Cost Effectiveness of Ceritinib and Alectinib Versus Crizotinib in First-Line Anaplastic Lymphoma Kinase-Positive Advanced Non-small-cell Lung Cancer.
- 作者列表："Li H","Lai L","Wu B
BACKGROUND:Crizotinib, ceritinib, and alectinib improved survival in patients with anaplastic lymphoma kinase (ALK) arrangement non-small-cell lung cancer (NSCLC); however, the long-term economic outcomes of using ceritinib and alectinib versus crizotinib are still unclear. OBJECTIVE:This analysis aimed to evaluate the cost effectiveness of ceritinib and alectinib versus crizotinib in the Chinese healthcare setting. METHODS:A Markov model was developed to project the economic and health outcomes for the treatment of advanced NSCLC with ceritinib, alectinib or crizotinib. A network meta-analysis was performed to calculate the hazard ratios of ceritinib and alectinib versus crizotinib by pooling published trials. Cost and utility values were obtained from the literature, and one-way and probabilistic sensitivity analyses were carried out to determine the robustness of the model outcomes. The primary outputs included total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS:Treatment with alectinib and ceritinib yielded an additional 1.00 and 1.09 QALYs and incremental costs of $62,232 and $15,165, resulting in an ICER of $62,231 and $13,905 per QALY compared with crizotinib, respectively. Parameters related to drug costs and progression-free survival were the main drivers of the model outcomes. From the probabilistic sensitivity analysis, ceritinib and alectinib had a 99.9% and 0% probability of being cost effective, respectively, at a willingness-to-pay threshold of US$28,410/QALY. CONCLUSIONS:Our results indicate that compared with crizotinib and alectinib, ceritinib is a cost-effective option for treatment-naïve patients with ALK-positive advanced NSCLC.
背景: 克唑替尼、色瑞替尼和阿来替尼改善了间变性淋巴瘤激酶 (ALK) 排列非小细胞肺癌 (NSCLC) 患者的生存期; 然而，使用色瑞替尼和阿来替尼对比克唑替尼的长期经济结局仍不清楚。 目的: 本分析旨在评估色瑞替尼和阿来替尼与克唑替尼在中国医疗机构中的成本效益。 方法: 开发了Markov模型来预测色瑞替尼、阿来替尼或克唑替尼治疗晚期NSCLC的经济和健康结果。通过汇总已发表的试验，进行网络荟萃分析以计算色瑞替尼和阿来替尼与克唑替尼的风险比。从文献中获得成本和效用值，并进行单向和概率敏感性分析，以确定模型结果的稳健性。主要产出包括总成本、生命年 (LYs) 、质量调整的LYs (QALYs) 和增量成本效益比 (ICER)。 结果: 与克唑替尼相比，阿来替尼和色瑞替尼治疗产生了额外的 1.00 和 1.09 的QALYs以及 62,232 美元和 15,165 美元的增量成本，导致每个QALY的ICER为 62,231 美元和 13,905 美元。分别。与药物费用和无进展生存期相关的参数是模型结果的主要驱动因素。从概率敏感性分析来看，在 99.9% 美元/QALY的支付意愿阈值下，色瑞替尼和阿来替尼具有成本效益的概率分别为 0% 和 28,410。 结论: 我们的结果表明，与克唑替尼和阿来替尼相比，色瑞替尼是ALK阳性晚期NSCLC初治患者的一种具有成本效益的选择。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.