【導讀： 本文是FDA的官方文獻，闡述了FDA批準的第一個、也是目前唯一的液體活檢測試法的審批思路。這個測試是羅氏的cobas EGFR突變測試v2，以前的v1版本是組織活檢。V1和V2都是針對非小細胞肺癌患者來檢測EFGR的兩個特定位點的突變，都是為鑒定是否適合服用某種特定抗癌藥物，所以這是個體化診療的一部分。 在組織活檢的陽性患者中，有76.7％的患者在液態(tài)活檢中也是陽性。 這個復合率雖然并不高，但是FDA認可了液態(tài)活檢的優(yōu)勢，可以用于病重或者不能提供組織活檢的患者，這促使FDA批準了V2產品。 而且，FDA在這里推薦，對患者首選用液體活檢V2做篩查，篩查結果如果是陰性則用組織活檢V1確認。 所以FDA的思路是用液體活檢做一線的篩查方法學，而傳統的組織活檢是二線方法學，用來做陰性樣本的確認。英文版在本文末端， 原文發(fā)表在FDA官網

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm】

2016年6月1日，美國食品和藥物管理局批準cobas EGFR突變測試v2（羅氏分子系統公司）使用血漿標本作為檢測外顯子19刪除或外顯子21（L858R）替代突變的伴隨診斷測試表皮生長因子受體（EGFR）基因來鑒定適合用Tarceva®（厄洛替尼）治療的轉移性非小細胞肺癌（NSCLC）患者。 cobas EGFR突變測試v2已經使用福爾馬林固定石蠟包埋（FFPE）組織標本被批準用于該適應癥。新用途是用于檢測從血漿樣品（也稱為液體活檢標本）分離的無循環(huán)腫瘤DNA（cfDNA）中的這些特定突變，以幫助醫(yī)生鑒定可首先用TARCEVA（厄洛替尼）治療的患者。這是FDA批準使用的第一個“液體活檢測試”。這種新的測試可能有益于因為病重或者不能提供用于EGFR測試的腫瘤標本的患者。使用血漿標本檢測EGFR外顯子19缺失或L858R突變存在的cobas EGFR突變測試v2陽性的患者是用Tarceva（厄洛替尼）治療的候選者。通過該測試為陰性的患者應該進行常規(guī)活檢和用FFPE組織樣品類型檢測EGFR突變。

該批準是基于多中心，開放標簽，隨機，III期研究，評估Tarceva與吉西他濱加順鉑作為IIIB / IV期NSCLC患者一線治療（ENSURE研究）的療效和安全性。進入ENSURE研究的患者具有通過cobas EGFR突變測試v1測定的EGFR外顯子19缺失或L858R突變測試為陽性的腫瘤組織標本。在601名（86.0％）患者中篩選了ENSURE研究的513名有效cobas EGFR突變試驗v1測試結果中的五百一十七名可用血漿樣品。在招募的患者中，98.6％（214/217）具有可用于測試的血漿樣品。評價在篩選參與ENSURE的NSCLC患者中EGFR突變（實施例19del和L858R突變）的檢測，在血漿中cobas EGFR突變測試v2和cobas EGFR突變測試v1之間的一致性。在76.7％（70.5％，81.9％）的組織陽性標本中，血漿對EGFR突變也是陽性的。在98.2％（95.4％，99.3％）組織陰性病例中，EGFR突變的血漿陰性。基于cobS EGFR突變試驗v2在血漿中的TARCEVA的藥物功效通過在ENSURE研究中基于cobas EGFR突變試驗v1在組織中橋接至藥物功效來評價。

與用化療治療的患者相比，血漿結果為外顯子19缺失陽性的患者和/或用厄洛替尼治療的L858R突變改善了無進展生存（PFS）。

用于血漿測試的cobas EGFR突變測試v2旨在用于最初篩選患有EGFR突變的轉移性NSCLC的患者。那些在其血漿樣品中未檢測到外顯子19缺失和/或L858R突變的患者然后應當從其FFPE組織標本中確定其EGFR狀態(tài)。

