Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 1616942 10.3389/fphar.2025.1616942 Pharmacology Original Research Cost-effectiveness analysis of toripalimab plus chemotherapy versus standard chemotherapy in first-line treatment for extensive-stage small cell lung cancer: perspectives from the United States and China Ouyang et al. 10.3389/fphar.2025.1616942 Ouyang Ming 1 Wang Jiangbo 1 Zhang Gaofeng 2 Huang Bei 2 Deng Lin 2 Deng Lian 2 Lang Wenwang 1 * 1 Department of Pharmacy, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China 2 Department of Oncology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China

Edited by: Shusen Sun, Western New England University, United States

Reviewed by: Hong Sun, Fudan University, China

George Gourzoulidis, Health Through Evidence, Greece

Dongzhe Hong, Brigham and Women’s Hospital, United States

 *Correspondence: Wenwang Lang, 290702062@qq.com 20 08 2025 2025 16 1616942 23 04 2025 24 07 2025 Copyright © 2025 Ouyang, Wang, Zhang, Huang, Deng, Deng and Lang. 2025 Ouyang, Wang, Zhang, Huang, Deng, Deng and Lang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Background

Toripalimab combined with chemotherapy has demonstrated significant clinical advantages in improving overall survival compared with chemotherapy alone as a first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC).

 Method

An economic evaluation was conducted using a Markov state-transition model to reflect the perspectives of the United States payer and Chinese healthcare systems. Primary outcomes included quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB).

 Results

Base-case analysis indicated that incorporating toripalimab into chemotherapy produced an ICER of $45,629.27 per QALY, exceeding China’s willingness-to-pay (WTP) threshold of $38,042.49 per QALY. Subgroup analyses revealed ICERs of $22,345.99 and $30,867.38 per QALY for patients with low intratumor heterogeneity (ITH-L) and A11+/B62- histology, respectively, both below the China WTP threshold. In contrast, in the United States, the additional cost led to unfavorable ICERs of $842,855.23, $328,694.61, and $520,412.03 per QALY for the overall population, the ITH-L subgroup, and the A11+/B62− subgroup, respectively, each exceeding the United States WTP threshold of $150,000.00.

 Conclusion

The combination of toripalimab and chemotherapy was not found to be a cost-effective first-line treatment for ES-SCLC in China or the United States, except for patients in China with ITH-L and A11+/B62- histology.

 cost-effectiveness extensive-stage small-cell lung cancer toripalimab chemotherapy Markov model section-at-acceptance Drugs Outcomes Research and Policies Introduction

Lung cancer remains a leading cause of cancer-related mortality globally and is the second most common cancer diagnosed (Rudin et al., 2021; Sung et al., 2021; Oronsky et al., 2022), with small cell lung cancer (SCLC) accounting for approximately 15% of cases. Extensive-stage SCLC (ES-SCLC), comprising 80%–85% of SCLC diagnoses, is associated with poor prognosis and limited survival rates despite advances in therapy. Epidemiologically, China reports approximately 150,000 new ES-SCLC cases annually, while the United States sees around 40,000 cases, with most patients presenting at an advanced stage at diagnosis (Sung et al., 2021). Traditional first-line treatment, consisting of platinum-based chemotherapy combinations, has historically offered median survival rates of only 10 months and 5-year survival rates below 5% (Rossi et al., 2012; Rudin et al., 2016; Sathiyapalan et al., 2022).

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for ES-SCLC. Several phase III trials have demonstrated better survival with ICIs, such as atezolizumab, durvalumab, adebrelimab, and serplulimab combined with chemotherapy (Horn et al., 2018; Paz-Ares et al., 2019; Cheng et al., 2022; Wang et al., 2022; Cheng et al., 2024a). Toripalimab, a novel PD-1 antibody with unique binding properties (Rajasekaran et al., 2024), showed enhanced efficacy in combination with chemotherapy in the EXTENTORCH trial. This study established the benefits of toripalimab in improving progression-free survival (PFS) by 5.8 months and overall survival (OS) by 14.6 months in ES-SCLC patients, as observed in the EXTENTORCH trial (Cheng et al., 2024b).

Although the clinical efficacy of toripalimab is apparent, its cost-effectiveness remains unclear. High drug costs pose significant financial challenges, particularly for patients in middle-income countries such as China, where healthcare coverage may be limited and out-of-pocket expenses can represent a substantial burden. For example, the high price of toripalimab can exceed the annual income of many families, requiring policy interventions or subsidy programs to ensure affordability. Additionally, toripalimab has entered the United States market and may soon be included in NCCN guidelines, underscoring the need for cost-effectiveness data to inform clinical and policy decisions in both regions. This study evaluated the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone for ES-SCLC treatment from the perspectives of Chinese and United States healthcare, focusing on the general population and subgroups characterized by low intratumor heterogeneity (ITH-L), as defined by a Mutant-Allele Tumor Heterogeneity score of less than 29, and HLA-A11+/B62- haplotypes. In the EXTENTORCH study, patients with ITH-L in the toripalimab group experienced significantly improved PFS and OS. Moreover, patients with the HLA-A11+ HLA-B62− haplotype exhibited extended clinical benefits following toripalimab treatment.

 Methods Patients and intervention

This study was reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist (Husereau et al., 2022). The targeted patients were ≥18 years of age and had histologically or cytologically confirmed ES-SCLC. Other key characteristics aligned with the EXTENTORCH study.

The induction phase comprised four 21-day cycles of intravenous (IV) toripalimab 240 mg or placebo administered every 3 weeks (Q3W), combined with etoposide (100 mg/m2 intravenously on days 1–3 of each cycle) and carboplatin (area under the plasma or serum concentration-time curve = 5) on the first day of each cycle. Subsequently, maintenance therapy with 240 mg IV toripalimab or placebo Q3W continued until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. Tumor imaging evaluations were conducted 6 weeks after initiating treatment and subsequently every 6 weeks for the first 54 weeks, then every 12 weeks until disease progression, loss of follow-up, death, withdrawal of consent, or initiation of new anticancer therapy.

