ESMO-2017-NSCLC免疫治疗进展-PPT

*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,esmo,.org,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,esmo,.org,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,ESMO-2017-NSCLC免疫治疗进展,主要内容,惊天海啸：,PACIFIC,研究,又现曙光,：血液肿瘤突变负荷（,bTMB,）研究,王者依旧：,Checkmate017,和,Checkmate057,三年,随访分析,2,PACIFIC,研究,: Durvalumab,对照安慰剂在,III,期局部进展期不可切除的非小细胞肺癌同步放化疗后巩固治疗的一项双盲三期临床研究,Luis Paz-Ares,1, Augusto Villegas,2, Davey Daniel,3, David Vicente,4, Shuji Murakami,5, Rina Hui,6, Takashi Yokoi,7, Alberto Chiappori,8, Ki Hyeong Lee,9, Maike de Wit,10, Byoung Chul Cho,11, Maryam Bourhaba,12, Xavier Quantin,13, Takaaki Tokito,14, Tarek Mekhail,15, David Planchard,16, Haiyi Jiang,17, Yifan Huang,17, Phillip A. Dennis,17, Mustafa zgrolu,18,Acknowledgement: Dr. Scott J. Antonia of H. Lee Moffitt Cancer Center and Research Institute is the lead author for this study; Dr. Paz-Ares is presenting on his behalf,1,Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain;,2,Cancer Specialists of North Florida, Jacksonville, FL, USA;,3,Tennessee Oncology, Chattanooga, TN, and Sarah Cannon Research Institute, Nashville, TN, USA;,4,Hospital Universitario Virgen Macarena, Seville, Spain;,5,Kanagawa Cancer Center, Yokohama, Japan;,6,Westmead Hospital and the University of Sydney, Sydney, NSW, Australia;,7,Kansai Medical University Hospital, Hirakata, Japan;,8,H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA;,9,Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea;,10,Vivantes Klinikum Neukoelln, Berlin, Germany;,11,Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea;,12,Centre Hospitalier Universitaire de Lige, Lige, Belgium;,13,CHU Montpellier and ICM Val dAurelle, Montpellier, France;,14,Kurume University Hospital, Kurume, Japan;,15,Florida Hospital Cancer Institute, Orlando, FL, USA;,16,Gustave Roussy,Villejuif, France;,17,AstraZeneca, Gaithersburg, MD, USA;,18,Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey,背景,初诊时,III,期不可切除的非小细胞肺癌患者约占全部,NSCLC,患者的,1/3,1,以含铂双药为基础的同步放化疗是对于状态良好的,III,期不可切除的非小细胞肺癌患者的标准治疗,从同步放化疗,(cCRT),开始，这部分患者的中位无进展生存时间约为,8-10,个月，,5,年生存率约为,15%,16,近年来，对于进展期非小细胞肺癌患者的治疗进展缓慢,79,; III,期不可切除的,NSCLC,患者，如何在,cCRT,之后应用新的治疗手段进一步改善生存获益,存在未被满足的临床需求。,PACIFIC,研究是第一个在,III,期局部进展不可切除的患者人群中采用免疫检查点抑制剂治疗并进行疗效评估的三期随机对照研究,cCRT, concurrent chemoradiation therapy; PFS, progression-free survival;,NSCLC, non-small cell lung cancer;,SOC, standard of care.,1.,Auprin A, et al. J Clin Oncol 2010;28:218190; 2.,Yoon SM, et al. World J Clin Oncol 2017;8:1,20; 3. Ahn JS, et al. J Clin Oncol 2015;33:2660,6; 4. Furuse J, et al. Clin Oncol 1999;17:2692,9; 5. Belderbos J, et al. Eur J Cancer 2007;43:114,21; 6. Clamon G, et al. J Clin Oncol 1999;17:4,11; 7. NCCN guidelines for NSCLC V4.2017. Available at: . Updated 18 January 2017 (accessed June 2017); 8.,Vansteenkiste, J., et al. Ann Oncol 2013;24(Suppl 6):vi89-98; 9. Tsujino K, et al. J Thorac Oncol 2013;8:11819,4,Durvalumab,阻断,PD-L1,与,PD-1,和,CD80,的结合,Immune cell,Tumor cell,T cell,Tumor antigen,MHC I,TCR,MHC II,TCR,PD-1,PD-L1,Inhibition,X,CD80,PD-L1,CD80,Inhibition,X,Activation,CD28,CD80,PD-1,PD-L1,Tumor antigen,Durvalumab,1,是,人源化,IgG1,单克隆抗体,灭活了,ADCC,效应，主要作用原理是,阻断,PD-1/L1,抑制信号通路，增强效应性,T,细胞的杀伤功能。