本申請在2012年醫(yī)療器械用戶費用修正案（MDUFA III）的目標日期為2016年8月23日之前獲得批準。cobas EGFR突變測試v2上市前應用（PMA）被授予優(yōu)先審查。安全性和有效性概述cobas EGFR突變測試v2的數據和標簽將在大約30天內提供，網址為：http：//www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

醫(yī)療保健專業(yè)人員應通過在線http://www.fda.gov/medwatch/report.htm在線填寫表格，將所有與使用任何藥物和設備相關的嚴重不良事件報告給FDA的MedWatch報告系統，傳真（ 1-800-FDA-0178）或通過在線或通過電話（1-800-FDA-1088）提供的郵資支付地址表。

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm

cobas EGFR Mutation Test v2

On June 1, 2016, the U. S. Food and Drug Administration approved cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) using plasma specimens as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the epidermal growth factor recptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with Tarceva® (erlotinib).  The cobas EGFR Mutation Test v2 is already approved for this indication using formalin-fixed paraffin-embedded (FFPE) tissue specimens.  The new use is for detection of these specific mutations in circulating-free tumor DNA (cfDNA) isolated from plasma specimens, also called liquid biopsy specimens, to aid physicians in identifying patients who may be treated first with TARCEVA (erlotinib).  This is the first “l(fā)iquid biopsy test” approved for use by FDA. This new test may benefit patients who may be too ill or are otherwise unable to provide a tumor specimen for EGFR testing.  Patients positive by cobas EGFR Mutation Test v2 using plasma specimens for the presence of EGFR exon 19 deletions or L858R mutations are candidates for treatment with Tarceva (erlotinib). Patients who are negative by this test should undergo routine biopsy and testing for EGFR mutations with the FFPE tissue sample type.

The approval was based on a multicenter, open-label, randomized, Phase III study, to evaluate the efficacy and safety of Tarceva versus gemcitabine plus cisplatin as first-line treatment for stage IIIB/IV NSCLC patients (ENSURE study).  Patients entering the ENSURE study had tumor tissue specimens that tested positive for the EGFR exon 19 deletion or L858R mutations as determined by the cobas EGFR Mutation Test v1. Five hundred seventeen of the 601 (86.0%) patients screened for the ENSURE study with valid cobas EGFR Mutation Test v1 test results had available plasma samples available.  Of the patients enrolled, 98.6% (214/217) had a plasma sample available for testing.  The agreement between the cobas EGFR Mutation Test v2 in plasma and the cobas EGFR Mutation Test v1 in tissue was evaluated for detection of EGFR mutations (Ex. 19del and L858R mutations) in NSCLC patients screened for participation in ENSURE. In 76.7% (70.5%, 81.9%) of tissue-positive specimens, plasma was also positive for an EGFR mutation.  Plasma was negative for EGFR mutation in 98.2% (95.4%, 99.3%) of tissue-negative cases. The drug efficacy of TARCEVA, based on the cobas EGFR Mutation Test v2 in plasma, was evaluated by bridging to the drug efficacy based on the cobas EGFR Mutation Test v1 in tissue in the ENSURE study.

The patients whose plasma results were positive for exon 19 deletion and/or an L858R mutations treated with erlotinib had improved progression-free survival (PFS) compared to those treated with chemotherapy.   

The cobas EGFR Mutation Test v2 for use with plasma test is intended to be used to initially screen patients with metastatic NSCLC for EGFR mutations.  Those patients in whom no exon 19 deletion and/or an L858R mutation is detected in their plasma specimens should then be reflexed to having their EGFR status determined from their FFPE tissue specimen. 

This application was approved before the Medical Device User Fee Amendments 2012 (MDUFA III) goal date of August 23, 2016. The cobas EGFR Mutation Test v2 premarket application (PMA) was granted Priority Review.  Summary of Safety and Effectiveness Data and labeling for the cobas EGFR Mutation Test v2 will be available in approximately 30 days at:  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).