Among the patients, 55.2% in the toripalimab group and 69.4% in the placebo group received additional systemic anticancer treatments after discontinuing the study medications. Common treatments in the toripalimab group included conventional chemotherapies (49.3%), tyrosine kinase inhibitors (32.3%), and PD-1/PD-L1 inhibitors (13.9%), while in the placebo group, these were 59.4%, 43.8%, and 25.1%, respectively.

As the median progression-free survival (mPFS) did not exceed 6 months in either group, the selected chemotherapies adhered to the National Comprehensive Cancer Network (NCCN) (NCCN, 2025), the Chinese Society of Clinical Oncology (CSCO) guidelines (Yaoch, 2025), and the EXTENTORCH trial. The recommended combinations included topotecan with cisplatin, anlotinib as a tyrosine kinase inhibitor, and toripalimab as a PD-1/PD-L1 inhibitor. Body surface area and creatinine clearance rates were assumed to be similar to those reported in previous studies.

The cost implications of adverse events (AEs) were evaluated using data from the RATIONALE-312 trial. The focus was exclusively on grade 3 or 4 serious adverse events (SAEs), with an incidence rate above 5%. These SAEs included anemia, reduced platelet and neutrophil counts, hyponatremia, hypokalemia, and pneumonia (Tables 1–3).

Model parameters (China).

Parameters Baseline value Range Distribution Reference
Minimum Maximum
Survival model for OS
Toripalimab plus chemotherapy Shape = 2.558Scale = 17.166 Loglogistic Cheng et al. (2024b)
Placebo plus chemotherapy Shape = 2.734Scale = 15.127 Loglogistic Cheng et al. (2024b)
Survival model for PFS
Toripalimab plus chemotherapy Shape = 1.839Scale = 22.624 Loglogistic Cheng et al. (2024b)
Placebo plus chemotherapy Shape = 2.603Scale = 15.128 Loglogistic Cheng et al. (2024b)
Survival model for OS (ITH-L)
Toripalimab plus chemotherapy Shape = 1.839Scale = 22.624 Loglogistic Cheng et al. (2024b)
Placebo plus chemotherapy mu = 2.4562sigma = 0.6261Q = −0.9901 Gengamma Cheng et al. (2024b)
Survival model for PFS (ITH-L)
Toripalimab plus chemotherapy Meanlog = 2.169Sdlog = 0.876 Lognormal Cheng et al. (2024b)
Placebo plus chemotherapy Shape = 3.589Scale = 6.302 Loglogistic Cheng et al. (2024b)
Survival model for OS(A11+/B62-)
Toripalimab plus chemotherapy Meanlog = 3.062Sdlog = 0.507 Lognormal Cheng et al. (2024b)
Placebo plus chemotherapy Meanlog = 2.733Sdlog = 0.638 Lognormal Cheng et al. (2024b)
Survival model for PFS (A11+/B62-)
Toripalimab plus chemotherapy Meanlog = 2.154Sdlog = 0.643 Lognormal Cheng et al. (2024b)
Placebo plus chemotherapy Shape = 3.078Scale = 5.934 Loglogistic Cheng et al. (2024b)
Drug cost, $/per cycle
Cost of toripalimab 346.07 276.86 415.28 Gamma Yaoch (2025)
Cost of carboplatin 51.26 41.01 61.51 Gamma Yaoch (2025)
Cost of cisplatin 35.03 28.02 42.04 Gamma Yaoch (2025)
Cost of etoposide 6.63 5.30 7.96 Gamma Yaoch (2025)
Cost of topotecan 246.69 197.35 296.03 Gamma Yaoch (2025)
Cost of anlotinib 563.24 450.59 675.89 Gamma Yaoch (2025)
Cost of the laboratory test 92.99 74.39 111.59 Gamma Zhu et al. (2022)
Enhanced CT/MRI 241.67 193.34 290.00 Gamma Yaoch (2025)
Cost of end-of-life 1,460.30 1,168.24 1752.36 Gamma Cao et al. (2022), Liu et al. (2023a)
Best supportive care 345.60 276.48 414.72 Gamma (17)
Cost of drug administration per unit Preventive medication per intravenous administration 93.93 75.14 112.72 Gamma Cao et al. (2022), Liu et al. (2023a)
Infusion fee per intravenous administration 1.86 1.49 2.23 Gamma Cao et al. (2022), Liu et al. (2023a)
Preventive medication 39.14 31.31 46.97 Gamma Cao et al. (2022), Liu et al. (2023a)
Proportion of receiving subsequent treatment
Toripalimab plus chemotherapy group 55.20% 44.16% 66.24% Beta Cheng et al. (2024b)
Placebo plus chemotherapy 69.40% 55.52% 83.28% Beta Cheng et al. (2024b)
Subsequent treatment in Toripalimab plus Chemotherapy group
Cytotoxic agents 49.30% 39.44% 59.16% Beta Cheng et al. (2024b)
Tyrosine kinase inhibitors 32.30% 25.84% 38.76% Beta Cheng et al. (2024b)
PD-1/PD-L1 inhibitors 13.90% 11.12% 16.68% Beta Cheng et al. (2024b)
Subsequent treatment in Placebo plus Chemotherapy group
Cytotoxic agents 59.40% 47.52% 71.28% Beta Cheng et al. (2024b)
Tyrosine kinase inhibitors 43.80% 35.04% 52.56% Beta Cheng et al. (2024b)
PD-1/PD-L1 inhibitors 25.10% 20.08% 30.12% Beta Cheng et al. (2024b)
Discount rate (China) 5% 4.00% 6.00% Beta
BMI/m2 1.72
Weight/kg 65.00
$1 = ¥7.0467 38,042.49

ITH-L, low intratumor heterogeneity; OS, overall survival; PFS, progression-free survival; PD, progression disease; BMI, body mass index.

