免疫檢查點抑制劑之有效性與種族(白種人與亞洲人)之相關性: 系統性回顧與統合分析

背景近年來，免疫檢查點抑製劑（Immune checkpoint inhibitors）已成為一類重要的癌症治療方法。根據文獻報告，免疫檢查點抑製劑或其組合治療效果在不同癌症類型存在很大的個體差異，目前觀察到的反應率約莫在15％到25％之間; 而造成該療效差異的預後因子仍在研究中，尚未得出一致的結論。統合分析已被應用於探討多種預後因子，包括PD-1和PD-L1表現，其他數種生物標記如年齡以及性別。本研究旨在針對白種人與亞洲人, 透過統合分析探討種族對免疫檢查點抑制的影響。方法作者從Pubmed和Embase數據庫中進行了系統性文獻檢索，搜尋自2015年1月1日至2020年12月30日之間相關的隨機對照試驗。我們萃取了27項研究比較了免疫檢查點抑製劑與標准治療（Standard of Care）或安慰劑 (Placebo) 在亞洲人以及白種人整體存活療效的隨機分派試驗 (Randomized Controlled Trials) 。非隨機分派試驗，生物標記研究，世代研究，回顧性研究，社論，評論文章均不包含在分析內。統合分析是在隨機效應模型下各別採用deft (靈巧的, 意即僅考量研究內的交互作用) 和deluded (誤導的, 意即考量研究間的以及研究內的交互作用)以統合迴歸方法進行，然後進行試驗序列分析(Trials sequential analysis, TSA)，以查看該信息量是否已達到有統計學意義的閾值。結果所有27項研究的統合分析顯示，在混合效應模型下，亞洲人（hazard ratio [HR] 0.81; 95％CI 0.72-0.92; p = 0.07）和白種人（HR 0.83; 95％CI 0.76-0.90; p <0.01）使用免疫檢查點抑製劑相對於對照組均有整體存活優勢。使用統合迴歸分析並未觀察到兩個族群的整體存活效益之間存在有統計上顯著差異（p = 0.8407）。按第幾線治療、癌症部位、是否與化療合併使用, 以及免疫檢查點抑制劑種類分層的子分析，在亞洲人和白種人之間在免疫療法的療效上也沒有統計上的顯著差異。同樣的，試驗序列分析的數據顯示在亞洲人和白種人兩組之間沒有統計上差異，且在80％ power的設定下，增加更多試驗可能不會改變結果。討論及結論通過這項統合分析，並且結合試驗序列分析數個免疫檢查點抑製劑的隨機臨床試驗結果，無論是亞洲和白種人的分析結果均顯示了相對於標準治療或是安慰劑, 免疫療法治療的整體存活療效較佳; 且兩組相比，無統計上差異。該結果表示在亞裔或白種人種族使用免疫治療時應可預期相近的治療效果。

關鍵字

統合分析；免疫檢查點抑制劑；種族；試驗序列分析； PD-1 ； PD-L1 ； CTLA-4

並列摘要

Background Immune checkpoint inhibitors (ICIs) have become one important class of cancer therapy in recent years. Large individual differences in treatment effect have been reported and the response rates can range from 15% to 25% depending on cancer types, treatment selected, or its combination. These prognosis factors’ effectiveness are still under research and yet to reach unanimous conclusions. Meta-analysis has been conducted to explore several prognostic factors, including PD-1 and PD-L1 expression, several other biomarkers, age, and gender. This study aims to investigate the racial differences in the treatment responses to immune checkpoint inhibitor, with particular focus on White and Asian. Method A comprehensive literature search from PubMed and Embase databases were reviewed for relevant randomized controlled trials (RCTs) published from Jan 1st, 2015 up to December 30th, 2020. Twenty-seven RCT studies comparing the overall survival (OS) of immune checkpoint inhibitors versus standard of care (SOC) or placebo in various types of cancer in Asian and White were extracted for meta-analysis. Non-RCT, biomarker studies, cohort, retrospective studies, editorials, peer review articles were excluded. Meta-regression was carried out under the random effect model with both deluded (meaning misleading or deceiving, refers to an estimation of both the across-trial and within-trial interaction combined) and deft approach (cleverness, refers to estimation of the within-trial interaction alone), followed by a trial sequential analysis (TSA) to see if the information size has reached the threshold of statistical significance. Results The meta-analysis of 27 studies showed that for both Asian（hazard ratio [HR] 0.81; 95％CI 0.72-0.92; p = 0.07）and White（HR 0.83; 95％CI 0.76-0.90; p <0.01）under mixed effect model, immune checkpoint inhibitors demonstrated OS advantages against control arm. Meta-regression suggested that the difference in the OS benefit between the two racial groups was not statistically significant (p = 0.8407）. Subgroup analysis stratified by lines of therapy, cancer sites, used in combination with or without chemotherapy, and type of immune checkpoint inhibitor also yielded no statistically significant differences in the efficacy of immunotherapy between Asian and White. Similarly, trial sequential analysis (TSA) with 80% power found no statistical differences between the two groups and suggested additional trials in the future be unlikely to alter the result. Conclusion From this meta-analysis with TSA on available immune checkpoint inhibitors randomized clinical trials, the OS benefits were demonstrated for immunotherapy against either standard of care or placebo in both Asian and White, but no statistically significant difference was found between the two groups. This result may be interpreted as similar treatment effect can be expected when given to Asian as to White.

並列關鍵字

Meta-analysis ； Immune checkpoint inhibitors ； Race ； Trial Series Analysis ； PD-1 ； PD-L1 ； CTLA-4

參考文獻

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免疫檢查點抑制劑之有效性與種族(白種人與亞洲人)之相關性: 系統性回顧與統合分析

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