Cost-Effectiveness of Perioperative Immune Checkpoint Therapy for NSCLC in Japan, the United States, and Brazil

Abstract

Introduction

Immune checkpoint inhibitors (ICIs) are increasingly being used to treat lung cancer perioperatively. Although ICI use has led to long-term improvements in patient outcomes, its high costs have increased medical expenses. We evaluated the cost-effectiveness of perioperative ICI therapy for NSCLC in Japan, the USA, and Brazil.

Methods

Hazard ratios of disease-free survival and overall survival for neoadjuvant or adjuvant chemotherapy and neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy with ICI were estimated from landmark phase III trials using a network meta-analysis. A partitioned survival model was used to estimate quality-adjusted life-years and life-years. Drug and hospitalization costs were included using standard regimens as of April 2023, discounted at 2% annually.

Results

The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-years for neoadjuvant chemotherapy compared with no perioperative treatment was ¥714,940 ($4468) in Japan. That for neoadjuvant therapy by ICI compared with neoadjuvant chemotherapy was ¥5,285,770 ($33,036). The ICERs for other regimens were not calculated because of their dominance. In the USA and Brazil, the ICERs for neoadjuvant chemotherapy were $32,726 and $29,320, respectively, whereas those for neoadjuvant therapy with ICI were $228,467 and $92,573, respectively.

Conclusions

The ICER threshold in Japan is generally ¥5 million and ¥7.5 million for essential drugs such as anticancer agents. The ICER of neoadjuvant chemotherapy was lower than the former threshold, whereas that of neoadjuvant nivolumab was lower than only the latter threshold. Therefore, neoadjuvant chemotherapy is cost-effective in Japan, the USA, and Brazil, whereas neoadjuvant nivolumab is only cost-effective in Japan.

Introduction

Lung cancer is a malignant tumor with one of the highest morbidity and mortality rates worldwide. It is the leading cause of death from malignant tumors in Japan, with 124,531 new cases diagnosed in 2021 and 75,762 deaths in 2023.1, 2, 3 NSCLC accounts for approximately 80% of all lung cancers, especially stages II to III NSCLC. The goal of curative treatment for NSCLC is to improve the therapeutic effects using multiple treatment options, including surgery, radiotherapy, chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors (ICIs), alone or in combination.

ICIs bind to inhibitory receptors or their ligands, such as programmed cell death protein 1 and cytotoxic T-lymphocyte antigen-4, which are immune checkpoint molecules, and block inhibitory signaling, thereby releasing the brakes on the immune system and enhancing the immune response against tumors. Programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte antigen-4 inhibitors are currently used in cancer therapy and have demonstrated marked efficacy in advanced and metastatic NSCLC, resulting in prolonged survival and improved quality of life.⁴

Multiple phase III clinical trials have demonstrated that the perioperative (neoadjuvant, adjuvant, and neoadjuvant plus adjuvant) use of ICIs has recently emerged as a promising strategy for patients with stages II to III NSCLC.⁵ Neoadjuvant ICIs promote tumor shrinkage, increase the success rate of radical surgery, improve disease-free survival (DFS) and overall survival (OS), and protect lung function by reducing the extent of resection. In addition, ICIs may contribute to the suppression of micrometastasis and the reduction of recurrence risk when used as an adjuvant therapy. Recently, neoadjuvant plus adjuvant therapy has been studied as a combination therapy to achieve a combined effect.

Atezolizumab was approved in 2022 as an adjuvant ICI in Japan, whereas a combination of nivolumab with chemotherapy was approved in 2023 as a neoadjuvant ICI. Several clinical trials for neoadjuvant and adjuvant therapies are currently underway. Atezolizumab was approved in 2021 and pembrolizumab in 2023 in the USA for adjuvant ICI therapy; nivolumab was approved in 2022 for neoadjuvant ICI therapy, and pembrolizumab was approved in 2023 for neoadjuvant plus adjuvant therapy. However, ICIs are expensive, and their expanded uses and long-term administration have increased medical costs. The national health care costs in Japan reached approximately 45 trillion yen in FY2021, of which medical costs for lung cancer were approximately 600 billion yen, both of which are increasing annually since then.⁶ Drug prices have grown at a rate of 0% to 15% annually in the United States in the last 20 years, and health insurance premiums have grown at a rate of 0% to 7% annually since 2010, with medical expenses increasing from $2.658 trillion in 2009 to $3.543 trillion in 2019.7, 8, 9 Health care expenditure was $50 billion in 2000 in Brazil (approximately 7.8% of the gross domestic product) and increased to $1.614 trillion by 2021 (approximately 9.9% of gross domestic product).¹⁰