Model parameters of AEs(China).

Parameters Baseline value Range Distribution Reference
Minimum Maximum
Cost of AEs, $
Anaemia 138.75 112.32 166.50 Gamma Zhu et al. (2022)
Decreased platelet count 1,505.92 1,219.06 1807.10 Gamma Zhu et al. (2022)
Decreased neutrophil count 115.01 80.92 138.01 Gamma Zhu et al. (2022)
Hyponatraemia 3,223.00 2,578.40 3,867.60 Gamma Liu et al. (2023b)
Hypokalaemia 3,000.00 2,400.00 3,600.00 Gamma Liu et al. (2023b)
Pneumonia 2,105.00 1,684.00 2,526.00 Gamma Jiang and Wang (2022)
Utilities
Utility of PFS 0.69 0.55 0.83 Beta Vedadi et al. (2021)
Utility of PD 0.60 0.48 0.72 Beta Vedadi et al. (2021)
Disutility estimates
Anemia 0.07 0.06 0.09 Beta Zhu et al. (2022)
Decreased platelet count 0.05 0.04 0.06 Beta Zhu et al. (2022)
Decreased neutrophil count 0.20 0.16 0.24 Beta Zhu et al. (2022)
Hyponatraemia 0.04 0.03 0.05 Beta Liu et al. (2023b)
Hypokalaemia 0.04 0.03 0.05 Beta Liu et al. (2023b)
Pneumonia 0.09 0.07 0.11 Beta Zhu et al. (2021)
Risk for main AEs in Toripalimab plus Chemotherapy group
Anemia 30.60% 24.48% 36.72% Beta Cheng et al. (2024b)
Decreased platelet count 24.80% 19.84% 29.76% Beta Cheng et al. (2024b)
Decreased neutrophil count 74.30% 59.44% 89.16% Beta Cheng et al. (2024b)
Hyponatraemia 6.30% 5.04% 7.56% Beta Cheng et al. (2024b)
Hypokalaemia 5.90% 4.72% 7.08% Beta Cheng et al. (2024b)
Pneumonia 6.80% 5.44% 8.16% Beta Cheng et al. (2024b)
Risk for main AEs in Placebo plus Chemotherapy group
Anemia 34.70% 27.76% 41.64% Beta Cheng et al. (2024b)
Decreased platelet count 34.30% 27.44% 41.16% Beta Cheng et al. (2024b)
Decreased neutrophil count 75.00% 60.00% 90.00% Beta Cheng et al. (2024b)
Hyponatraemia 6.50% 5.20% 7.80% Beta Cheng et al. (2024b)
Hypokalaemia 6.50% 5.20% 7.80% Beta Cheng et al. (2024b)
Pneumonia 3.20% 2.56% 3.84% Beta Cheng et al. (2024b)

PFS, progression-free survival; PD, progression disease; AE, adverse event.

Model parameters (United States).

Parameters Baseline value Range Distribution Reference
Minimum Maximum
Drug cost, $/per cycle
Cost of Toripalimab 8,892.03 7,113.62 10,670.44 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of Carboplatin 55.83 44.66 67.00 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of Cisplatin 45.79 36.63 54.95 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of Etoposide 62.76 50.21 75.31 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of Topotecan 2,720.26 2,176.21 3,264.31 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of the laboratory test 111.65 89.32 133.98 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Enhanced CT/MRI 438.21 350.568 525.85 Gamma Centers_for_Medicare_and_Medicaid_Services (2025)
Cost of end-of-life 21,603.00 17,282.40 25,923.60 Gamma Shao et al. (2023)
Best supportive care 1,447.79 1,158.23 1737.35 Gamma Shao et al. (2023)
Cost of drug administration first hour 142.55 114.04 171.06 Gamma Liu et al. (2021)
Administration intravenous, additional hour 30.68 24.54 36.82 Gamma Liu et al. (2021)
Cost of AEs, $
Anaemia 7,941.00 6,352.80 9,529.20 Gamma Shao et al. (2023)
Decreased platelet count 13,105.00 10,484.00 15,726.00 Gamma Shao et al. (2023)
Decreased neutrophil count 13,105.00 10,484.00 15,726.00 Gamma Shao et al. (2023)
Hyponatraemia 4,685.00 3,748.00 5,622.00 Gamma Wong et al. (2018)
Hypokalaemia 4,685.00 3,748.00 5,622.00 Gamma Wong et al. (2018)
Pneumonia 10,756.00 8,604.80 12,907.20 Gamma Wong et al. (2018)
Discount rate 3% 4.00% 6.00% Beta
BMI/m2 1.79
Weight/kg 65

AE, adverse event, BMI, body mass index.

 Model structure

A three-state Markov model (“progression-free survival,” “progressive disease,” and “death”) was used to simulate treatment outcomes over a 10-year horizon (Figure 1). The model outcomes were developed and analyzed using the TreeAge Pro 2022 software (Williamstown, MA, United States) and R software (version 4.2.3, Vienna, Austria). The model inputs included the survival curves for PFS and OS. All patients entered the model in the PFS state and received chemotherapy alone or chemotherapy combined with toripalimab until disease progression or unacceptable toxicity was observed. Patients transitioning to the PD state received subsequent therapies following the discontinuation of toripalimab or placebo in combination with chemotherapy. The proportion of patients in the PD state was determined using the area under the OS curve, proportion of patients alive with OS, proportion of patients alive with PFS, and difference between the OS and PFS curves. Cost-effectiveness analyses (CEAs) were conducted from the perspective of the United States payer and Chinese healthcare system. Only direct medical costs were included in the United States perspective, whereas the Chinese perspective considered broader healthcare system costs (Dieleman et al., 2020).