,mAb, monoclonal antibody; MHC, major histocompatibility complex; PD-1, programmed cell dealth-1;,PD-L1, programmed cell death ligand-1;,TCR, T-cell receptor,1. Stewart R, et al. Cancer Immunol Res 2015;3:1052-62,Durvalumab,5,PACIFIC:,研究设计,三期随机双盲安慰剂对照的多中心研究,*Defined as the time from randomization (which occurred up to 6 weeks post-cCRT) to the first documented event of tumor progression or death in the absence of progression.,ClinicalTrials.gov number: NCT02125461,BICR, blinded independent central review; cCRT, concurrent chemoradiation therapy; DoR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes; PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization,期局部进展期不可切除的,NSCLC,，经过至少,2,个周期的同步放化疗后没有疾病进展,18,岁以上（包含）,PS,评分,0-1,预计生存,12,周以上,收集患者的组织标本,Durvalumab,10 mg/kg q2w forup to 12 months,N=476,Placebo,10 mg/kg q2w for up to 12 months,N=237,2:1,随机分组,分层因素：年龄、性别、吸烟史,N=713,次要研究终点,ORR (per BICR),DoR (per BICR),安全性和耐受性,PROs,主要研究终点,PFS,(,BICR,应用,RECIST v1.1,标准,),*,OS,R,cCRT,之后,1-42,天,6,统计分析,计划样本量,:,N = 702 (2:1,随机化,),共同主要研究终点,:,PFS,、,OS,PFS,假设,:,研究应用双侧, 0.025,，对,458,例事件进行,HR,为,0.67,的,log-rank,检验，把握度,95%,计划在,367 (80%),例事件发生后进行,PFS,的中期分析（,IA,）,实际,IA,在,371,例事件后进行，并对,PFS,分析结果进行了报道,OS,假设,:,研究应用双侧, 0.025,，对,491,例事件进行,HR,为,0.73,的,log-rank,检验，把握度, 85%,研究目前仍对,OS,保持盲态，对于,OS,的最终分析计划在目标事件数完成后开始,HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival,7,大家应该也有点累了，稍作休息,大家有疑问的，可以询问和交流,8,基线特征,(ITT),*Not reported or missing (durvalumab, placebo, total): WHO performance status (0.4% each), prior radiotherapy (0.2%, 0.4%, 0.3%).,Other: durvalumab, 2.5%; placebo, 2.1%; total, 2.4%.,No sample collected or no valid test result,.,Not evaluable/not applicable: durvalumab, 2.3%; placebo, 2.1%; total, 2.2%.,cCRT, concurrent chemoradiation therapy; CR, complete response; ITT, intention-to-treat; PD, progressive disease;,PD-L1, programmed cell death ligand-1;,PR, partial response; SD, stable disease;,TC, tumor cell; TC 25%, 25% PD-L1 expression on tumor cells; TC 25%, 25% PD-L1 expression on tumor cells; WHO, World Health Organization,9,中位随访时间,14.5,个月,(,范围,0.229.9),患者情况,BICR, blinded independent central review,10,PFS by BICR (,首要研究终点，,ITT,人群,),PFS probability,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,3,6,9,12,15,18,21,24,27,Time from randomization (months),Placebo,Durvalumab,476,377,301,264,159,86,44,21,4,237,163,106,87,52,28,15,4,3,1,0,No. at risk,Durvalumab,Placebo,BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-free