In this scenario, the importance of efficacy and safety studies is evident. However, the cost-effectiveness of each treatment modality requires an in-depth analysis, wherein setting cost-effectiveness thresholds is an important objective. Little is known about the cost-effectiveness of perioperative treatment with ICIs for NSCLC, and real-world data for making treatment selection decisions are scarce. To address these concerns, we evaluated and compared the cost-effectiveness of ICIs as perioperative therapy for stage II to III NSCLC using the results of representative clinical trials of neoadjuvant, adjuvant, and neoadjuvant plus adjuvant therapy and by simulating medical costs in Japan, the United States, and Brazil.

Materials and Methods

Study Design

We compared the cost-effectiveness of ICIs used as neoadjuvant, adjuvant, and neoadjuvant plus adjuvant therapies with neoadjuvant and adjuvant chemotherapies in clinical settings in Japan. We extracted the efficacy data (hazard ratio [HR]) from the findings of major clinical trials on ICIs (the landmark phase III trial used for regulatory approval for each regimen) to assess the relative efficacy of each regimen using network meta-analysis (NMA)11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and the Bucher method for indirect comparison.²¹ Because no direct head-to-head trials have compared adjuvant and neoadjuvant strategies, we linked these treatments through a common comparator (i.e., surgery alone). The baseline risk of NSCLC without perioperative treatment (DFS and OS) was based on the median survival of the surgery-alone arm reported by Scagliotti et al.,¹² a study that was also used in the NMA. For this baseline risk, we considered the survival curve to have an exponential distribution for all treatments and performed a partitioned survival model analysis using the HR for the placebo group (surgery-alone arm). The patient in this analysis was assumed to be in one of the following states: disease free, disease progression, or death. Based on the baseline risk and HR, we calculated the risks of disease progression and death with each adjuvant therapy and generated survival curves for DFS and OS. We used these survival curves to estimate the effects of quality-adjusted life-years (QALYs) and life-years (LYs) as the area under the curve.

The values reported by Das et al.²² were used to perform a cost-effectiveness analysis of adjuvant atezolizumab in patients with NSCLC. According to this analysis, a score of 0.76 was used for disease free (utility for “DFS” in Das et al.²²) and 0.67 was used for post-progression (utility for “second-line metastatic recurrence”).

The cost was calculated separately for the first and subsequent months to account for initial dosing and hospitalization for therapy administration. The treatment process was based on a standard regimen and dosage setting, adding together the drug price and associated medical fees. The cost of neoadjuvant plus adjuvant therapy was calculated separately before and after surgery because the regimens differed. In addition, adjuvant ICI therapy involved different regimens between the initial and later cycles, so the costs were calculated separately.

Dosage was calculated under the assumption that the patients had a height of 170 cm and body weight of 60 kg (body surface area 1.69 m² according to the Du Bois formula²³). The number of vials required was calculated based on the minimum necessary drug dose, using the combination of available vial sizes that minimized the total drug cost. Drug sharing across vials was not permitted, and any remaining drug in each vial was assumed to be discarded as waste. All drug prices and reimbursements were calculated as of July 2024 according to the official government tariff in Japan.^24,25

Statistical Analysis

The analysis was performed from the perspective of those who pay public medical expenses, including public health insurance providers and patient co-payers. The cycle length was set at 1 week, and the time horizon was set at 5 years (260 wk). Both the cost and effectiveness were discounted by 2% annually. We performed NMA using R (version 4.2.2) and analyzed the cost-effectiveness model using Microsoft Excel. Because the base-case model did not include toxicity-related costs, a simple one-way sensitivity analysis was performed that varied utility values within the ranges reported in previous studies.