Markov model structure.

Flowchart with three blue ovals labeled "Progression-free," "Progression disease," and "Death." Arrows show transitions from "Progression-free" to "Progression disease" and both of these to "Death." Curved arrows revert each step back to the previous one. Outcomes

The outcomes were measured in quality-adjusted life years (QALYs) and costs in United States dollars. Both costs and utilities were discounted annually at 3% in the United States and 5% in China (Su et al., 2021; Yue et al., 2021). In China, costs were updated to 2023 values using the local consumer price index and converted to United States dollars based on an exchange rate of $1 = ¥7.0467. CEAs were performed, with the results expressed as incremental cost-effectiveness ratios (ICERs). ICERs were calculated as the incremental cost per QALY gained: ICER = [Cost (toripalimab plus chemotherapy) − Cost (placebo plus chemotherapy)]/[QALY (toripalimab plus chemotherapy) − QALY (placebo plus chemotherapy)].

The willingness-to-pay (WTP) threshold was defined as three times the per capita gross domestic product (GDP) of China in 2023, corresponding to $38,042.49 and $150,000.00 for the United States(Ding et al., 2025; Dong et al., 2025), following the WHO recommendations (Murray et al., 2000; Neumann et al., 2014). The analysis also included the incremental net health benefit (INHB) and incremental net monetary benefit (INMB), calculated as follows: INHB (λ) = (μE1 - μE0) - (μC1 - μC0)/λ = ΔE - ΔC/λ and INMB (λ) = (μE1 − μE0) × λ − (μC1 − μC0) = ΔE × λ − ΔC, where μCi and μEi are the costs and utility values associated with the toripalimab plus chemotherapy regimens (i = 1) or placebo plus chemotherapy (i = 0) regimens, and λ represents the WTP threshold.

 Clinical data input

A previously published method was used to construct survival curves for OS and PFS in the RATIONALE-312 trial (Guyot et al., 2012). The GetData Graph Digitizer (version 2.26, www.getdata.graph.digitizer.com) was used to digitize time-to-event data from the Kaplan-Meier survival curves for OS and PFS. Various parametric survival models including, Exponential, Weibull, Weibull proportional hazards (Weibull PH), Gamma, Log-normal, Gompertz, Generalized Gamma, and Log-logistic distributions, were used to extract data points.

The selection of the most suitable survival curves for PFS and OS was guided by assessments using the Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), supported by visual inspection of the fitted curves. Table 1 provides each model’s estimated shape (g) and scale (λ) parameters. Further details on long-term survival data are presented in Tables 4–6 and Figures 2–4.

The Akaike information criteria (AIC) and Bayesian information criteria (BIC).

Type of distribution Toripalimab plus chemotherapy (OS) Placebo plus chemotherapy (OS) Toripalimab plus chemotherapy (PFS) Placebo plus chemotherapy (PFS)
AIC BIC AIC BIC AIC BIC AIC BIC
Exponential 1,240.0290 1,243.4360 1,260.0970 1,263.4860 864.9728 868.3800 768.0160 771.4050
Gamma 1,171.6110 1,178.4260 1,176.8070 1,183.5850 799.8772 806.6916 635.2843 642.0625
Generalized gamma 1,164.2260 1,174.4470 1,172.4790 1,182.6470 776.9676 787.1891 633.3803 643.5475
Gompertz 1,215.7410 1,222.5550 1,222.4340 1,229.2120 854.2128 861.0272 701.2803 708.0585
Weibull 1,183.4780 1,190.2920 1,188.9210 1,195.6990 817.4874 824.3017 653.3102 660.0883
WeibullPH' 1,161.2000 1,168.0140 1,168.0280 1,174.8060 817.4874 824.3017 653.3102 660.0883
Log-logistic 1,161.2000 1,168.0140 1,168.0280 1,174.8060 780.0376 786.8519 625.0739 631.8521
Lognormal 1,162.5260 1,169.3400 1,170.5080 1,177.2860 781.2917 788.1060 631.4413 638.2195

OS, overall survival; PFS, progression-free survival; AIC, akaike information criterion; BIC, bayesian information criterion.

The Akaike information criteria (AIC) and Bayesian information criteria (BIC) of patients with ITH-L.

Type of distribution Toripalimab plus chemotherapy (OS) Placebo plus chemotherapy (OS) Toripalimab plus chemotherapy (PFS) Placebo plus chemotherapy (PFS)
AIC BIC AIC BIC AIC BIC AIC BIC
Exponential 330.5549 332.7744 467.5742 470.0169 268.6060 270.8255 351.1980 353.6406
Gamma 325.8386 330.2776 440.7276 445.6129 262.0757 266.5147 298.7040 303.5893
Generalized gamma 326.6067 333.2652 431.5464 438.8744 258.7887 265.4472 299.1890 306.5169
Gompertz 331.1119 335.5509 459.7345 464.6198 269.9976 274.4366 323.4500 328.3353
Weibull 327.0066 331.4456 446.6638 451.5492 264.5628 269.0019 304.8615 309.7468
WeibullPH' 327.0066 331.4456 446.6638 451.5492 264.5628 269.0019 304.8615 309.7468
Log-logistic 323.8783 328.3173 436.2306 441.1159 257.7820 262.2210 297.0506 301.9359
Lognormal 324.6991 329.1382 434.0331 438.9184 257.5093 261.9483 297.1891 302.0744

OS, overall survival; PFS, progression-free survival; AIC, akaike information criterion; BIC, bayesian information criterion; ITH-L, low intratumor heterogeneity.

The Akaike information criteria (AIC) and Bayesian information criteria (BIC) of patients with HLA-A11+/B62-.