survival,分层,HR, 0.52 (95% CI, 0.420.65),Two-sided P0.0001,11,PFS,亚组分析,BICR,评估,(ITT),*,Hazard ratio and 95% CI not calculated if the subgroup has less than 20 events.,BICR, blinded independent central review; CI, confidence interval; CR, complete response; HR, hazard ratio; ITT, intention-to-treat; EGFR,epidermal growth factor receptor,0.25,0.5,1,2,Favors durvalumab,Favors placebo,抗肿瘤活性, BICR,评估,(ITT),*Patients with measurable disease at baseline, as determined by either of the two independent reviewers;,One patient could not be grouped into any of the best overall response categories due to inconsistency in the baseline assessment for measurable disease between the two independent central reviewers.,Percentages calculated by Kaplan-Meier method;,Placebo was the reference group when RR and HR were calculated; therefore, an RR value greater than 1 is in favor of durvalumab and an HR value less than 1 is in favor of durvalumab,BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; RR, relative risk,P0.001,(24.2832.89),(11.3121.59),(RR 95% CI),:,1.78 (1.27,2.51),13,新发病灶情况,BICR,评估,(ITT),*A patient may have had more than one new lesion site.,Includes lesions in: abdominal wall, biliary tract, breast, chest wall, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum, retroperitoneum, skin, spleen, uterus and other (unspecified).,BICR, blinded independent central review; ITT, intention-to-treat,14,发生远处转移或死亡的时间,-,BICR,评估,(ITT),1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,1,3,6,9,12,15,18,21,24,27,30,Probability of death or distant metastasis,Time from randomization (months),Placebo,Durvalumab,No. at risk,Durvalumab,Placebo,476,407,336,288,173,91,46,22,4,1,0,237,184,129,106,63,32,16,5,4,0,0,Durvalumab,Placebo,14.6 (10.618.6),23.2 (23.2NR),Median time (95% CI),months,BICR, blinded independent central review; ITT, intention-to-treat,分层,HR, 0.52 (95% CI, 0.390.69),Two-sided P11% of patients in either treatment arm.,Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for safety reporting.,Pneumonitis/radiation pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor.In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis. AE, adverse event,17,肺炎及放射性肺炎,Safety analysis set (all-causality). *Pneumonitis/radiation pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor.In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis.,Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for safety reporting.,18,总结,按计划进行的,PFS,中期分析显示，相对照安慰剂，,Durvalumab,在,PFS,方展示了显著的统计学差异和临床获益,(HR 0.52; P11,月,),所有的预设亚组中均观察到,Durvalumab,组,PFS,的延长,相比于对照组，,Durvalumab,显示出了显著的,ORR,获益,(28.4% vs 16.0%; P16,作为界值,血液采集、血浆分离、,cfDNA,提取,等位基因突变频率大于,0.5%,去除已知的驱动基因和体细胞突变多态性,bTMB,POPLAR,(,测试,),OAK,(,验证,),22,Atezolizumab,在,POPLAR,研究中,bTMB,亚组中,的临床获益（,N=211,）,PFS,和,OS,的获益在,bTMB10,16,20,的各个亚组均有体现，但在,16,亚组中获益最大（,PFS