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| 研究生： |
陳彥孜 Chen, Yen-Tzu |
|---|---|
| 論文名稱： |
晚期非小細胞肺癌使用免疫檢查點抑制劑之真實世界證據:台灣多中心觀察性研究 Real world evidence of immune checkpoint inhibitors for advanced non-small cell lung cancer: a multicenter observational study in Taiwan |
| 指導教授： |
徐之昇
Hsu, Chih-Sheng 楊思雋 Yang, Szu-Chun |
| 學位類別： |
碩士 Master |
| 系所名稱： |
醫學院 - 臨床藥學與藥物科技研究所 Institute of Clinical Pharmacy and Pharmaceutical sciences |
| 論文出版年： | 2019 |
| 畢業學年度： | 107 |
| 語文別： | 中文 |
| 論文頁數： | 95 |
| 中文關鍵詞： | 非小細胞肺癌 、免疫檢查點抑制劑 、Programmed death 1 、真實世界研究 、比較效果分析 |
| 外文關鍵詞： | Non-small cell lung cancer, Immune checkpoint inhibitor, Programmed death 1, Real-world, Comparative effectiveness and safety |
| 相關次數： | 點閱：88 下載：0 |
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研究背景
非小細胞肺癌是106年台灣癌症死因死亡率排名第一的癌症，過去治療藥物只有化學治療或標靶治療，近年來免疫檢查點抑制劑則是一項新興的治療選擇。免疫檢查點抑制劑可藉由PD1、PD-L1負向調節T細胞的功能，活化人體免疫對腫瘤細胞的攻擊達到治療效果。許多隨機對照試驗已證實第一線及第二線的免疫檢查點抑制劑可改善病人的整體存活期，尤其是PD-L1表現量高的族群可能有較好的療效，甚至可併用化學治療藥物提升治療反應率。然而亞洲肺癌族群在流行病學上有些特徵與西方國家不同，過去文獻大多來自臨床試驗的結果，目前針對亞洲真實世界的實證研究相對較少。
研究目的
本研究目的為瞭解使用免疫檢查點抑制劑的台灣晚期非小細胞肺癌病人人口學與臨床病理學特性，並比較在不同臨床治療情境下與傳統化學治療之療效與安全性差異，進一步分析免疫檢查點抑制劑的療效和嚴重不良事件相關因子。
研究方法
本研究為台灣多中心回溯性世代研究，為了比較免疫檢查點抑制劑與傳統化學治療用於晚期非小細胞肺癌的療效，研究對象將分為接受免疫抑制劑的治療組與接受化學治療的對照組。治療組納入2016年1月至2018年12月期間於台灣三家醫學中心(國立成功大學附設醫院、永康奇美醫院和中國醫藥大學附設醫院)就醫且使用過pembrolizumab、nivolumab或atezolizumab任一種免疫檢查點抑制劑，並排除參加臨床試驗和使用過兩種以上免疫檢查點抑制劑的晚期非小細胞肺癌病人；對照組則納入2016年1月至2018年12月期間於國立成功大學附設醫院使用第一線或後線化學治療組合，並排除參加臨床試驗和觀察期間只使用過一種化療藥物的晚期非小細胞肺癌病人。兩組病人的研究資料從醫院電子病歷獲得，並依據性別、年紀、肺癌基因突變有無(EGFR/ALK mutation)、日常體能狀態評分(performance status)為0-1或2-4和第一線、第二線或三線以上治療情境等五項特性進行1:1非隨機性配對，獲得配對後治療組和對照組。接著，使用存活分析中的存活曲線圖(kaplan-meier curves)比較治療組與對照組之整體存活期差異，並以Cox迴歸分析(cox proportional hazard regression analysis)計算兩組間的死亡風險比率(hazard ratio)。免疫檢查點抑制劑存活療效相關因子以Cox迴歸模式進行單變項分析和多變項分析，嚴重藥物不良事件相關因子以Cox迴歸模式進行單變項分析，研究病人臨床病理特性與存活和不良事件之相關性。
研究結果
本研究治療組收入91位於2016至2018年期間使用免疫檢查點抑制的晚期非小細胞肺癌病人，其中使用pembrolizumab為37人(40.7%)，使用nivolumab為42人(46.2%)，使用atezolizumab為12人(13.2%)，平均治療時間為5.24個月(範圍: 1天-32.6個月)。治療組病人平均年紀為62.87歲，大部分為男性、無吸菸習慣、組織學型態為非鱗狀細胞癌、臨床分期為第四期、日常體能狀態為0-1和無腦部轉移。大多數病人未攜帶EGFR/ALK突變基因，然而PD-L1表現量僅有54人(59.3%)檢測，其中46人(50.5%)為陽性，表現量小於1%為3人(3.3%)、1-49%為19人(20.9%)、大於50%為22人(24.2%)。大多數免疫檢查點抑制劑為病人自費使用，其中第一線治療有30人(33%)，第二線治療有17人(18.7%)，第三線以上治療有44人(48.4%)。約一半的病人有合併化學治療，大部分未合併放射線治療。