Type of distribution Toripalimab plus chemotherapy (OS) Placebo plus chemotherapy (OS) Toripalimab plus chemotherapy (PFS) Placebo plus chemotherapy (PFS)
AIC BIC AIC BIC AIC BIC AIC BIC
Exponential 364.1528 366.7875 308.7186 310.6699 326.4818 329.1165 218.1105 220.0618
Gamma 321.1152 326.3846 289.8667 293.7692 297.7616 303.0310 193.6630 197.5654
Generalized gamma 319.8627 327.7669 289.6635 295.5172 295.7284 303.6325 195.5209 201.3747
Gompertz 338.3224 343.5919 300.9050 304.8075 315.9746 321.2440 203.0393 206.9417
Weibull 325.9785 331.2479 292.8411 296.7436 302.6443 307.9138 195.3103 199.2128
WeibullPH' 325.9785 331.2479 292.8411 296.7436 302.6443 307.9138 195.3103 199.2128
Log-logistic 320.1675 325.4370 288.1730 292.0755 294.8727 300.1422 193.5773 197.4798
Lognormal 318.6670 323.9364 287.7892 291.6917 294.2969 299.5664 193.8541 197.7566

OS, overall survival; PFS, progression-free survival; AIC, akaike information criterion; BIC, bayesian information criterion.

The Kaplan-Meier overall survival curves. (a) Overall survival, (b) Progression-free survival.

Two graphs compare overall survival (a) and progression-free survival (b) over time in months. Each graph includes four curves: red and blue for placebo, and green and purple for a treatment labeled Toclprimab, using Kaplan-Meier and log-logistic methods. Survival percentages decrease over time for all cohorts.

The Kaplan-Meier overall survival curves for patients with ITH-L. (a) Overall survival, (b) Progression-free survival.

Two line graphs depict survival analysis. Graph (a) shows overall survival over 60 months, comparing placebo and topilumab groups using Kaplan-Meier and log-logistic models. Graph (b) illustrates progression-free survival over 40 months for the same groups and models. Both graphs show decreasing survival rates over time.

The Kaplan-Meier overall survival curves for patients with HLA-A11+/B62-. (a) Overall survival, (b) Progression-free survival.

Two survival graphs are depicted. Chart (a) shows overall survival over 60 months, comparing treatments: placebo and Tolpamib. Chart (b) shows progression-free survival over 40 months with the same treatments. Both use Kaplan-Meier and log-normal plots with color-coded lines for different treatment groups. Cost input

Only direct medical costs were analyzed, including drug expenses, laboratory test fees, PET-CT scans, prophylactic medications for intravenous treatments, best supportive care, end-of-life care, drug administration, subsequent treatments, and management of SAEs. To determine the costs of medications, local charges from the China Health Industry Data Platform (https://data.yaozh.com/) were utilized (Yaoch, 2025), using the national median price as the reference point, while other cost-related data were obtained from previous studies and relevant publications.

Drug doses followed the RATIONALE-312 study protocol, and treatment cycle costs were calculated accordingly using local price data (Tables 1–3) (Wong et al., 2018; Liu et al., 2021; Cao et al., 2022; Zhu et al., 2022; Liu et al., 2023a; Shao et al., 2023; Centers_for_Medicare_and_Medicaid_Services, 2025; Yaoch, 2025). The AE-related costs were determined by multiplying the estimated incidence rates by the respective treatment expenses. All AEs were assumed to occur during the initial treatment cycle; detailed incidence rates are provided in Tables 1–3 (Wong et al., 2018; Zhu et al., 2021; Jiang and Wang, 2022; Zhu et al., 2022; Liu et al., 2023b; Shao et al., 2023).

 Utility inputs

Health utility scores range from 0 (death) to 1 (perfect health). As the RATIONALE-312 trial did not report quality of life outcomes, utility values were obtained from published literature. The utility scores for PFS and PD were assigned as 0.69 and 0.60 (Vedadi et al., 2021) (Table 2 ). The impact of AEs on health utility (disutility) was considered only during the first cycle of the model (Zhu et al., 2021; Zhu et al., 2022; Liu et al., 2023b).

 Sensitivity analysis

One-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to address the model uncertainty. In the OWSA, the literature informed parameter ranges, with values fluctuating by ±20% from the baseline estimates. For PSA, the model parameters were varied simultaneously in 10,000 Monte Carlo simulations to estimate the likelihood of cost-effectiveness for each intervention at different WTP thresholds per additional QALY. Beta distributions were applied to the utility parameters, whereas gamma distributions were used for the cost variables. The results are presented as a scatter plot and cost-effectiveness acceptability curve.

 Subgroup analyses

Subgroup analyses examined the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone as a first-line treatment for ES-SCLC in China and the United States These analyses focused on patients with ITH-L and A11+/B62−. As specific data on follow-up treatments, drug use, and AE incidence in these subgroups were unavailable from the EXTENTORCH trial, these characteristics were assumed to be aligned with those of the overall study population.

 Results Base-case analysis

Over a 10-year analysis horizon, the base-case results revealed that the toripalimab plus chemotherapy group achieved an additional 0.81 QALYs at an incremental cost of $16,515.81. In contrast, the chemotherapy-only group attained 0.71 QALYs for $11,827.35. The comparative analysis demonstrated an average incremental effect of 0.10 QALYs at an added cost of $4,688.46 for the toripalimab regimen, resulting in an ICER of $45,629.27 per QALY for toripalimab plus chemotherapy compared to chemotherapy alone (Table 7).

The base case analysis.

