Kohn Christine G, Zeichner Simon B, Chen Qiushi, Montero Alberto J, Goldstein Daniel A, Flowers Christopher R
Christine G. Kohn, University of Saint Joseph School of Pharmacy; Christine G. Kohn, University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT; Simon B. Zeichner, Daniel A. Goldstein, and Christopher R. Flowers, Winship Cancer Institute at Emory University; Qiushi Chen, Georgia Institute of Technology, Atlanta, GA; Alberto J. Montero, Cleveland Clinic, Cleveland, OH; and Daniel A. Goldstein, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
J Clin Oncol. 2017 Apr 10;35(11):1194-1202. doi: 10.1200/JCO.2016.69.6336. Epub 2017 Feb 21.
Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.
被诊断为IV期转移性黑色素瘤的患者，其估计5年相对生存率仅为17%。美国食品药品监督管理局近期批准的免疫检查点抑制剂——帕博利珠单抗（PEM）、纳武利尤单抗（NIVO）和伊匹木单抗（IPI）的随机对照试验表明患者预后有所改善，但BRAF野生型转移性黑色素瘤患者的最佳治疗顺序仍不明确。为了让政策制定者了解这些治疗方法的价值，我们开发了一个马尔可夫模型，以比较用于治疗晚期黑色素瘤的新型药物不同序贯策略的成本效益。
我们从美国医保支付方的角度，采用终身视角开发马尔可夫模型，以估算一线使用NIVO、IPI、NIVO + IPI、每2周一次PEM以及每3周一次PEM的治疗序列的成本（2016年美元）和质量调整生命年（QALY）。为初始治疗、首次和第二次进展以及死亡定义了健康状态。从随机III期试验中获得的药物停药率、不良事件发生率、疾病进展率和死亡率用于确定状态之间转换的可能性。进行了确定性和概率敏感性分析以评估模型的不确定性。
每3周一次PEM然后二线使用IPI，比达卡巴嗪然后IPI再NIVO，或IPI然后NIVO更有效且成本更低。与一线达卡巴嗪治疗策略相比，NIVO然后IPI产生的增量成本效益比为90,871美元/QALY，一线NIVO + IPI然后卡铂加紫杉醇化疗产生的增量成本效益比为198,867美元/QALY。
对于未经治疗的BRAF野生型晚期黑色素瘤患者，每3周一次一线PEM然后二线IPI或一线NIVO然后二线IPI是转移性黑色素瘤最具成本效益的基于免疫的治疗策略。
