Longitudinal circulating tumour DNA (ctDNA) monitoring for early detection of disease progression and resistance in advanced NSCLC in FLAURA
Longitudinal circulating tumour DNA (ctDNA) monitoring for early detection of disease progression and resistance in advanced NSCLC in FLAURA
复制标题
FLAURA 纵向循环肿瘤 DNA (ctDNA) 监测可早期检测晚期 NSCLC 的疾病进展和耐药性
DOI：
10.1093/annonc/mdz394.083
复制
发表时间：
2019
影响因子：
50.5
通讯作者：
S. Ramalingam
中科院分区：
文献类型：
--
作者：
J. Gray;N. Peled;A. Markovets;N. Nogami;J. Lee;B. Cho;B. Chewaskulyong;M. Majem;T. Reungwetwattana;K. Vishwanathan;A. Todd;Y. Rukazenkov;Martin Johnson;C. Barrett;J. Chmielecki;R. Hartmaier;S. Ramalingam
背景：在FLAURA III期研究（NCT02296125）中，第三代EGFR-TKI奥西替尼在先前未经治疗的egfr突变（EGFRm）晚期非小细胞肺癌（NSCLC）中表现出优于比较EGFR-TKIs的疗效。在这里，我们报告了一项针对FLAURA疾病进展（PD）早期检测的ctDNA探索性分析的结果。方法首次治疗的EGFRm （ex19del/L858R）局部晚期/转移性NSCLC患者（n = 556）按1:1随机分组（奥西替尼80 mg qd：比较剂[吉非替尼250 mg qd/厄洛替尼150 mg qd]）。在第1、8和15天采集血浆样本，然后在第3-18周每21天采集一次，之后每6W采集一次。对于血浆样本为PD和/或停药的患者，在所有可用时间点对EGFRm （ex19del/L858R/T790M）进行ctDNA液滴数字PCR （ddPCR; Biodesix）检测，对w6后时间点进行C797S检测。C797S和T790M是唯一检测到的抗性突变。根据最低ctDNA结果及其与ddPCR检测和定量限的接近程度来定义ctDNA进展。结果ctDNA进展分析包括122/556（22%）例患者，具有有效的纵向监测ddPCR数据和DCO1的RECIST PD（2017年6月12日）。在两组中，80/122（66%）患者的ctDNA进展先于PD或与PD同时发生，中位提前期为2.7个月；9.5个月的中位无进展生存期（mPFS; n = 80）。在ctDNA进展的患者中，57/122（47%）检测到获得性C797S或T790M（奥西替尼4/50 [8%]C797S，比较剂53/72 [74%]T790M）；奥希替尼组和比较组的中位检测时间分别为16.7个月和8.4个月，反映了总体mPFS。在ctDNA进展合并PD的患者（n = 106）中，41/106（38%）患者（奥西替尼2/39[5%]，比较剂39/67[58%]）同时或早于PD检测到获得性T790M和C797S；中位提前期为1.4个月。结论：ctDNA监测可以早期识别一线EGFR-TKI治疗进展的患者，并在EGFR-TKI治疗的NSCLC发生PD之前检测egfr介导的耐药机制。未来的工作旨在探索非egfr介导的耐药性的早期检测。临床试验鉴定NCT02296125。编辑致谢：Donna Tillotson博士，来自iMed communications， Macclesfield， UK, Ashfield Company， UDG Healthcare plc的一部分，由AstraZeneca根据良好出版物规范（GPP3）指南资助。负责这项研究的法律实体阿斯利康。阿斯利康资金。J.E. Gray：荣誉（个人），咨询/咨询，研究资助/资助（机构）：阿斯利康；研究补助金/资助（院校）：阵列；研究资助/资助（机构）：默克；研究资助/资助（机构）：Genentech；研究资助/资助（机构）：勃林格殷格翰公司；荣誉（个人），咨询/咨询，研究资助/资助（机构）：百时美施贵宝；咨询/咨询：Celgene；荣誉（自我），顾问/顾问：武田。A. Markovets：股东/股东/股票期权，全职/兼职：AstraZeneca。Nogami N. Nogami：荣誉（自我）：辉瑞公司、Chugai制药有限公司、礼来公司、太浩制药有限公司、阿斯利康、协和客谷麒麟、小野制药有限公司、百时美施贵宝、默沙东。bc . Cho：荣誉（机构）、咨询/咨询、演讲局/专家证言、研究资助/资助（机构）：诺华；荣誉（机构）、咨询/咨询、研究资助/资助（机构）：拜耳、阿斯利康、MOGAM研究所、东亚科技、杨森、Yuhan、小野制药、Dizal制药、默沙东；荣誉（机构）、咨询/咨询、研究资助/资助（机构）、许可/版税：Champions Oncology；荣誉（机构），咨询/咨询：勃林格殷格翰、罗氏、百时美施贵宝、辉瑞、礼来、武田；股东/股东/股票期权：TheraCanVac Inc.B. Chewaskulyong：荣誉（个人），咨询/顾问，演讲局/专家证词，研究资助/资助（机构）：AstraZeneca。M. Majem：咨询/咨询，发言人局/专家证词：罗氏；演讲局/专家证言、研究经费/资助（自付）、差旅/住宿/费用：百时美施贵宝；咨询/咨询、演讲局/专家证言、差旅/住宿/费用：MSD；咨询/咨询、演讲局/专家证言、差旅/住宿/费用：阿斯利康；咨询/咨询、演讲局/专家证言：勃林格殷格翰；咨询/咨询：Tesaro；发言人局/专家证词：Hellsin；旅行/住宿/费用：lily；咨询/顾问：武田；咨询/顾问，发言人局/专家证言：Pierre Fabre；发言人局/专家证词：安进。N. Peled：荣誉（自我）、咨询/咨询、研究资助/资助（自我）：阿斯利康、勃林格殷格翰、百时美施贵宝、默沙杜、诺华、辉瑞、罗氏、武田；咨询/咨询：礼来公司；荣誉（自我）：基础医学；股东/股东/股票期权：Novellus Dx；荣誉（自我）：守卫360。K. Vishwanathan：股东/股东/股票期权，全职/兼职工作：AstraZeneca。A.托德：全职/兼职：阿斯利康。Y. Rukazenkov：股东/股东/股票期权，全职/兼职工作：AstraZeneca。约翰逊先生：股东/股东/股票期权，全职/兼职：阿斯利康。C. Barrett：股东/股东/股票期权，全职/兼职：AstraZeneca。J. Chmielecki：股东/股东/股票期权，全职/兼职：AstraZeneca。R. Hartmaier：股东/股东/股票期权，全职/兼职：AstraZeneca；股东/股东/股票期权，许可/特许权使用费，Nfe2l2外显子2和/或外显子3在基础医学进行的工作损失；申请临时专利：基础医学。S.S. Ramalingam：咨询/咨询，研究资助/资助（自行）：安进，阿斯利康，百时美施贵宝，默克；咨询/咨询：AbbVie、Celgene、Genentech、Lilly、Loxo、Takeda；研究补助金/资助（自我）：Tesaro。