Treatment Cost QALY Incremental cost Incremental QALY INHB INMB ICER
Toripalimab plus chemotherapy (China) 16,515.81 0.81 4,688.46 0.10 −0.02 −779.55 45,629.27
Chemotherapy (China) 11,827.35 0.71
Toripalimab plus chemotherapy (China) (ITH-L) 21,306.20 1.18 7,534.87 0.34 0.14 5,292.72 22,345.99
Chemotherapy (China) (ITH-L) 13,771.32 0.84
Toripalimab plus chemotherapy (China) (A11+/B62–) 17,968.93 0.90 6,122.63 0.20 0.04 1,423.20 30,867.38
Chemotherapy (China) (A11+/B62–) 11,846.30 0.70
Toripalimab plus chemotherapy (United States) 167,278.59 0.83 90,483.17 0.11 −0.50 −74380.20 842,855.23
Chemotherapy (United States) 76,795.42 0.72
Toripalimab plus chemotherapy (ITH-L) (United States) 200,248.24 1.22 117,073.22 0.36 −0.42 −63646.78 328,694.61
Chemotherapy (ITH-L) (United States) 83,175.02 0.86
Toripalimab plus chemotherapy (A11+/B62–) (United States) 183,732.16 0.92 105,797.65 0.20 −0.50 −75303.26 520,412.03
Chemotherapy (A11+/B62–) (United States) 77,934.51 0.71

QALY, Quality-adjusted life year, ICER, Incremental cost-effectiveness ratio, INMB:the incremental net monetary benefits, INHB, the incremental net health benefits, ITH-L, low intratumor heterogeneity.

When assessed against China’s WTP threshold of $38,042.49 per QALY, toripalimab plus chemotherapy was not cost-effective compared with chemotherapy alone. INHB was calculated as −0.02 QALYs, with an INMB of $-779.55 (Table 7). The ICER for toripalimab plus chemotherapy in the United States was $842,855.23 per QALY, far exceeding the United States WTP threshold of $150,000.00 per QALY. At this threshold, the INHB was −0.50 QALYs, and the INMB was $-74,380.20 compared to chemotherapy alone (Table 7).

 Subgroup analysis

In subgroup analyses, the ICER for toripalimab plus chemotherapy compared to chemotherapy alone was $22,345.99 per QALY gained for patients with ITH-L and $30,867.38 per QALY for those with A11+/B62-, both falling below China’s WTP threshold of $38,042.49 per QALY (Table 7). The INHB for toripalimab plus chemotherapy was calculated as 0.14 QALYs for ITH-L patients and 0.04 QALYs for A11+/B62- patients. The corresponding INMB values were $5,292.72 and $1,423.20, respectively, at the WTP threshold of $38,042.49 per QALY (Table 7).

In contrast, in the United States, the ICER for toripalimab plus chemotherapy compared to chemotherapy alone was $328,694.61 per QALY for ITH-L patients and $520,412.03 per QALY for A11+/B62- patients, exceeding the United States WTP threshold of $150,000.00 per QALY (Table 7). The INHB for toripalimab plus chemotherapy was −0.42 QALYs for ITH-L patients and −0.50 QALYs for A11+/B62- patients, while INMB values were $-63,646.78 and $-75,303.26, respectively, at a WTP threshold of $150,000.00 per QALY (Table 7).

 Sensitivity analysis

Figures 5–7 present a tornado diagram from the OWSA, analyzing China’s entire population and subgroups. It highlights the factors most significantly affecting base-case outcomes, including the utility value of PFS, the cost of toripalimab, and the proportion of tyrosine kinase inhibitors used in subsequent treatments in the toripalimab plus chemotherapy group. Figures 5–7 show that, for United States patients, the ICER was most influenced by the cost of toripalimab, the utility value of PFS, and the utility value of PD. However, due to substantial differences in health outcomes between the two treatment strategies in China and the United States, the parameter values did not alter the overall study conclusions.

The tornado diagram of one-way sensitivity analysis. (a) China, (b) The United States.

Two tornado diagrams labeled a and b, comparing various parameters affecting ICERs (Incremental Cost-Effectiveness Ratios) measured in cost per QALY (quality-adjusted life year). Horizontal bars represent different factors, with values plotted on a horizontal axis from about 30,000 to 60,000 ICERs in diagram a, and from about 72,000 to 88,000 in diagram b. Key values such as WTP (Willingness To Pay) and EV (Expected Value) are marked on the diagrams, with multiple factors such as cost and utility affecting the outcomes.

The tornado diagram of one-way sensitivity analysis for patients with ITH-L. (a) China, (b) The United States.

Two tornado charts labeled a and b comparing various cost-related variables. Both charts display horizontal bars in red and blue, representing different costs and utility values affecting ICER/QALY. Chart a centers around an EV of 22,345.99 with costs like Utility of PFS and Toripalimab, while chart b focuses on an EV of 32,696.61 with similar elements, emphasizing the Cost of Toripalimab.

The tornado diagram of one-way sensitivity analysis for patients with A11+/B62-. (a) China, (b) The United States.

Two tornado plots labeled "a" and "b," comparing the incremental cost-effectiveness ratios (ICER) in dollars per quality-adjusted life year (QALY). Each plot features mirrored horizontal bars in red and blue, with categories like "Cost of Toripalimab" and "Utility of PFS." Central lines mark expected values: 30,667.38 for plot "a" and 520,214.03 for plot "b." Categories are listed on the right.

Figures 8–10 provide acceptability curves and probabilistic scatter plots, clearly representing the cost-effectiveness landscape. These tools, essential for decision-making, illustrate the probability that toripalimab plus chemotherapy is cost-effective at different WTP thresholds, and as the WTP increases, the likelihood of cost-effectiveness in the toripalimab plus chemotherapy group grows. At a WTP threshold of $150,000.00 in the United States, the acceptability curves revealed that almost 0% probability of serplulimab plus chemotherapy was cost-effective in various groups (the overall population, ITH-L subgroup, and A11+/B62- subgroup).

The cost-effectiveness acceptability curve. (a) China, (b) The United States.

