang C, Bernards R, Qin W. Exploring liver cancer biology through functional genetic screens. Nat Rev Gastroenterol Hepatol. 2021;18(10):690–704. pmid:34163045
- 4. Cai M, Huang W, Huang J, Shi W, Guo Y, Liang L, et al. Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study. Front Immunol. 2022;13:848387. Published 2022 Mar 1. pmid:35300325
- 5. Yahoo N, Dudek M, Knolle P, Heikenwälder M. Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation. J Hepatol. 2023;79(2):538–551. pmid:36893854
- 6. Aravalli RN, Steer CJ. Immune-Mediated Therapies for Liver Cancer. Genes (Basel). 2017;8(2):76. Published 2017 Feb 17. pmid:28218682
- 7. Gigante E, Hobeika C, Le Bail B, Paradis V, Tougeron D, Lequoy M, et al. Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma. Liver Cancer. 2022;11(5):460–473. Published 2022 Jun 14. pmid:36158591
- 8. Toh TB, Lim JJ, Hooi L, Rashid MBxMA, Chow EK. Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma. J Hepatol. 2020;72(1):104–118. https://doi.org/10.1016/j.jhep.2019.08.035.
- 9. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial [published correction appears in JAMA Oncol. 2021 Jan 1;7(1):140]. JAMA Oncol. 2020;6(11):e204564. https://doi.org/10.1001/jamaoncol.2020.4564.
- 10. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a Bevacizumab biosimilar (IBI305) versus Sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study [published correction appears in Lancet Oncol. 2021 Aug;22(8):e347]. Lancet Oncol. 2021;22(7):977–990. https://doi.org/10.1016/S1470-2045(21)00252-7.
- 11. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38(3):193–202. pmid:31790344
- 12. Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, et al. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial [published online ahead of print, 2023 Oct 5]. JAMA Oncol. 2023;e234003. https://doi.org/10.1001/jamaoncol.2023.4003.
- 13. Qiuping Chen, Mingyi Shao, Hongyan Cui, Lv Lanqing, Chen Xiaoqi, et al. Cost-utility analysis of Dovalizumab combined with Tramezumab in the first-line treatment of advanced hepatocellular carcinoma. Pharmaceutical Review, 2023,42 (10): 1492–1497.
- 14. Qin S, Kruger E, Tan SC, Cheng S, Wang N, Liang J. Cost-effectiveness analysis of FOLFOX4 and Sorafenib for the treatment of advanced hepatocellular carcinoma in China. Cost Eff Resour Alloc. 2018;16:29. Published 2018 Aug 4. pmid:30087583
- 15. He Y, Lin W, Cai Z, Huang Y, You M, Lei M, et al. Cost-effectiveness analysis of transarterial chemoembolization combined with lenvatinib as the first-line treatment for advanced hepatocellular carcinoma. Front Pharmacol. 2023;14:1219694. Published 2023 Sep 7. pmid:37745079
- 16. Xu Z, Ye ZM, Tang YK, Deng DF, Zhou Q, Fang M, et al. Cost-effectiveness analysis of Sintilimab plus IBI305 versus Sorafenib for unresectable hepatic cell carcinoma in China. Cancer Med. 2023;12(14):14871–14880. pmid:37434398
- 17. Chiang CL, Chan SK, Lee SF, Choi HC. First-Line Atezolizumab Plus Bevacizumab versus Sorafenib in Hepatocellular Carcinoma: A Cost-Effectiveness Analysis. Cancers (Basel). 2021;13(5):931. Published 2021 Feb 24. pmid:33668100
- 18. Han Jiaqi, She Longjiang, Yao Linli, Huang Jin, et al. Cost-effectiveness analysis of Nivolumab in the treatment of advanced gastric cancer after chemotherapy failure based on Markov model. Chinese Journal of General Surgery, 2019, 28 (03): 327–334.
- 19. van den Hurk CJ, van den Akker-van Marle ME, Breed WP, van de Poll-Franse LV, Nortier JW, Coebergh JW. Cost-effectiveness analysis of scalp cooling to reduce chemotherapy-induced alopecia. Acta Oncol. 2014;53(1):80–87. pmid:24059270
- 20. Cammà C, Cabibbo G, Petta S, Enea M, Iavarone M, Grieco A, et al. Cost-effectiveness of Sorafenib treatment in field practice for patients with hepatocellular carcinoma. Hepatology. 2013;57(3):1046–1054. pmid:23299720
- 21. Gu X, Zhang Q, Chu YB, Zhao YY, Zhang YJ, Kuo D, et al. Cost-effectiveness of afatinib, gefitinib, erlotinib and pemetrexed-based chemotherapy as first-line treatments for advanced non-small cell lung cancer in China. Lung Cancer. 2019;127:84–89. pmid:30642557
- 22. Jin H, Shi Y, Lv Y, Yuan S, Ramirez CFA, Lieftink C, et al. EGFR activation limits the response of liver cancer to lenvatinib. Nature. 2021;595(7869):730–734. pmid:34290403
- 23. Yang W, Wang B, Yu Q, Liu T, Li T, Tian T, et al. ARHGAP24 represses β-catenin transactivation-induced invasiveness in hepatocellular carcinoma mainly by acting as a GTPase-independent scaffold. Theranostics. 2022;12(14):6189–6206. Published 2022 Aug 21. https://doi.org/10.7150/thno.72134.
- 24. Saruwatari K, Sato R, Nakane S, Sakata S, Takamatsu K, Jodai T, et al. The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients. Cancers (Basel). 2019;11(2):140. Published 2019 Jan 24. pmid:30682845
- 25. Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022;40(26):3065–3076. pmid:35442766
- 26. Yang Y, Pan J, Wang H, Zhao Y, Qu S, Chen N, et al. Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023;41(6):1061–1072.e4. pmid:37207654
- 27. Friedlander M, Meniawy T, Markman B, Mileshkin L, Harnett P, Millward M, et al. Pamiparib in combination with Tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 2019;20(9):1306–1315. pmid:31378459