Ethics Statement

This study was based entirely on previously published and publicly available data and did not involve the recruitment of human participants or the use of identifiable personal information. Therefore, ethics committee approval and informed consent were not required.

Results

Study Characteristics

Based on the results of the main phase III trials reported at the time of the study, DFS and OS data were available for atezolizumab, nivolumab, and pembrolizumab for adjuvant and neoadjuvant ICI and neoadjuvant plus adjuvant therapy. A summary of each study and the extracted HRs are presented in Table 1. Supplementary Figure 1 reveals a network diagram of the NMA used to construct networks in these studies. In comparative trials of chemotherapy and ICI, comparisons were performed within the same treatment type, such as adjuvant or neoadjuvant. Thus, no study has compared adjuvant and neoadjuvant therapies. Therefore, adjuvant and neoadjuvant treatments were indirectly connected through placebo-controlled studies (i.e., surgery alone). Table 2 reveals the HRs of DFS and OS for each perioperative treatment obtained from the NMA compared with surgery alone. According to the surgery-alone arm reported by Scagliotti et al., the median DFS was 2.9 years and the median OS was 4.8 years. Based on these median survival rates and assuming an exponential distribution of the survival function, the baseline risk per week (cycle) was 0.46% for progression and 0.28% for death.

Table 1.

Studies and Parameters Extracted

Study Identifier	Study Design	OS [HR]	PFS [HR]	Reference
Butts et al. (2010)	Adjuvant chemo vs. placebo	0.78 [0.61–0.99]	0.60 [0.45–0.79]	11
Scagliotti et al.(2012)	Neoadjuvant chemo vs. placebo	0.63 [0.43–0.92]	0.70 [0.50–0.97]	12
Douillard et al.(2006)	Adjuvant chemo vs. placebo	0.80 [0.66–0.96]	0.76 [0.64–0.91]	13
Pisters et al. (2010)	Neoadjuvant chemo vs. placebo	0.79 [0.60–1.06]	0.80 [0.61–1.04]	14
Arriagada et al. (2010)	Adjuvant chemo vs. placebo	0.91 [0.81–1.02]	0.88 [0.78–0.98]	15
Felip et al. (2010)	Neoadjuvant chemo vs. placebo	0.88 [0.69–1.12]	0.92 [0.81–1.04]	16
CheckMate-816	Neoadjuvant nivolumab vs. neoadjuvant chemo	0.62 [0.36–1.05]	0.63 [0.43–0.91]	17
IMpower010	Adjuvant atezolizumab vs. adjuvant chemo	0.995 [0.78–1.28]	0.81 [0.67–0.99]	18
KEYNOTE-091	Adjuvant pembrolizumab vs. adjuvant chemo	0.87 [0.67–1.15]	0.76 [0.63–0.91]	19
KEYNOTE-671	Neoadjuvant + adjuvant pembrolizumab vs. neoadjuvant chemo	0.73 [0.54–0.99]	0.58 [0.46–0.72]	20

Chemo, chemotherapy; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Table 2.

HRs Relative to No Perioperative Treatment

Regimen	OS [HR]	PFS [HR]
Adjuvant chemo	0.86 [0.79–0.95]	0.81 [0.74–0.89]
Neoadjuvant chemo	0.80 [0.67–0.94]	0.87 [0.79–0.97]
Adjuvant atezolizumab (IMpower010)	0.86 [0.66–1.12]	0.66 [0.53–0.82]
Adjuvant pembrolizumab (KEYNOTE-091)	0.75 [0.57–0.99]	0.62 [0.50–0.76]
Neoadjuvant nivolumab (CheckMate-816)	0.49 [0.28–0.86]	0.55 [0.37–0.81]
Neoadjuvant + adjuvant pembrolizumab (KEYNOTE-671)	0.58 [0.41–0.82]	0.51 [0.40–0.65]
No perioperative treatment	Reference	Reference

HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Supplementary Table 1 reveals the assumptions used to calculate the associated costs, fees, and drug prices for each regimen. We assumed that the same surgery would be required for all treatments evaluated, and therefore, the same amount of surgery fee would apply. In cases where preoperative drug therapy was required (i.e., neoadjuvant and neoadjuvant plus adjuvant), we recorded surgical costs only for patients who survived until surgery. We assessed the risk of bias of the included clinical trials using the Cochrane Collaboration’s tool, and the results are summarized in Supplementary Table 2.