Two CE Acceptability Curves are shown. Graph (a) displays the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone, with a willingness-to-pay (WTP) threshold at $38,042.49 per QALY. Graph (b) shows the same comparison with a WTP threshold at $150,000.00 per QALY. Each graph plots willingness-to-pay on the x-axis against the percentage of iterations cost-effective on the y-axis. Blue and red lines represent the interventions, intersecting at the WTP thresholds.

The cost-effectiveness acceptability curve for patients with ITH-L. (a) China, (b) The United States.

Two CE Acceptability Curves compare Toripalimab plus Chemotherapy (blue line) with Chemotherapy alone (red line) based on willingness-to-pay per quality-adjusted life year (QALY). In panel (a), thresholds and cross-points reflect cost-effectiveness at $38,042/QALY. In panel (b), data is plotted with a different threshold at $150,000/QALY, showing crossover points at a higher value. Both graphs illustrate cost-effectiveness probabilities across a range of values.

The cost-effectiveness acceptability curve for patients with A11+/B62-. (a) China, (b) The United States.

Two CE Acceptability Curves show the cost-effectiveness of Toripalimab plus Chemotherapy versus Chemotherapy alone. In both graphs, the x-axis represents willingness-to-pay per QALY, and the y-axis represents the percentage of iterations cost-effective. Graph (a) shows a willingness-to-pay of $38,042.49/QALY and graph (b) shows $150,000.00/QALY. The blue curve for Toripalimab plus Chemotherapy increases, indicating higher cost-effectiveness at greater willingness-to-pay, while the red curve for Chemotherapy decreases.

In China, these probabilities were 29.95% for the overall population, 97.88% for patients with ITH-L, and 79.50% for the A11+/B62- subgroup, evaluated against a WTP threshold ($38,042.49) (Figures 11–13). In the United States, the probabilities were 0% for the entire population, 0.16% for ITH-L patients, and 0% for the A11+/B62- subgroup, based on a WTP threshold of $150,000.00 (Figures 11–13).

The cost-effectiveness probabilistic scatter plot. (a) China, (b) The United States.

Two scatter plots show incremental cost-effectiveness with incremental effectiveness measured in QALY on the x-axis and incremental cost in dollars on the y-axis. In plot (a), red and green dots represent data points with a threshold Willingness-To-Pay (WTP) line at $38,042.5, and a data cluster is enclosed in an ellipse. Plot (b) contains red dots with a higher WTP line at $150,000, and a similar elliptical cluster. Both plots analyze cost-effectiveness, indicating variability in incremental costs and effectiveness at two different WTP thresholds.

The cost-effectiveness probabilistic scatter plot for patients with ITH-L. (a) China, (b) The United States.

Scatter plots labeled a and b show incremental costs on the y-axis and incremental effectiveness (QALY) on the x-axis. Plot a has mostly green dots with a few red, under the line WTP=38042.5. Plot b has mostly red dots with a few green, under the line WTP=150000. Both include ellipses encompassing the majority of points.

The cost-effectiveness probabilistic scatter plot for patients with A11+/B62-. (a) China, (b) The United States.

Scatter plot panels labeled "a" and "b" show incremental cost versus effectiveness in QALY (Quality-Adjusted Life Years). Panel "a" has a mix of green and red dots with a dotted line for WTP (Willingness to Pay) at thirty-eight thousand forty-two point five. Panel "b" displays red dots with a dashed WTP line at one hundred fifty thousand. Both panels include ellipses around data clusters. Discussion

This study represents the first evaluation of the cost-effectiveness of toripalimab combined with chemotherapy as first-line therapy for ES-SCLC. Our findings indicate that this combination is not a cost-effective option from the perspective of the Chinese healthcare system or the United States payer. This conclusion is supported by the INHB and INMB results, which were −0.02 and −0.50 QALYs and $-779.55 and $-74,380.20 for China and the United States, respectively.

Previous economic evaluations of ES-SCLC treatments in China and the United States (Zhou et al., 2019; Ding et al., 2021; Liu et al., 2021; Wang et al., 2021; Zhu et al., 2021; Zhu et al., 2022; Gan et al., 2023; Long et al., 2023; Shao et al., 2023; Xiang et al., 2023) have similarly highlighted the significant financial burden imposed by ICIs, despite notable gains in QALYs. Many studies have suggested that ICIs may not provide cost-effective alternatives to chemotherapy, with drug costs for PD-1/PD-L1 antibodies being a significant determinant of outcomes in both countries.

Our findings provide growing evidence supporting the use of cost-effective, domestically manufactured anticancer therapies. They highlight the implications for the Chinese government, as it seeks to balance finite healthcare resources with an increasing demand for cancer treatments. Clinically, we recommend that physicians tailor treatment plans based on the patient’s disease status and financial capabilities, prioritizing affordable and effective therapies. In the United States, the ICER for toripalimab plus chemotherapy significantly exceeded the WTP threshold of $150,000.00 per QALY, with a cost-effectiveness acceptability curve showing a 0% probability that the combination is cost-effective.

For SCLC, racial disparities in disease characteristics—associated with differential gene expression and transcriptional subtypes—lead to distinct therapeutic responses and prognoses (Liu et al., 2023c). Asians generally exhibit lower treatment tolerance and different economic baselines than Caucasians and Africans, potentially influencing treatment access and survival outcomes. In the United States, CMS Part B reimbursement schedules reflect clinician-administered drug payments rather than actual acquisition costs (Centers_for_Medicare_and_Medicaid_Services, 2025), which may overestimate drug expenses and bias cost-effectiveness results. However, given the ICER’s substantial exceedance of the WTP threshold, this bias does not alter the study’s conclusions.

Our findings add to the growing evidence supporting the adoption of cost-effective, domestically manufactured anticancer therapies. These insights underscore critical implications for health policymakers, who must balance finite healthcare resources against the escalating demand for cancer treatments. Clinically, we recommend that physicians customize treatment plans based on patients’ disease profiles and financial capacities, prioritizing affordable yet efficacious therapies. This evidence base can inform adjustments to health insurance reimbursement directories by medical insurance bureaus and guide the recommended tiering of drugs in clinical practice guidelines.

