Multi-omics analysis reveals the association between elevated KIF18B expression and unfavorable prognosis, immune evasion, and regulatory T cell activation in nasopharyngeal carcinoma.

Background: Nasopharyngeal carcinoma (NPC) is prevalent in Southern China. The expression profile and functions of kinesin family member 18B (KIF18B) remain unclear in NPC. Methods: Bulk and single-cell transcriptome data for NPC were downloaded. KIF18B expression differences in NPC and normal tissues and its prognostic value were validated by immunohistochemistry and Cox model. We performed multi-faceted functional enrichment analysis on KIF18B. Immune infiltration was analyzed comprehensively by the CIBERSORT, EPIC, and quanTIseq algorithms and the BisqueRNA package and confirmed by immunofluorescence assay. The intercellular communication were investigated by the CellChat package. We explored the dynamics of KIF18B expression by pseudotime trajectory. M6A modification analysis rely on SRAMP platform. The treatment response were evaluated by Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore and IC50 value. Results: KIF18B overexpression in NPC led to unfavorable prognosis, and significantly associated with advanced T, N, and stage classifications. Functional analysis demonstrated that KIF18B was involved in immune suppression, epithelial-mesenchymal transition (EMT), N6-methyladenosine (m6A) modification and therapeutic responses. The deconvolution algorithm indicated that activated regulatory T cells (Tregs) had the strongest positive correlation with KIF18B among immune cells (R = 0.631). Validated by immunofluorescence assay, the high KIF18B expression group displayed a notable rise in Tregs infiltration, accompanied by a substantial decrease in the infiltration of CD8+ T cells and macrophages. In the intercellular communication network, malignant cells with high KIF18B expression implicated in more interactions, and activated and recruited Tregs by modulating cytokines, chemokines, and immune checkpoints. KIF18B was upregulated in more advanced malignant cells and influenced EMT by regulating ITGA6, VIM, and ZEB1/2. KIF18B expression was positively related to m6A "writer" and "reader" genes, and negatively related to "eraser" genes. The KIF18B high expression group exhibited a higher TIDE score and elevated IC50 values for the commonly used chemotherapy drugs, gemcitabine, oxaliplatin, and 5-fluorouracil. Conclusion: KIF18B is a significant prognostic marker in NPC, and may modulate immune evasion and EMT. M6A modification may account for the aberrant overexpression of KIF18B in NPC. Furthermore, KIF18B may predict response to immunotherapy and chemotherapy.

First-line immunotherapy combinations for recurrent or metastatic nasopharyngeal carcinoma: An updated network meta-analysis and cost-effectiveness analysis.

OBJECTIVES: Recently updated results of randomized clinical trials (RCTs) have confirmed that toripalimab, camrelizumab, and tislelizumab plus chemotherapy (TOGP, CAGP, and TIGP) significantly prolonged survival compared to placebo plus chemotherapy (PLGP) in the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). However, the high cost of immunotherapies imposes a huge financial burden on patients and health care systems. MATERIALS AND METHODS: RCTs estimating immunotherapies for R/M-NPC were searched. A Bayesian network meta-analysis (NMA) was carried out; the main outcomes were hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The cost and efficacy of four first-line therapies were evaluated using the Markov model. The main outcome in the cost-effectiveness analysis (CEA) was incremental cost-utility ratios (ICURs). The model robustness was assessed by one-way, three-way, and probabilistic sensitivity analyses. RESULTS: Three RCTs (JUPITER-02, CAPTAIN-1st, and RATIONALE-309) involving 815 patients were included in the NMA. Compared with PLGP, chemo-immunotherapies have significantly longer PFS and OS. Compared to the PLGP group, TOGP, CAGP, and TIGP groups resulted in additional costs of $48 339, $22 900, and $23 162, with additional 1.89, 0.73, and 0.960 QALYs, respectively, leading to the ICURs of $25 576/QALY, $31 370/QALY, and $31 729/QALY. Pairwise comparisons showed TOGP was the most cost-effective option among chemo-immunotherapy groups. CONCLUSION: From the Chinese payers' perspective, first-line immunotherapy combination therapies provided significant survival and cost-effectiveness superiority over chemotherapy alone for patients with R/M-NPC at the WTP of $38 029/QALY. Among the three chemo-immunotherapy groups, TOGP was the most cost-effective option.

Cost-effectiveness analysis of metronomic capecitabine as adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

Background: Adding metronomic capecitabine to concurrent chemoradiotherapy (CCRT) brings failure-free survival (FFS) benefits to patients with locoregionally advanced nasopharyngeal carcinoma (NPC). This study assesses the cost-effectiveness of metronomic capecitabine in locoregionally advanced NPC. Methods: We created a Markov model to calculate the expense and health outcomes of metronomic capecitabine compared to those observed in locoregionally advanced NPC. Related costs, like life-years (LYs), quality-adjusted life years (QALYs), and incremental cost-effective ratios (ICERs) were measured at a willingness-to-pay (WTP) threshold of $33,585 per QALY. A combination of different sensitivity analyses was used to test for model robustness. Additionally, a subgroup analysis was also performed. Results: In contrast to what is observed in the locoregionally advanced NPC, adding the metronomic adjuvant capecitabine yielded an additional 1.11 QALYs with an incremental cost of $10,741.59, which obtained an ICER of $9,669.99 per QALY. The result of one-way sensitive analysis indicated that the utility of FFS, progression disease (PD), and the cost of follow-up were the most significant factors. The probability of metronomic capecitabine being cost-effective was 97.1% at a WTP of $33,585 per QALY. Conclusion: Metronomic capecitabine as adjuvant chemotherapy is a cost-effective strategy for locoregionally advanced NPC patients.