Costs and Effectiveness of the Pivotal Study

The cost, LY, and QALY of each treatment, which were calculated using the partitioned survival model based on the HRs obtained from the NMA and baseline risk, are found in Table 3 and Figure 1A-C.

Table 3.

Costs and Effectiveness (LYs and QALYs)

Treatment strategy	Cost (Discounted)	ΔCost	Effectiveness (LY: Discounted)	ΔEffectiveness (LY: Discounted)	Effectiveness (QALY: Discounted)	ΔEffectiveness (QALY: Discounted)
No perioperative treatment	835,340	−	3.57	−	2.55	−
Neoadjuvant chemo	955,845	120,505	3.82	0.243	2.71	0.169
Adjuvant chemo	1,039,018	83,173	3.73	−0.083	2.67	−0.044
Neoadjuvant nivolumab (CheckMate-816)	2,551,511	1,512,493	4.22	0.488	3.02	0.346
Adjuvant pembrolizumab (KEYNOTE-091)	8,120,548	5,569,037	3.87	−0.349	2.79	−0.230
Neoadjuvant + adjuvant pembrolizumab (KEYNOTE-671)	8,333,797	213,249	4.10	0.225	2.95	0.160
Adjuvant atezolizumab (IMpower010)	9,394,941	1,061,144	3.74	−0.359	2.70	−0.251

Δ, delta (difference from the previous row); chemo, chemotherapy; LY, life year; QALY, quality-adjusted life-year.

Figure 1.

Cost-effectiveness plane. The cost and QALYs of each treatment were calculated for each country using the partitioned survival model, which was based on the hazard ratio and baseline risk obtained from the network meta-analysis. Red dots indicate no perioperative treatment, yellow dots indicate superior treatment in terms of ICER per QALY, and black dots indicate dominated treatment. (A) Japan, (B) USA, and (C) Brazil. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Table 3 lists the treatments in the ascending order of cost. Adjuvant chemotherapy, neoadjuvant plus adjuvant therapy, and adjuvant ICI were less effective (in terms of LYs and QALYs) than the less costly treatments listed previously. Therefore, these regimens were excluded from Table 4, and the incremental cost-effectiveness ratios (ICERs) were calculated only for the remaining nondominant treatments.

Table 4.

ICERs Based on Japan, USA, and Brazil

Treatment strategy	Effectiveness				Japan (JPY)				US (USD)				Brazil (USD)
	Effectiveness (QALY: Discounted)	ΔEffectiveness (QALY)	Effectiveness (LY: Discounted)	ΔEffectiveness (LY)	Cost (Discounted)	ΔCost	ICER per QALY	ICER per LY	Cost (discounted)	ΔCost	ICER per QALY	ICER per LY	Cost (Discounted)	ΔCost	ICER per QALY	ICER per LY
No perioperative treatment	2.55	–	3.57	–	835,340	–	–	–	104,623	–	–	–	2439	–	–	–
Neoadjuvant chemo	2.71	0.169	3.82	0.243	955,845	120,505	714,940	496,092	110,139	5516	32,726	22,709	7727	5289	31,376	21,772
Neoadjuvant nivolumab (CheckMate-816)	3.02	0.302	4.22	0.404	2,551,511	1,595,666	5,285,770	3,945,133	179,108	68,969	228,467	170,520	35,676	27,949	92,583	69,101

Δ, delta (difference from the previous row); ICER, incremental cost-effectiveness ratio; JPY, Japanese yen; LY, life year; QALY, quality-adjusted life year, USD, United States dollar.

