比較第三代與上一代表皮生長因子接受器抑制劑用在第一線治療轉移性表皮生長因子接受器突變非小細胞肺癌之系統性回顧、統合分析及臨床試驗計畫書

Abstract

背景 肺癌是全球癌症死亡原因之首。依據病理分類，其中80−85% 屬於非小細胞肺癌（NSCLC），當中肺腺癌和鱗狀上皮細胞肺癌為主要形態。精準醫療是現今非小細胞肺癌治療的主流，病人在接受治療前須檢測有無標靶藥物相對應的致癌驅動基因。在東亞大多數的非小細胞肺癌，至少一半以上的肺腺癌病人會帶有一個致癌驅動基因突變（oncogenic driver mutation）。而在亞洲群族中最常發生的致癌驅動基因是表皮生長因子接受器突變（EGFR mutation），肺腺癌當中有50−60% 帶此突變。目前針對晚期NSCLC而且帶有表皮生長因子接受器突變的病人，首選用藥是使用表皮生長因子接受器-酪胺酸酶抑制劑（EGFR-TKIs）。目前雖已有臨床試驗去比較不同世代藥物之間對病人療效的差異，但是單一臨床試驗所納入的病人是有限的，本篇研究最主要的目的是希望經由系統性回顧及統合分析比較晚期非小細胞肺癌病人在第一線治療使用不同世代的EGFR-TKIs在臨床上之療效及藥物安全性。 方法 通過系統性回顧及統合分析，使用NSCLC、第三代EGFR-TKIs、第一線治療做為關鍵字，透過PubMed、Embase、Cochrane 資料庫及ASCO、WCLC、ESMO摘要中進行檢索，篩選過去十年間發表的臨床試驗，比較第三代和上一代EGFR-TKIs使用在第一線治療帶有表皮生長因子接受器突變晚期非小細胞肺癌的療效和藥物安全性。主要對無惡化存活期（PFS）、藥物毒性（AE）和次組群包括性別、吸菸狀態、表皮生長因子接受器突變分型及有無腦轉移進行分析。 結果 透過系統回顧共有五個第三代相較於上一代EGFR-TKIs之臨床試驗可進行統合分析。PFS整體而言第三代（除了naquotinib）優於上一代，其PFS (hazard ratio [HR] = 0.57; 95% CI: 0.39−0.81, p = 0.002)。在次組群包括性別、吸菸狀態、表皮生長因子接受器突變分型 (exon19 deletion及L858R）及有無腦轉移進行分析，使用第三代（除naquotinib）其PFS都相對於上一代有較好的表現。而針對藥物毒性部分，使用第三代則與上一代類似，AEs grade 3−5 (relative risk [RR] = 1.00; 95% CI: 0.81−1.26, p = 0.99)，統計上無顯著差異。除了osimertinib外，由於多數臨床試驗的總存活率尚未有成熟的資料，因此在本次統合分析總存活率部分沒有做分析。

Background Lung cancer is the leading cause of cancer-related death worldwide. Of them, non-small cell lung cancer (NSCLC) represents about 80 to 85%, including majorly adenocarcinoma and squamous cell carcinoma. At present, precision medicine is the mainstream for NSCLC treatment. Oncogenic driver gene tests are important before the treatment. In East Asia, NSCLC, especially adenocarcinoma, more than half of the patients will harbor the driver gene mutation. Epidermal growth factor receptor (EGFR) mutation is the major one, 50−60% in lung adenocarcinoma patients in East Asia. Nowadays, EGFR-tyrosine kinase inhibitors (TKIs) are the first-line treatment for advanced EGFR mutant NSCLC patients. Although previous clinical trials had demonstrated the clinical efficacies in different generations of EGFR-TKIs, but the patients enrolled in any single trial were limited. Therefore, we conducted this study to compare the treatment outcomes and side effects between different generation EGFR-TKIs through systematic review and meta-analysis. Methods To compare the efficacy and safety of the third-generation with prior generation EGFR-TKIs, we performed meta-analysis EGFR-TKIs use as first-line treatment for advanced EGFR mutant NSCLC patients in literature search of Pubmed, Embase, Cochrane databank, ASCO, WCLC, and ESMO meeting abstracts with keywords of third-generation EGFR inhibitors, osimertinib, aumolertinib, furmonertinib, naquotinib, lazertinib, first-line, and non-small cell lung cancer, NSCLC. Results Five eligible randomized controlled trials (RCTs) were included and analysis was performed by ReviewManager version 5.4. The third-generation (except naquotinib) had better progression-free survival (PFS) than prior generation EGFR-TKIs (hazard ratio [HR] = 0.57; 95% CI: 0.39−0.81, p = 0.002). In the subgroup analysis of PFS, third-generation (excluding naquotinib) had better performance than prior generation EGFR-TKIs regardless of sex, smoking status, EGFR mutation subtypes or central nervous system (CNS) metastasis status. As for the grade 3−5 adverse events (AEs), there were no differences between third-generation and first-generation EGFR-TKIs (relative risk [RR] = 1.00; 95% CI: 0.81−1.26, p = 0.99). Overall survival (OS) analysis was not performed as most studies (except osimertinib) did not have mature OS data.