Table1_First-line tremelimumab plus durvalumab and chemotherapy versus chemotherapy alone for metastatic non-small cell lung cancer: a cost-effectiveness analysis in the United States.doc

Importance: In the open-label phase III POSEIDON randomized clinical trial (RCT), a limited course of tremelimumab plus durvalumab and chemotherapy (T + D + CT) indicated in the first-line treatment of metastatic non-small cell lung cancer (mNSCLC), progression-free survival, and overall survival (OS) were substantially improved without significant additional tolerance burden compared to chemotherapy (CT). However, given the high cost of T + D + CT, its value needs to be evaluated in terms of both potency and cost.
Objective: To evaluate the cost-effectiveness of T + D + CT versus CT in individuals with previously untreated mNSCLC from a U.S. payer perspective.
Design, setting, and participants: A three-state Markov model was adopted to weigh the lifetime costs and effectiveness of T + D + CT versus CT for the treatment of first-line mNSCLC, according to the results of the POSEIDON phase III RCT involving 675 individuals with mNSCLC. Individuals were simulated to undergo either T + D + CT for up to four 21-day cycles, followed by durvalumab once every 4 weeks until disease progression or unacceptable toxic effects and one additional tremelimumab dose, or CT for up to six 21-day cycles (with or without pemetrexed maintenance; all groups) in the analysis.
Main outcomes and measures: Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were evaluated with a willingness-to-pay (WTP) threshold of $ 100,000 to $ 150,000 per QALY. The uncertainty of the model was investigated using univariate and probabilistic sensitivity analysis.
Results: T + D + CT produced additional 0.36 QALYs with additional costs of $ 217,694, compared to CT, giving rise to ICERs of $ 608,667.86/QALY. The univariate sensitivity analysis demonstrated that the outcomes were most sensitive to the cost of durvalumab. Other variables with a large or moderate influence were the utility of progression-free survival state, utility of progressive disease state, and cost of tremelimumab. Probability sensitivity analysis revealed that T + D + CT had a 0% probability of cost-effectiveness in individuals with mNSCLC at a willingness-to-pay threshold of $ 100,000 to $ 150,000 per QALY.
Conclusion and relevance: In this model, T + D + CT was estimated to be less cost-effective than CT for patients with mNSCLC at a WTP threshold of $ 100,000 to $ 150,000 per QALY in the United States. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of durvalumab and tremelimumab may be necessary to achieve cost-effectiveness in future possible context.

研究背景：在开放标签的III期POSEIDON随机临床试验（randomized clinical trial, RCT）中，针对转移性非小细胞肺癌（metastatic non-small cell lung cancer, mNSCLC）的一线治疗，曲美木单抗（tremelimumab）联合度伐利尤单抗（durvalumab）与化疗（T + D + CT）方案，相比单纯化疗（CT），可显著改善患者的无进展生存期与总生存期（overall survival, OS），且未带来额外的显著耐受负担。但鉴于T + D + CT方案成本高昂，其临床价值需从疗效与成本两方面进行综合评估。
研究目的：从美国医疗支付方视角出发，评估未经治疗的转移性非小细胞肺癌患者采用T + D + CT方案对比单纯化疗方案的成本效益。
研究设计、场景与研究对象：本研究基于纳入675例转移性非小细胞肺癌患者的POSEIDON III期随机临床试验结果，采用三状态马尔可夫模型（three-state Markov model）对比T + D + CT与CT方案一线治疗转移性非小细胞肺癌的终身成本与临床效益。模拟受试者接受最多4个21天周期的T + D + CT治疗，后续每4周给予一次度伐利尤单抗，直至疾病进展或出现不可接受的毒性反应，并追加一剂曲美木单抗；对照组则接受最多6个21天周期的化疗（可联合或不联合培美曲塞维持治疗，所有分组均适用）。
主要结局与测量指标：以每质量调整生命年（quality-adjusted life-years, QALYs）100,000美元至150,000美元的支付意愿（willingness-to-pay, WTP）阈值为标准，评估两组方案的终身成本、质量调整生命年以及增量成本效果比（incremental cost-effectiveness ratio, ICER）。通过单因素与概率敏感性分析考察模型的不确定性。
研究结果：相较于单纯化疗组，T + D + CT组可额外获得0.36个质量调整生命年，但额外产生217,694美元的医疗成本，增量成本效果比为608,667.86美元/QALY。单因素敏感性分析显示，研究结果对度伐利尤单抗的成本最为敏感；其余具有较大或中等影响的变量包括无进展生存状态的效用值、进展性疾病状态的效用值以及曲美木单抗的成本。概率敏感性分析结果表明，在每QALY 100,000美元至150,000美元的支付意愿阈值下，T + D + CT方案用于转移性非小细胞肺癌患者的成本效益概率为0%。
研究结论与相关性：本模型估算结果显示，在美国每QALY支付意愿阈值为100,000美元至150,000美元的情境下，T + D + CT方案的成本效益劣于单纯化疗方案。当具有显著疗效的新型联合疗法成为一线治疗的核心方案时，降低度伐利尤单抗与曲美木单抗的价格，或可在未来场景中实现该联合方案的成本效益。