HR 0.57 OS HR 0.56,）,统计学差异在更高水平的,bTMB,亚组中并未体现，可能是因为样本量偏小的缘故,bTMB16,作为界值将在在,OAK,研究中进行确证性分析,BEP: bio-marker evaluable population,；,HR,：,hazard rate,；,ITT: intention to treat,23,Atezolizumab,经,OAK,研究确认的在,bTMB,亚组中的,PFS,临床获益,bTMB16,占全部,BEP,人群的,27%(N=158),bTMB16,亚组人群可以观察到,PFS,获益,预后效应未观察到；在,bTMB16,亚组的总生存和,BEP,人群一致,该结果反应的是疾病进展之后后续治疗的影响,在,bTMB16,亚组中, Atezolizumab,组的中位,OS,为,13.5,月，紫杉醇组的中位,OS,为,6.5,月。,BEP: bio-marker evaluable population,；,HR,：,hazard rate,；,ITT: intention to treat,25,OAK,研究中随,bTMB,界值增加生存获益明显,bTMB16,亚组的总生存和,BEP,人群一致,在,bTMB16,亚组中,可以观察到,Atezolizumab,组的,PFS,获益,26,OAK,研究中,bTMB,亚组的基线特征,与之前研究的数据一致，吸烟状态可能与,bTMB,表达相关,临床肿瘤体积（,SLD/,转移灶）可能与,TMB,的表达相关,SLD:,最大直径总和,27,基于组织检测的,TMB,和血液中,TMB,的比较,Sperman,相关系数,0.59,POPLAR(n=74),和,OAK,（,n=224,）的数据合并。,影响,PPA,的因素：,肿瘤异质性：单点活检,VS,循环,DNA,计算机方法学的差异：,bTMB 0.5%,仅有单核苷酸多态性,tTMB 0.5%,单核苷酸多态性,/,融合,/,插入,/,删失,标本获取时间的差异：,存档标本,VS,血浆检测标本,28,bTMB=16,与,PD-L1,高表达的,重复率有限,(OAK,研究,BEP),N=229,TC3: TC=50%,IC3: IC=10%,bTMB=16,与,PD-L1,高表达的重复部分没有统计学差异,Fisher,精确检验,P=0.62,bTMB=16,亚组中,19.2%,为,TC3 or IC3,TC3 or IC3,的患者中,29.1%,为,bTMB=16,N=126,N=30 N=73,bTMB=16,TC3 or IC3,29,结 论,该研究第一个阐明,TMB,可以在血液中检测，并且和免疫检查点抑制剂治疗的,PFS,相关,-,血液,TMB,检测大约可使初诊时不能为分子检测提供足够组织标本的大约,30%,患者提供新的检测途径,POPLAR,研究中，以,bTMB16,作为界值显示，可显著改善,PFS,获益；在,OAK,研究中，该界值的,PFS,改善也得到了独立确认。,-bTMB16,亚组的总生存和通过组织标本确认的,BEP,人群一致,在该项分析中，,bTMB,筛选出了独特的人群，与免疫组化技术检测出的,PD-L1,高表达有着统计学差异,应用此种方法对一线,NSCLC,的,bTMB,进行分析的研究目前正在进行中,30,王者依旧：,1301P,，,CheckMate 017/057,三年随访结果,: Nivolumab,对比多西他赛用于二线,NSCLC,患者的比较研究,Enriqueta Felip,1 Scott Gettinger,2 Marco Angelo Burgio,3 Scott J. Antonia,4 Esther Holgado,5 David Spigel,6 Oscar Arrieta,7 Manuel Domine,8 Osvaldo Arn Frontera,9 Julie Brahmer,10 Laura Q. Chow,11 Lucio Crin,3 Charles Butts,12Bruno Coudert,13 Leora Horn,14 Martin Steins,15 William J. Geese,16 Ang Li,16 Diane Healey,16 Everett E. Vokes171Hospital Universitari Vall dHebron, Barcelona, Spain;,2Yale Cancer Center, New Haven, CT, USA; 3IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy;,4H. Lee Moffitt Cancer Center ,10The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 11University of Washington, Seattle, WA, USA; 12Cross Cancer Institute, Edmonton, AB, Canada; 13Centre Georges Franois Leclerc, Dijon, France;14Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 15Thoraxklinik, Heidelberg University Hospital, Heidelberg, Germany; 16Bristol-Myers Squibb, Princeton, NJ, USA; 17University of Chicago Medicine & Biological Sciences, Chicago, IL, USA,31,研究背景和目的,Nivolumab,是抗,PD-1,抗体，在许多国家被批准用于治疗晚期非小细胞肺癌（,NSCLC,）患者和铂类化疗期间或之后疾病进展的患者,CheckMate 017,和,CheckMate 057,分别是二线鳞癌和非鳞癌,NSCLC,患者的,2,个关键,III,期研究，两个研究结果均显示,nivolumab,同多西他赛相比显著延长患者总生存期（,OS,），并具有良好的安全性。