Pembrolizumab with or without chemotherapy versus cetuximab plus chemotherapy to treat recurrent or metastatic head and neck squamous cell carcinoma: An updated KEYNOTE-048 based cost-effectiveness analysis.

OBJECTIVES: Recently, updated data from KEYNOTE-048 revealed that pembrolizumab with or without chemotherapy could improve progression-free survival (PFS)2 compared with cetuximab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A Markov structure was conducted to evaluate the cost and effectiveness of pembrolizumab monotherapy or pembrolizumab plus chemotherapy vs. cetuximab plus chemotherapy in the first-line treatment of recurrent or metastatic HNSCC from the United States payer's perspective. Total cost, health outcomes, and incremental cost-effective ratios (ICERs) were estimated. Additional analyses were conducted in the total population and in two different programmed cell death 1 ligand 1 (PD-L1) combined positive scores (CPSs) (≥1 and ≥ 20) population. Sensitivity analysis were used to test the stability of the model. RESULTS: When compared with cetuximab plus chemotherapy, the pembrolizumab monotherapy strategy was dominated by lower cost and better efficacy in all three populations. The incremental costs and quality adjusted life years (QALYs) yielded by pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy were $16016.88 and 0.11 in the total population, and $24467.47 and 0.18 and $30448.46 and 0.20 in the populations with a PD-L1 CPS ≥ 1 and CPS ≥ 20, respectively, leading to ICERs of $147876.14, $134237.84, and $153660.78 per QALY, respectively. CONCLUSION: First-line treatment with pembrolizumab or pembrolizumab plus chemotherapy are cost-effective strategies compared with cetuximab plus chemotherapy when the value of willingness-to-pay (WTP) was $150000 per QALY for the total and PD-L1 CPS ≥ 1 populations with recurrent or metastatic HNSCC.

Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.

BACKGROUND: The data from the phase III clinical trial KEYNOTE-426 indicated that pembrolizumab plus axitinib compared with sunitinib could generate clinical benefits in patients with previously untreated advanced renal cell carcinoma (RCC). Given the incremental clinical benefits, we examined the potential cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in the first-line setting for patients with advanced RCC from the U.S. payers' perspective. MATERIALS AND METHODS: Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters, and additional subgroup analyses were performed as well. RESULTS: Upon our analyses, the total treatment costs in the pembrolizumab plus axitinib and sunitinib groups were $522,796 and $348,424 and the QALYs gained 2.90 and 1.72, respectively. In the base-case analysis, compared with receiving sunitinib, patients with advanced RCC receiving pembrolizumab plus axitinib gained 1.18 more QALYs at an incremental cost-effectiveness ratio of $148,676/QALY. The results of subgroup analyses demonstrated that pembrolizumab plus axitinib was most cost-effective for patients who had one organ with metastasis. CONCLUSION: First-line treatment with pembrolizumab plus axitinib, compared with sunitinib, is a cost-effective strategy when the value of WTP is from $100,000 to $150,000 per QALY in patients with advanced RCC. For patients with one-organ metastasis and those in International Metastatic Renal Cell Carcinoma Database Consortium poor risk group, first-line treatment with pembrolizumab plus axitinib is more cost-effective than others. IMPLICATIONS FOR PRACTICE: This was the first study to examine the cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). This study found that first-line treatment with pembrolizumab plus axitinib is a cost-effective strategy when the value of willingness-to-pay is from $100,000 to $150,000 per quality-adjusted life-year in patients with advanced RCC from the U.S. payers' perspective.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab vs. Chemotherapy as First-Line Therapy in Advanced Non-Small Cell Lung Cancer.

Background: The CheckMate 227 trial has indicated that nivolumab plus ipilimumab compared with chemotherapy significantly increases long-term survival in the first-line setting of advanced non-small-cell lung cancer (NSCLC). Methods: A Markov model was built to estimate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy as the first-line therapy in patients with advanced NSCLC based on outcomes data from the CheckMate 227 trial. We calculated the cost and health outcomes at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in populations with different programmed death ligand 1 (PD-L1) expression levels (≥50, ≥1, and <1%) or a high tumor mutational burden (TMB) (≥10 mutations per megabase). Sensitivity analysis were used to test the model stability. Results: The outcomes showed that the incremental costs and QALYs by using nivolumab plus ipilimumab were $124180.76 and 1.16, $70951.42 and 0.53, $144093.63 and 0.83 for the advanced NSCLC patients with a PD-L1 expression ≥50%, ≥1%, and <1%, which led to an incremental cost-effective ratio (ICER) of $107403.72, $133732.20, and $172589.15 per QALY, respectively. For patients with a high TMB, nivolumab plus ipilimumab contributed an extra 2.04 QALYs at a cost of $69182.50 per QALY. Conclusion: Nivolumab plus ipilimumab as first-line therapy makes a better cost-effective strategy than chemotherapy in advanced NSCLC patients with PD-L1 expression levels ≥50% and ≥1% or a high TMB, at a willingness-to-pay threshold of $150,000 per QALY, but not in the patients with a PD-L1 expression <1%.

Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.

INTRODUCTION: The purpose of this study was to estimate the cost-effectiveness of atezolizumab plus chemotherapy in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) from the United States (US) payers' perspective in the first-line treatment. METHODS: A mathematical Markov model was developed to estimate cost and effectiveness of atezolizumab combination therapy versus carboplatin plus nab-paclitaxel alone in the first-line therapy of metastatic non-squamous NSCLC from the data of IMpower130. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were analyzed, and model robustness was assessed by sensitivity analysis. Additional subgroup analyses were performed as well. RESULTS: Compared to chemotherapy, treatment with atezolizumab plus chemotherapy yields an increase of 0.16 QALYs with an increase in cost of $109,809.13, resulting in an ICER of $670,309.66 per QALY. The most influential factor in this model was the cost of atezolizumab. Probabilistic sensitivity analysis showed that there was 0% probability that atezolizumab plus chemotherapy was cost-effective at willingness-to-pay (WTP) values of $150,000 per QALY. The results of subgroup analyses showed that the ICER remained greater than $150,000/QALY across the all patient subgroups. CONCLUSION: First-line treatment with atezolizumab in combination with carboplatin plus nab-paclitaxel is not a cost-effective option in patients with metastatic non-squamous NSCLC.

Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.

Cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advanced or metastatic non-small cell lung cancer with PD-L1 tumor proportion score 1% or greater.

OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advance or metastatic non-small cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) 1% or greater from the United States (US) payer perspective. MATERIALS AND METHODS: This Markov structure was developed to estimate cost and effectiveness of pembrolizumab vs chemotherapy in the first-line treatment of locally advance or metastatic NSCLC based on the data from KEYNOTE-042. Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in three PD-L1 TPS populations (≥50%, ≥20% and ≥1%). One-way, two-way and probabilistic sensitivity analysis were to test the model stability. Subgroup analysis were performed in three PD-L1 TPS populations (≥50%, ≥20% and ≥1%). RESULTS: The incremental costs and QALYs that pembrolizumab yielded, compared with chemotherapy, were $86164.87 and 0.63, $74562.25 and 0.46 and $70886.65 and 0.39 for the populations with a PD-L1 TPS ≥ 50%, TPS ≥ 20% and TPS ≥ 1%, leading an incremental cost-effective ratio (ICER) of $136,228.82, $160,625.98 and $179,530.17 per QALY, respectively. CONCLUSION: First-line treatment with pembrolizumab is a cost-effective strategy compared with platinum-based chemotherapy when the value of WTP was $150,000 per QALY in locally advanced or metastatic NSCLC patients with PD-L1 TPS ≥ 50% and without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations, but not in the TPS ≥ 20% and 1% populations.

Cost-effectiveness analysis of utidelone plus capecitabine for metastatic breast cancer in China.

Objective: To estimate the cost-effectiveness of utidelone plus capecitabine therapy compared to capecitabine alone in patients with metastatic breast cancer (MBC) resistant to anthracyclines and taxanes treatment in the Chinese context and provide a reference for the marketing of utidelone in China. Methods: A Markov model was developed based on the NCT02253459 clinical trial to simulate the clinical course of patients with metastatic breast cancer who had received taxanes and anthracycline therapy. The quality-adjusted life years (QALYs) and Incremental Cost Effectiveness Ratio (ICER) were then analyzed to evaluate the benefits. Two-parametric Weibull distribution was conducted to fit PFS and OS curves by using R. Sensitivity analyses were performed to evaluate the stability of the model designed. Results: The addition of utidelone increased the cost and QALYs by $13,370.25 and 0.1961, respectively, resulting in an increased ICER of $68,180.78 per QALY. The most sensitive influential parameter on ICER was the price of utidelone. At the threshold of willingness-to-pay (WTP) of $24,380 (3 per capita GDP of China), the cost of utidelone per 30 mg of less than $18.5, $33.7, and greater than $48.8 resulted in a 100%, 50%, and 0% possibility of cost-effectiveness, respectively. The addition of utidelone was not cost-effective when it was $115.4 per 30 mg-the price of its analog paclitaxel. In consideration of varied economics levels across China, cost-effectiveness could be achieved with the price of utidelone ranging from $5.2 to $35.9. Limitations: The survival curves extended beyond the follow-up time horizon, of which data were generated not from the real analyses but from our established two-parameter Weibull survival model. Conclusion: It is recommended that the price of utidelone would be less than $18.5 per 30 mg in order to obtain cost-effectiveness for metastatic breast cancer patients resistant to anthracyclines and taxanes treatment in China.