The ICERs per LY and QALY for neoadjuvant chemotherapy compared with no perioperative treatment were ¥496,092 and ¥714,940, respectively. In addition, the ICERs per LY and QALY for neoadjuvant ICI therapy compared with neoadjuvant chemotherapy were ¥3,945,133 and ¥5,285,770, respectively. In general, the threshold for ICER per QALY in Japan is ¥5 million per QALY for common diseases and ¥7.5 million per QALY for treatments that require consideration in cost-effectiveness analysis appraisals, such as anticancer drugs. Both chemotherapy and ICI-based neoadjuvant therapies meet the latter criterion and can be considered cost effective.

Sensitivity Analysis

The results of probabilistic sensitivity analysis are described in Figure 2A (neoadjuvant chemotherapy versus no perioperative treatment) and Figure 2B (i.e., neoadjuvant ICI versus neoadjuvant chemotherapy). For neoadjuvant chemotherapy, the ICER was below the threshold in 100.0% of the simulations for both ¥5 million and ¥7.5 million, and the probabilities of the ICER falling below ¥5 million and ¥7.5 million were 38.9% and 91.8%, respectively.

Figure 2.

Sensitivity analysis. Probabilistic sensitivity analysis of cost and QALYs for the two treatments. The ICERs per QALY thresholds in Japan are demonstrated as follows: dotted line: 5M JPY per QALY; solid line: 7.5M JPY per QALY. (A) Neoadjuvant chemotherapy versus no perioperative treatment. (B) Neoadjuvant ICI versus neoadjuvant chemotherapy. ICER, incremental cost-effectiveness ratio; ICI, immune checkpoint inhibitor; JPY, Japanese yen; QALY, quality-adjusted life-year.

Furthermore, a one-way sensitivity analysis varying the utility values within the ranges reported in previous studies demonstrated a minimal impact on the incremental cost-effectiveness ratios. The detailed results are presented in Supplementary Table 3. No changes were observed in the order of cost-effectiveness rankings across the treatment strategies.

For neoadjuvant plus adjuvant therapy, discontinuation of adjuvant ICI therapy was required for patients in whom a postoperative pathologic complete response (pCR) was confirmed. A pCR was confirmed in 18.1% of the patients in the KN-671 study. In the scenario analysis, it was assumed that 18.1% of patients who received neoadjuvant plus adjuvant therapy achieved a pCR and were selected to discontinue adjuvant ICI therapy. Furthermore, we calculated the cost of pCR confirmation and discontinuing adjuvant ICI therapy to focus on patients who achieved a pCR. The cost of the scenario in which 18.1% of patients discontinued treatment because of a pCR was ¥7,380,607. The costs for scenarios in which 30%, 50%, and 100% of patients discontinued treatment because of a pCR were ¥6,753,924, ¥5,700,675, and ¥3,067,554, respectively. Both scenarios were dominant in terms of cost-effectiveness; however, a substantial cost reduction was included in these assumptions. This implies that discontinuing treatment in patients with pCR markedly reduces costs. Although this analysis was conducted in the context of Japan’s expenses, costs were also analyzed using the expenses of other countries.

Scenario Analysis

The results of the scenario analysis performed using the U.S. and Brazilian drug prices, reimbursements, and cost-effectiveness are found in Table 4. First, in terms of the United States, according to Neumann et al.,²⁶ the ICER per QALY used by the U.S.-based nonprofit organizations was between $100,000 and $150,000. Based on this threshold, we conclude that the cost-effectiveness of neoadjuvant treatment with chemotherapy is excellent, whereas that of neoadjuvant treatment with ICI is not. In contrast, Ribeiro et al.²⁷ stated that no established threshold for cost-effectiveness evaluation exists in Brazil. However, studies that have evaluated cost-effectiveness in Brazil report that the 25% to 75% score for ICER per QALY is between R$8329 and R$89,011. A particularly high threshold was used in oncology, in which trastuzumab for breast cancer costs R$280,235 (United States dollar [USD] 53,333) per QALY (1 USD = 5.25 Real).²⁷ Because this study focuses on oncology, it can be concluded that the cost-effectiveness of neoadjuvant treatment with chemotherapy is excellent when a threshold of R$280,235 (USD 53,333) per QALY is applied, whereas the cost-effectiveness of neoadjuvant treatment with ICI is not. To further evaluate the feasibility of neoadjuvant immunotherapy in these high-cost settings, we also conducted a basic price-threshold analysis. When we compared neoadjuvant nivolumab plus chemotherapy with neoadjuvant chemotherapy alone, we found that the price of nivolumab required to meet each country’s willingness-to-pay threshold was 28.6% of the current price in the United States (USD 150,000 per QALY) and 55.9% of the current price in Brazil (USD 53,333 per QALY).