基于这些结果,nivolumab,被获批上市,在鳞癌或非鳞癌,NSCLC,患者中都观察到治疗效果，包括,PD-11,患者都观察到疗效,; PD-L1,高表达的非鳞癌患者获益更多,本研究根据,CheckMate 017,和,CheckMate 057,最少,3,年的随访结果，来进一步评估,nivolumab,的疗效和安全性,32,研究方法,CheckMate 017,和,CheckMate 057,是全球、随机、开放,III,期研究，比较了,NSCLC,患者二线使用,nivolumab,与多西紫杉醇的疗效和安全性,完成初步分析后，在研究期间多西他赛组允许患者在多西他赛治疗结束后进行,nivolumab,治疗,两项研究方案在,2016,年,9,月都进行了修订，接受,nivolumab,3 mg / kg,每,2,周（,Q2W,）用药方案的患者可以选择固定剂量,480 mg4,周（,Q4W,）方案或维持,nivolumab 3 mg / kg Q2W,用药方案,两项研究的最低生存随访时间为,40.3,个月（,2017,年,6,月,22,日数据库锁定）,33,研究设计,34,研究结果,使用,nivolumab,和多西他赛治疗患者的中位治疗时间分别为,2.8,个月（范围,0-51.8),和,2.1,个月,(,范围,0-20.0),CheckMate 017,和,057,最少随访时间大于,3,年，分别有,5,和,7,的,nivolumab,治疗患者仍然在治疗中,;,多西他赛组没有患者还在接受多西他赛治疗,35,OS (,最少,3,年随访,),36,3,年患者生存率分析,37,2-3,年的死亡事件分析,38,PFS (,最少随访,3,年,),39,治疗有效率,(,最少随访,3,年,),40,后续治疗,在,CheckMate 017,研究中,nivolumab,组和多西他赛组，分别有,42,和,35,的患者在研究治疗结束后接受了其他全身治疗，在,CheckMate 057,研究中这一比例为,48,和,54,41,两个研究中,nivolumab,组治疗安全性,总结（最少,3,年随访）,42,两个研究中,nivolumab,治疗相关,不良事件合并分析,43,结论,CheckMate 017,和,057,研究中进行最少,3,年的随访后发现：,在晚期鳞癌和非鳞癌,NSCLC,患者中，,Nivolumab,治疗表现出持续长期的,OS,和,PFS,获益,Nivolumab,的,3,年,OS,率在,CheckMate 017,中为,16,，,CheckMate 057,中为,18,第,3,年随访时未见新的不良事件发送，治疗相关不良事件的发生率与,2,年随访期间相似,44,1306PD:接受PD1/PD-L1单抗治疗的NSCLC患者，超进展（HPD）现象频繁出现,Roberto Ferrara1,*, Caroline Caramella2, Matthieu Texier3, Clarisse Audigier-Valette4, Laurent Tessonnier5, Laura Mezquita1, Jihene Lahmar1, Julien Mazieres6, Gerard Zalcman7, Solenn Brosseau7, Virginie Westeel8, Sylvestre Le Moulec9, Laura Leroy9, Boris Duchemann10, Rmi Veillon11, David Planchard1, Marie-Eve Boucher1, Serge Koscielny3, Jean Charles Soria12, Benjamin Besse1.,45,背景和目的,1.在既往的早期单中心回顾临床试验中，接受免疫治疗的131例晚期肿瘤患者中，有9%的患者出现了HPD.,2.在34例接受免疫治疗的难治复发性头颈部肿瘤患者中，有29%的患者出现了HPD.,3.MDM-2扩增和EGFR突变近来被认为是潜在的与HPD发生相关分子改变机制,4.既往的单中心研究中89例NSCLC患者，采用肿瘤生长速度（Tumor Growth Rate,TGR)描述HPD(一定时间内肿瘤增大50%）的发生率为10%,在这一回顾性分析中，我们在一个更大的多中心队列中，评估接受免疫治疗的晚期NSCLC患者，HPD的发生率。,1.ChampiatS.etal.ClinCancerRes.2017;23(8):1920-1928;2.Sada-BouzidE,etal.AnnOncol.2017;,3.KatoS.etal.ClinCancerRes.2017;4.LahmarJ.etal.AnnOncol2016,27(suppl_6):1222P;,46,方 法,收集了5个法国的研究中心，在2012年11月至2017年3月期间，接受免疫治疗的NSCLC患者的临床和影像学数据，进行回顾性分析。,患者入组条件：在免疫治疗前、基线和免疫治疗过程(6周）中，分别至少进行过1次CT扫描，,所有的影像学资料在统一的研究中心由资深的影像学专家采用RECIST 1.1标准统一评估，,采用K-M法估计患者的中位PFS和中位OS，并采用Log-rank法对比HPD和非HPD患者的PFS和OS,47,在治疗期间的TGR变化评估,Gomez-RocaCetal.EurJCancer2011,47:25126.,分别计算免疫治疗基线时的TGR(基线的CT扫描n vs. n-1CT扫描），免疫治疗过程中的TGR ( n+1CT扫描vs.基线的CT扫描n ），以及两者之间每个月的TGR变化值TGR.,如果TGR增加至少50%，则定义为HPD.,48,患者基线特征：共入组242例患者,49,相比于基线，64%的患者接受免疫治疗过程中，TGR下降（TGR0） ，,36%的患者TGR升高（TGR0）, 16%（40例）患者出现HPD,结 果,50,结果-疗效评估与HPD,仅3例患者（1.2%）为确认的假性进展，其中2例最初评价为HPD.,51,-,对比HPD和非HPD的患者，基线的肿瘤负荷、临床、分子、病理特征，PD-L1状态，接受免疫治疗之前的治疗疗效等，均无显著差异。对于免疫基线治疗前2个转移灶的患者，HPD发生率更高.,结 果,52,OS：HPD vs. PD RECIST,排除2例确认为假性进展的患者,HR,根据影响预后的因素进行了调整,(PS,评分，转移灶的个数，肿瘤分期，基线肿瘤负荷,).,中位随访时间为10个月,接受免疫治疗的ORR为15%,中位PFS为3.9个月,（95%CI:3-5m）,中位OS为13.4个月,（95%CI:9-42m）,结 果,53,242 例晚期NSCLC 患者中， 36%的患者在免疫治疗过程中肿瘤增大，40 例(16%)患者出现了HPD.,免疫基线治疗前2个转移灶，HPD发生率更高.,HPD为预后不良因素 (HPD 患者中位OS 3.5 m).,结 论,54,