標靶藥物作為表皮生長因子接受器突變之肺腺癌晚期第一線治療之成效分析

Cost-effectiveness of Targeted Therapies as the First-line Treatment for Advanced Lung Adenocarcinoma with Epidermal Growth Factor Receptor Mutation

黃茗沂(Ming-Yi Huang)

指導教授 ： 楊奕馨

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2019年)

摘要

背景
在台灣，依據2016年癌症登記年報，肺癌為第二常見、死亡率第一名的癌症，其中約有60%病人在被診斷時就已經是晚期。對於局部侵犯性或轉移性(第IIIB期或第IV期)合併有表皮生長因子接受器(epidermal growth factor receptor, EGFR)基因突變的肺腺癌病人，自2011年起陸續有三個標靶藥物(gefitinib、erlotinib以及afatinib)被給付作為第一線用藥，本研究討這些標靶藥物的使用情形、存活率並進行成本效益分析。
方法
本研究為回溯性世代研究，使用衛生福利資料科學中心的台灣癌症登記檔、死因檔及健保資料庫進行分析，首先納入癌症登記檔中2011-2015年20歲以上新診斷局部侵犯性或轉移性(第IIIB期或第IV期)合併有表皮生長因子接受器(EGFR)基因突變的肺腺癌病人，接著依據健保資料庫病人使用的第一線標靶藥分為三組：Gefitinib、Erlotinib以及Afatinib，探討各組的藥物使用情形、花費、存活率、再次治療時間並藉由計算遞增成本效果比值(incremental cost-effectiveness ratio, ICER)進行成本效益分析。本研究之存活分析以Kaplan-Meier存活曲線及Log-rank檢定比較各組存活率與再次治療時間，並以Cox proportional hazard model計算危險比(hazard ratio, HR)與95%信賴區間(confidence interval, CI)。
結果
本研究收錄了8,184位病人，其中5,539位接受Gefitinib，1,634位接受Erlotinib，1,011位接受Afatinib。Gefitinib組病人存活中位數(median survival time)為1.63年(95% CI 1.58-1.68)、Erlotinib組為1.74年(95% CI 1.65-1.81)、Afatinib組為2.05年(95% CI 1.94-2.25; Log-rank test p-value<.0001)，Afatinib組相較於Gefitinib及Erlotinib組的危險比(HR)分別為0.834 (95%CI 0.752-0.924; p-value=0.0005)、0.873 (95% CI 0.785-0.970; p-value=0.0114)。
Gefitinib組病人的再次治療時間中位數為0.85年(95% CI 0.82-0.88)、Erlotinib組為0.92年(95% CI 0.88-0.96)、Afatinib組為1.15年(95% CI 1.04-1.24; Log-rank test p-value<.0001)，Afatinib組相較於Gefitinib及Erlotinib組的危險比(HR)分別為0.778 (95%CI 0.711-0.850; p-value<.0001)、0.848 (95%CI 0.774-0.930; p-value=0.0004)。
在全部8,184位病人中，4,880位(59.63%)在停用第一線標靶藥後有接受後續治療，其中大部分是接受platinum-based化學治療。Gefitinib組中平均每人每月癌症治療藥品花費為新台幣28,434元；Erlotinib組為28,576元；Afatinib組為32,305元。
在成本效益分析中，相較於Gefitinib，病人接受Afatinib能提供額外0.42存活年並且增加新台幣196,265元費用，相當於每增加一個存活年需多花費467,298元；相較於Erlotinib，接受Afatinib的病人每增加一個存活年需多花新台幣570,435元。
結論
本研究結果顯示，在局部侵犯性或轉移性(第IIIB期或第IV期)合併有表皮生長因子接受器(EGFR)基因突變的肺腺癌病人中，使用Afatinib相較於Gefitinib與Erlotinib有較長的存活時間與再次治療時間並且符合成本效益。

關鍵字

肺腺癌 ； EGFR突變 ； 標靶藥物 ； 成本效益

並列摘要

Background
In Taiwan, according to the 2016 Cancer Registry Annual Report, lung cancer is the second most commonly diagnosed cancer and had the highest cancer-related death rate. Approximately 60% of newly diagnosed patients are in late stage. For patients with locally advanced or metastatic (stage IIIB or IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation, three targeted drugs (gefitinib, erlotinib, and afatinib) has been covered by National Health Insurance (NHI) as the first-line therapy since 2011. This study aims to investigate the treatment patterns and survival of these drugs and to conduct a cost-effectiveness analysis.
Methods
In this retrospective population-based cohort study, we used data from Taiwan Cancer Registry (TCR), Death Registry (DR) and National Health Insurance (NHI). Patients included were over 20 years old and were newly diagnosed locally advanced or metastatic (stage IIIB or IV) lung adenocarcinoma with EGFR mutation between 2011 to 2015. Patients were divided into three groups according to their first-line treatment: gefitinib, erlotinib, and afatinib. We investigated the drug utilization, medical expenses, survival, time to next treatment among them and estimated the incremental cost-effectiveness ratio (ICER) to conduct a cost-effectiveness analysis. We used Kaplan-Meier method and log-rank test to estimate and compare the survival rates and time to next treatment among groups. We estimated hazard ratios (HRs) and 95% (confidence interval, CI) using Cox proportional hazard model.
Results
Our study included 8,184 patients, with 5,539 in gefitinib group, 1,634 in erlotinib group, and 1,011 in afatinib group. The median survival time was 1.63 years (95% CI 1.58-1.68) for patients receiving gefitinib; 1.74 years (95% CI 1.65-1.81) for those receiving erlotinib; 2.05 years for those receiving afatinib (95% CI 1.94-2.25; log-rank test p-value<.0001). The hazard ratios (95% CI; p-value) were 0.834 (0.752-0.924; 0.0005) and 0.873 (0.785-0.970; 0.0114) for afatinib group comparing with gefitinib and erlotinib group, respectively.
Regarding time to next treatment (TTNT), the median TTNT for gefitinib, erlotinib and afatinib group were 0.85 years (95% CI 0.82-0.88), 0.92 years (95% CI 0.88-0.96), and 1.15 years (95% CI 1.04-1.24), respectively (log-rank test p-value<.0001). The hazard ratios (95% CI; p-value) were 0.778 (0.711-0.850; <.0001) and 0.848 (0.774-0.930; 0.0004) for afatinib group comparing with gefitinib and erlotinib group, respectively.
Among the whole study population of 8,184 patients, 4,880 (59.63%) received subsequent therapy after discontinuing the first TKIs. Most of them used platinum-based chemotherapy. The per-patient per-month medication cost was NTD (New Taiwan Dollar) 28,434 for patients receiving gefitinib, NTD 28,576 for erlotinib, and NTD 32,305 for afatinib.
The cost-effectiveness analysis indicated that comparing with gefitinib, patients in afatinib group had an additional 0.42 life-year at an increased cost of NTD 196,265. The ICER was NTD 467,298 per life-year gained. Besides, The ICER was NTD 570,435 per life-year gained for afatinib to erlotinib.
Conclusions
Afatinib improved outcomes of survival rates and time to next treatment in locally advanced or metastatic (stage IIIB or IV) lung adenocarcinoma patients with EGFR mutation compared with gefitinib and erlotinib. Despite of the higher cost, afatinib was still a cost-effective treatment.

並列關鍵字

lung adenocarcinoma ； EGFR mutation ； targeted therapy ； cost-effectiveness

參考文獻

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