本研究對照組納入236人，經過臨床治療情境分組，在第一線治療情境下治療組(N=30)與對照組(N=130)整體存活期中位數分別為14.4個月和17.4個月(HR：1.3；95 CI% 0.68-2.46；P=0.428)；在第二線治療情境下治療組(N=17)與對照組(N=92)整體存活期中位數分別為11.3個月和9.5個月(HR：0.76；95 CI% 0.36-1.59；P=0.46)；在第三線以上治療情境下治療組(N=44)與對照組(N=78)整體存活期中位數分別為10.8個月和8.6個月(HR：0.82；95 CI% 0.52-1.29；P=0.394)，二組皆未達統計上顯著差異。接著，依據性別、年紀、有無EGFR/ALK突變基因、日常體能狀態評分0-1或2-4和第一線、第二線或第三線以上治療情境進行配對，配對後治療組與對照組各有79人，其中第一線、第二線和第三線以上治療情境分別占42.9%、16.5%和45.6%。整體存活期中位數分別為11.2個月和10.5個月 (HR：0.96；95 CI% 0.64-1.44；P=0.838)，二組未達統計上顯著差異。
在安全性部分，配對後治療組和對照組的grade 3以上嚴重藥物不良事件發生率分別為12.7%和21.5%。治療組發生的不良事件大部分為免疫相關副作用，最常見的類型是pneumonitis(6.3%)和skin rash(3.8%)。對照組最常見的不良事件類型為neutropenia(12.7%)、alopecia(3.8%)和anemia(2.5%)。
在免疫檢查點抑制劑療效相關因子分析結果顯示，日常體能狀態評分為0-1和PD-L1表現量為陽性的病人有較好的存活，而治療初期使用全身性類固醇大於一周的病人則死亡風險較高；嚴重藥物不良事件相關因子分析結果顯示，合併使用化療發生不良事件的風險較高。
研究結論
本研究發現，台灣晚期非小細胞肺癌病人使用免疫檢查點抑制劑的整體存活期，不論是在第一線或是後線的治療情境下使用，與傳統化學治療之臨床表現相似。本研究也觀察到，相較於傳統化學治療，免疫檢查點抑制劑的嚴重藥物不良事件發生率較低。儘管如此併用化療可能增加發生風險，治療時仍需注意免疫相關副作用並盡早給予適當處置。另外，病人日常體能狀態和PD-L1檢測可作為臨床上評估免疫檢查點抑制劑療效的項目，建議治療初期避免併用全身性類固醇，減少對於免疫系統的影響。然而，因本研究樣本數較少和觀察期較短，仍有待更大型的世代研究來進一步證實台灣晚期非小細胞肺癌病人使用免疫檢查點抑制劑的療效及安全性。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in Taiwan. Immune checkpoint inhibitors (ICI) have been confirmed to improve survival in patients with advanced NSCLC. However, there is still inadequate knowledge among Asian patients on real-world effectiveness and safety of ICI compared to chemotherapy. We retrospectively reviewed patients with stage IIIB/IV NSCLC who received ICI or chemotherapy in Taiwan to compared overall survival and treatment related adverse events. Factor associated with survival and adverse events with ICI were investigated. Between January 1, 2016 and December 31, 2018, 91 and 236 patients were enrolled in ICI group and chemotherapy group. The median overall survival of ICI group and chemotherapy group were 14.4 and 17.4 months in first-line setting (HR:1.3;95 CI% 0.68-2.46; P=0.428), 11.3 and 9.5 months in second-line setting (HR: 0.76; 95 CI% 0.36-1.59; P=0.46), 10.8 and 8.6 months in more than third-line setting (HR: 0.82; 95 CI% 0.52-1.29; P=0.394), respectively. Treatment related adverse events of grade 3 or more occurred in 12.7% of the patients with ICI and 21.5% of the patients with chemotherapy. Good performance status and PD-L1 expression were associated with better survival and systemic steroid use at the time of initiating ICI was associated poorer survival. Combination with chemotherapy correlated with treatment related adverse events of above grade 3. The study showed ICI had similar survival to chemotherapy, regardless of first line or subsequent line setting. Large cohort studies are required for Asian patients with advanced NSCLC.
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校內：2024-09-01公開校外：2024-09-01公開