Abstract Background In the phase III FLAURA study (NCT02296125), the 3rd-generation EGFR-TKI osimertinib showed superior efficacy to comparator EGFR-TKIs in previously untreated EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC). Here we report results from an exploratory analysis of ctDNA for the early detection of disease progression (PD) in FLAURA. Methods Treatment-naive patients (pts) with EGFRm (ex19del/L858R) locally advanced/metastatic NSCLC (n = 556) were randomised 1:1 (osimertinib 80 mg qd: comparator [gefitinib 250 mg qd/erlotinib 150 mg qd]). Plasma samples were collected on Days 1, 8 and 15, then every 21 days for weeks (W) 3–18, then every 6W thereafter. In pts who had a plasma sample on PD and/or discontinuation, ctDNA droplet digital PCR (ddPCR; Biodesix) for EGFRm (ex19del/L858R/T790M) was performed at all available time points and C797S for post-W6 time points. C797S and T790M were the only resistance mutations assayed. ctDNA progression was defined with respect to the nadir ctDNA result and its proximity to the ddPCR detection and quantification limits. Results The ctDNA progression analysis included 122/556 (22%) pts with valid longitudinal monitoring ddPCR data and RECIST PD by DCO1 (12 June 2017). Across both arms, ctDNA progression preceded or co-occurred with PD in 80/122 (66%) pts with 2.7 months (mo) median lead time; 9.5 mo median progression-free survival (mPFS; n = 80). Acquired C797S or T790M was detected in 57/122 (47%) pts with ctDNA progression (osimertinib 4/50 [8%] C797S, comparator 53/72 [74%] T790M); median time to detection was 16.7 and 8.4 mo for the osimertinib and comparator arms, respectively, mirroring overall mPFS. In pts with ctDNA progression and PD (n = 106), acquired T790M and C797S were detected either at the same time as, or earlier than PD in 41/106 (38%) pts (osimertinib 2/39 [5%], comparator 39/67 [58%]); median lead time was 1.4 mo. Conclusions ctDNA monitoring may allow for earlier identification of pts who progress on first-line EGFR-TKI therapy and the detection of EGFR-mediated resistance mechanisms in advance of PD in EGFRm NSCLC. Future work aims to explore early detection of non-EGFR-mediated resistance. Clinical trial identification NCT02296125. Editorial acknowledgement Donna Tillotson, PhD, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda. A. Markovets: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. N. Nogami: Honoraria (self): Pfizer Inc., Chugai Pharmaceutical Co. Ltd, Eli Lilly, Taiho Pharmaceutical Co. Ltd., AstraZeneca, Kyowa Hakko Kirin, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, MSD. B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. N. Peled: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Advisory / Consultancy: Eli Lilly; Honoraria (self): Foundation Medicine; Shareholder / Stockholder / Stock options: Novellus Dx; Honoraria (self): Guardant360. K. Vishwanathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Todd: Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Chmielecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Hartmaier: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options, Licensing / Royalties, Nfe2l2 exon 2 ano/or exon 3 loss from work conducted at Foundation Medicine; provisional patent filed: Foundation Medicine. S.S. Ramalingam: Advisory / Consultancy, Research grant / Funding (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Merck; Advisory / Consultancy: AbbVie, Celgene, Genentech, Lilly, Loxo, Takeda; Research grant / Funding (self): Tesaro.