In the United States, the ICER for toripalimab plus chemotherapy substantially exceeded the $150,000.00 per QALY WTP threshold, with cost-effectiveness acceptability curves showing a 0% probability of cost-effectiveness. OWSA identified toripalimab costs and utility values as the most influential drivers of ICER in both China and the United States To address this, patient assistance programs could be leveraged to support low-income patients, particularly those with PD-1 progression, intolerance to ICIs, or limited access to alternative therapies. Alternatively, price reductions for toripalimab could enhance accessibility and benefit a broader patient population.

Similar to other analyses, our research confirms that the combination of ICIs and chemotherapy does not achieve cost-effectiveness for ES-SCLC due to the high cost of the drugs and limited improvements in efficacy. There are some differences in the economic analysis standards adopted by different institutions. Therefore, this study highlights the need for more evaluations, including network meta-analyses (NMA) and cost-effectiveness studies that incorporate the perspectives of United States payers, to comprehensively compare ICIs.

Toripalimab will be marketed globally to benefit all patients. Given that only economic analyses of the United States and China were conducted, developed countries such as Europe, America, Japan, and South Korea can refer to the economic analysis of the United States, whereas developing countries in Asia, Africa, and Latin America can refer to the economic analysis results of China.

The EXTENTORCH trial demonstrated that the therapeutic effects on PFS and OS were independent of tumor PD-L1 expression or TMB status, consistent with findings from other phase 3 studies in ES-SCLC. This finding highlights the need for novel biomarkers. ITH has emerged as a potential predictive biomarker of SCLC treatment outcomes associated with improved OS and PFS (Chowell et al., 2018). Additionally, HLA-I genes affect the survival of patients with ICIs. For example, the HLA-B44 supertype is associated with prolonged survival, whereas HLA-B62 or somatic loss of heterozygosity in HLA-I is associated with worse outcomes (Chowell et al., 2018). Biomarker analysis in EXTENTORCH revealed that patients with a lower ITH or HLA-A11+ HLA-B62- haplotype showed more favorable responses to toripalimab plus chemotherapy (Stewart et al., 2020; George et al., 2024).

Given that the HLA-A11 haplotype is more prevalent in East Asians (approximately 30%) than in white individuals (5%–10%), further research is needed to clarify the roles of HLA-A11 and B62 in presenting neoantigens from SCLC tumors. Unlike other studies that do not have subgroup analysis, our subgroup analysis uniquely showed that patients with ITH-L and HLA-A11+ HLA-B62 had lower ICERs than the overall population in China and the United States These subgroups present a cost-effective first-line treatment option for ES-SCLC in China, offering potentially more favorable patient alternatives.

Sensitivity analysis identified the utility values of PFS and PD as critical determinants of cost-effectiveness outcomes. Owing to the lack of EQ-5D and cost-per-QALY data in the EXTENTORCH trial, utility values were derived from the literature, introducing some uncertainty. However, unlike many studies that rely on utility data from non-small cell lung cancer (NSCLC), our study used data specific to SCLC, thus improving the accuracy and relevance of the results.

This study has several limitations. First, clinical data were derived from a phase 3 trial conducted in China, whereas the cost-effectiveness evaluation incorporated a United States perspective, potentially introducing bias. Second, management costs and disutility associated with grade 1–2 AEs were excluded. Although the toripalimab plus chemotherapy group exhibited a higher incidence of these AEs, which could theoretically increase costs and reduce QALYs, the absolute difference in AE rates between groups was minimal. One-way sensitivity analysis further indicated that grade 1–2 AEs had a low impact on ICER, suggesting limited influence on overall results. Additionally, while the longer survival period in the toripalimab group might incur higher indirect costs (e.g., supportive care), sensitivity analysis showed that variations in best supportive care costs did not affect outcomes, implying minimal impact of indirect costs on conclusions. Third, CMS Part B physician fee schedules reflect reimbursement for services and clinician-administered drugs, representing provider payments rather than actual drug acquisition costs. The lack of adjustment for rebates may overestimate drug expenses, potentially biasing cost-effectiveness results against the treatment. In addition, for the general population, the toripalimab plus chemotherapy group only needs 6 years to achieve 99% mortality rate, to be consistent with the subgroup used it for 10 years, this will overestimate ICER. However, it has little impact on the results. Despite these challenges, this cost-effectiveness analysis based on EXTENTORCH data provides critical insights for treatment decision making.

 Conclusion

This investigation revealed that toripalimab combined with chemotherapy is a cost-effective first-line treatment for patients with ES-SCLC with ITH-L and A11 +/B62-histology in China. However, this combination is not cost-effective for the overall patient population in China or any patient group and subgroup in the United States These findings provide critical information for policymakers and healthcare professionals and offer evidence to support the broader application of toripalimab in clinical practice worldwide.

 Data availability statement

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

 Author contributions

MO: Software, Methodology, Writing – original draft, Conceptualization, Resources, Data curation. JW: Validation, Funding acquisition, Writing – review and editing, Project administration, Resources, Data curation. GZ: Conceptualization, Funding acquisition, Methodology, Investigation, Writing – original draft, Data curation. BH: Data curation, Conceptualization, Software, Writing – original draft, Resources. LnD: Supervision, Data curation, Conceptualization, Writing – original draft, Methodology. LaD: Supervision, Conceptualization, Writing – review and editing, Project administration, Validation, Data curation. WL: Writing – review and editing, Supervision, Investigation, Writing – original draft, Data curation, Software, Methodology, Conceptualization, Resources, Formal Analysis, Funding acquisition, Project administration, Visualization, Validation.

 Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

 Conflict of interest

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.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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