Based on these findings, it can be concluded that neoadjuvant chemotherapy is cost-effective in the United States and Brazil in terms of drug price, reimbursement, and ICER per QALY threshold, whereas it is also considered cost-effective in Japan. In contrast, neoadjuvant ICI therapy is considered cost-effective in Japan, but not in the USA or Brazil.

Discussion

To the best of our knowledge, this is the first study to provide a cost-effectiveness analysis of perioperative therapy with ICIs in patients with stages II to III NSCLC. The results demonstrated that preoperative ICIs were the most cost-effective. However, this could be attributed to the fact that the HR of DFS was comparable to that of perioperative treatment, including other ICIs, despite the absence of the postoperative administration of expensive ICIs.

Although certain patients may benefit more from neoadjuvant plus adjuvant therapy than from neoadjuvant ICI therapy, trials directly comparing the two are currently lacking. Neoadjuvant plus adjuvant therapy may be omitted in patients who can achieve a pCR with neoadjuvant ICI therapy alone. Further studies are needed to evaluate the health economics. The usefulness of minimal residual disease (MRD), such as circulating tumor DNA, for predicting the efficacy of adjuvant chemotherapy and recurrence has been reported,²⁸ and we believe that using MRD to determine the indication for treatment and the timing of treatment termination may also be useful in evaluating health economics.

We conducted a health economic evaluation based on current medical scenarios in Japan, the United States, and Brazil. The total health care expenditures in Japan, the United States, and Brazil were approximately $370 billion (2023), $4.15 trillion (2022), and $178 billion (2022), respectively, revealing an upward yearly trend. As found in Supplementary Table 1, nivolumab is the least expensive drug in Japan when compared with the price per 100 mg. However, the results of the scenario analysis using drug prices and reimbursements in the United States and Brazil indicated that the cost-effectiveness of neoadjuvant therapy with ICI was not excellent, in contrast to the findings obtained for Japan. The price of nivolumab in Japan has decreased by one-fifth since its initial launch, which may be a factor in the improved cost-effectiveness observed in Japan. These findings underscore the importance of incorporating evidence of cost-effectiveness into health policy decisions. The differences in drug pricing, health care infrastructure, and access to biomarker testing across countries suggest that economic sustainability should be carefully considered when implementing perioperative ICI therapy in clinical practice.

