【导读： 本文是FDA的官方文献，阐述了FDA批准的第一个、也是目前唯一的液体活检测试法的审批思路。这个测试是罗氏的cobas EGFR突变测试v2，以前的v1版本是组织活检。V1和V2都是针对非小细胞肺癌患者来检测EFGR的两个特定位点的突变，都是为鉴定是否适合服用某种特定抗癌药物，所以这是个体化诊疗的一部分。 在组织活检的阳性患者中，有76.7％的患者在液态活检中也是阳性。 这个复合率虽然并不高，但是FDA认可了液态活检的优势，可以用于病重或者不能提供组织活检的患者，这促使FDA批准了V2产品。 而且，FDA在这里推荐，对患者首选用液体活检V2做筛查，筛查结果如果是阴性则用组织活检V1确认。 所以FDA的思路是用液体活检做一线的筛查方法学，而传统的组织活检是二线方法学，用来做阴性样本的确认。英文版在本文末端， 原文发表在FDA官网

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

2016年6月1日，美国食品和药物管理局批准cobas EGFR突变测试v2（罗氏分子系统公司）使用血浆标本作为检测外显子19删除或外显子21（L858R）替代突变的伴随诊断测试表皮生长因子受体（EGFR）基因来鉴定适合用Tarceva®（厄洛替尼）治疗的转移性非小细胞肺癌（NSCLC）患者。 cobas EGFR突变测试v2已经使用福尔马林固定石蜡包埋（FFPE）组织标本被批准用于该适应症。新用途是用于检测从血浆样品（也称为液体活检标本）分离的无循环肿瘤DNA（cfDNA）中的这些特定突变，以帮助医生鉴定可首先用TARCEVA（厄洛替尼）治疗的患者。这是FDA批准使用的第一个“液体活检测试”。这种新的测试可能有益于因为病重或者不能提供用于EGFR测试的肿瘤标本的患者。使用血浆标本检测EGFR外显子19缺失或L858R突变存在的cobas EGFR突变测试v2阳性的患者是用Tarceva（厄洛替尼）治疗的候选者。通过该测试为阴性的患者应该进行常规活检和用FFPE组织样品类型检测EGFR突变。

该批准是基于多中心，开放标签，随机，III期研究，评估Tarceva与吉西他滨加顺铂作为IIIB / IV期NSCLC患者一线治疗（ENSURE研究）的疗效和安全性。进入ENSURE研究的患者具有通过cobas EGFR突变测试v1测定的EGFR外显子19缺失或L858R突变测试为阳性的肿瘤组织标本。在601名（86.0％）患者中筛选了ENSURE研究的513名有效cobas EGFR突变试验v1测试结果中的五百一十七名可用血浆样品。在招募的患者中，98.6％（214/217）具有可用于测试的血浆样品。评价在筛选参与ENSURE的NSCLC患者中EGFR突变（实施例19del和L858R突变）的检测，在血浆中cobas EGFR突变测试v2和cobas EGFR突变测试v1之间的一致性。在76.7％（70.5％，81.9％）的组织阳性标本中，血浆对EGFR突变也是阳性的。在98.2％（95.4％，99.3％）组织阴性病例中，EGFR突变的血浆阴性。基于cobS EGFR突变试验v2在血浆中的TARCEVA的药物功效通过在ENSURE研究中基于cobas EGFR突变试验v1在组织中桥接至药物功效来评价。

与用化疗治疗的患者相比，血浆结果为外显子19缺失阳性的患者和/或用厄洛替尼治疗的L858R突变改善了无进展生存（PFS）。

用于血浆测试的cobas EGFR突变测试v2旨在用于最初筛选患有EGFR突变的转移性NSCLC的患者。那些在其血浆样品中未检测到外显子19缺失和/或L858R突变的患者然后应当从其FFPE组织标本中确定其EGFR状态。

本申请在2012年医疗器械用户费用修正案（MDUFA III）的目标日期为2016年8月23日之前获得批准。cobas EGFR突变测试v2上市前应用（PMA）被授予优先审查。安全性和有效性概述cobas EGFR突变测试v2的数据和标签将在大约30天内提供，网址为：http：//www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

医疗保健专业人员应通过在线http://www.fda.gov/medwatch/report.htm在线填写表格，将所有与使用任何药物和设备相关的严重不良事件报告给FDA的MedWatch报告系统，传真（ 1-800-FDA-0178）或通过在线或通过电话（1-800-FDA-1088）提供的邮资支付地址表。

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 “liquid 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).