This study has several limitations. First, the utility values used were based on limited trial data, primarily from the IMpower010 study. Although regional differences in utility are important, we used values from this multinational trial to reduce the potential confounding factors between country-specific drug prices and population-specific utility estimates. At this point, a cost-effectiveness analysis requires citing data from clinical trials. Despite this, we believe that conducting a cost-effectiveness analysis is meaningful, even when using limited data. Second, the calculated costs did not include detailed estimates of toxicity management. Although we approximated toxicity-related costs as 1 week of readmission for all regimens, we did not fully capture specific costs for immune-related adverse events because of the lack of comprehensive clinical cost data. Because immune-related adverse events may have prolonged clinical and economic effects, particularly with ICI regimens, the ICERs for these treatments may have been underestimated in our model. Third, although this analysis used data from a pivotal phase III clinical trial, only one clinical trial involving neoadjuvant therapy with ICI was included. The HRs for DFS and OS for neoadjuvant ICI therapy is relatively favorable compared with that for neoadjuvant plus adjuvant therapy, and if this result is incidental, it may affect the interpretation of the results. Fourth, this study calculated anticancer drug doses based on the standard body size of the Japanese population and drug prices were based on the drug prices in each country. Therefore, the drug prices used in our analysis for the United States and Brazil may have been lower than those used in actual clinical practice. Thus, further studies using real-world data are required to overcome these limitations. Fifth, we assumed an exponential distribution for all the survival curves in the partitioned survival model. Although alternative models, such as the Weibull or log-logistic distributions, may more accurately reflect time-varying hazards, we adopted the exponential distribution because of its simplicity and the limited availability of detailed survival data (e.g., only median survival was reported in published trials). Under these constraints, more complex modeling approaches are not feasible, and we applied a constant hazard assumption as a practical and transparent choice. Finally, this analysis was limited by the availability of clinical trial data at the time of modeling. As long-term survival data become available from ongoing studies, we plan to update the model to improve the accuracy and relevance of our estimates.

In conclusion, we evaluated the health economics of perioperative treatment for stages II to III NSCLC with ICI in combination with neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy. Neoadjuvant nivolumab therapy is the most cost-effective treatment option in Japan. Certain patients who are eligible for neoadjuvant plus adjuvant therapy may achieve sufficient efficacy with neoadjuvant ICI therapy alone. Using biomarkers such as pCR and MRD to determine treatment eligibility and assess the discontinuation of adjuvant ICI therapy may improve the cost-effectiveness of health care in the future.

CRediT Authorship Contribution Statement

Masahiro Fujioka: Conceptualization, Methodology, Resources, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review and editing, Visualization.

Toshihiko Aranishi: Conceptualization, Methodology, Resources, Software, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Visualization.

Takehito Shukuya: Conceptualization, Methodology, Resources, Formal analysis, Data curation, Writing - original draft, Visualization, Supervision.

Luiz Araujo: Resources, Investigation, and Writing - review and editing.

Dwight Owen: Resources, Investigation, Writing - review and editing.

Tina Sowers: Resources, Investigation, Writing - review and editing.

Yukina Shirai: Resources, Investigation, Writing - review and editing.

David P. Carbone: Resources, Investigation, Writing - review and editing, Supervision.

Kazuhisa Takahashi: Resources, Writing - review and editing, Project administration.

Disclosure

Dr. Aranishi is an employee of Eli Lilly Japan K.K. and a stockholder of Eli Lilly and Company and Chugai Pharmaceutical Co., Ltd. Dr. Shukuya reports receiving grants or contracts from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Novartis, and Merck Sharp & Dohme (MSD); honoraria from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Novartis, MSD, Taiho Pharma, Daiichi Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, Nippon Kayaku, Pfizer, Takeda, Eli Lilly Company, Eisai, and Kyowa Kirin. Dr. Owen reports receiving grants or contracts from Bristol Myers Squibb, Merck, Palobiofarma, Genentech, Pfizer, and Onc.AI; honoraria from Chugai Pharmaceutical Co., Ltd.; travel support from Genentech, Amgen, and AstraZeneca. Dr. Carbone reports receiving grants or contracts from Merck; serving on the data safety monitoring board for EORTC, AbbVie, and Eli Lilly; having advisory board participation for GlaxoSmithKline, Iovance Biotherapeutics, Arcus Biosciences, Roche, AbbVie, Regeneron, Genentech, Novocure, OncoHost, AstraZeneca, Amgen, Daiichi Sankyo, Eli Lilly, Janssen/JNJ, Pfizer, Bristol Myers Squibb, Iovance, and Merck KGaA (Germany). Dr. Takahashi reports receiving grants or contracts from Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., and Taiho Pharmaceutical Co., Ltd.; honoraria from Chugai Pharmaceutical Co., Ltd., MSD K.K., AstraZeneca K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Bristol Myers K.K.; being a member of the Board of Directors for The Japan Lung Cancer Society and The Japanese Respiratory Society. The remaining authors declare no conflict of interest.