1、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-Ares1, Augusto Villegas2, Davey Daniel3, David Vicente4, Shuji Murakami5, Rina Hui6, Takashi Yokoi7, Alberto Chiappori8, Ki Hyeong Lee9, Maike de Wit10, Byoung Chul Cho11, Maryam Bourhaba12, Xavier Quantin13, Takaaki Tokito
2、14, Tarek Mekhail15, David Planchard16, Haiyi Jiang17, Yifan Huang17, Phillip A. Dennis17, Mustafa zgrolu18Acknowledgement: 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 behalf1Hospital Universitario 1
3、2 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain; 2Cancer Specialists of North Florida, Jacksonville, FL, USA; 3Tennessee Oncology, Chattanooga, TN, and Sarah Cannon Research Institute, Nashville, TN, USA; 4Hospital Universitario Virgen Macarena, Seville, Spain; 5Kanagawa Canc
4、er Center, Yokohama, Japan; 6Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; 7Kansai Medical University Hospital, Hirakata, Japan; 8H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 9Chungbuk National University Hospital, Chungbuk National University Colleg
5、e of Medicine, Cheongju, Korea; 10Vivantes Klinikum Neukoelln, Berlin, Germany; 11Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 12Centre Hospitalier Universitaire de Lige, Lige, Belgium; 13CHU Montpellier and ICM Val dAurelle, Montpellier, France; 14Kurume University Hos
6、pital, Kurume, Japan; 15Florida Hospital Cancer Institute, Orlando, FL, USA; 16Gustave Roussy, Villejuif, France; 17AstraZeneca, Gaithersburg, MD, USA; 18Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey cCRT, concurrent chemoradiation therapy; PFS, progression-free survival; NSCLC
7、, 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;8:120; 3. Ahn JS, et al. J Clin Oncol 2015;33:26606; 4. Furuse J, et al. Clin Oncol 1999;17:26929; 5. Belderbos J, et al. Eur J Cancer 2007;43:11421; 6. Cla
8、mon G, et al. J Clin Oncol 1999;17:411; 7. NCCN guidelines for NSCLC V4.2017. Available at: https:/www.nccn.org/professionals/physician_gls/f_guidelines.asp. 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 O
9、ncol 2013;8:11819Immune cellTumor cellT cellTumor antigenMHC ITCRMHC IITCRPD-1PD-L1InhibitionXCD80 PD-L1CD80 InhibitionXActivationCD28CD80PD-1PD-L1Tumor antigenDurvalumab1 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;
10、 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;3:1052-62Durvalumab*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
11、 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; PRO
12、s, 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Durvalumab10 mg/kg q2w forup to 12 monthsN=476Placebo10 mg/kg q2w
13、 for up to 12 monthsN=2372:1 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)*OSRcCRT之后1-42天HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival*Not reported or missing (durvalumab, placebo, total): WHO p
14、erformance 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 re
15、sponse; 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 OrganizationBICR, blinded independent
16、 central reviewPFS probability1.00.90.80.70.60.50.40.30.20.10.00369121518212427Time from randomization (months)PlaceboDurvalumab4763773012641598644214237163106875228154310No. at riskDurvalumabPlaceboBICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, prog
17、ression-free survival分层分层HR, 0.52 (95% CI, 0.420.65)Two-sided P0.0001Durvalumab PlaceboUnstratified HR*No. of patients(95% CI)全部患者4762370.55 (0.450.68)性别男3341660.56 (0.440.71)女142710.54 (0.370.79)随机年龄65 岁2611300.43 (0.320.57)65 岁2151070.74 (0.541.01)吸烟状态吸烟4332160.59 (0.470.73)不吸烟43210.29 (0.150.57)疾
18、病分期Stage IIIA2521250.53 (0.400.71)Stage IIIB2121070.59 (0.440.80)组织学类型鳞癌 2241020.68 (0.500.92)非鳞癌2521350.45 (0.330.59)对cCRT的反应CR97PR2321110.55 (0.410.75)SD2221140.55 (0.410.74)PD-L1 状态25%115440.41 (0.260.65)25%1871050.59 (0.430.82)未知174880.59 (0.420.83)EGFR 状态突变型29140.76 (0.351.64)野生型3151650.47 (0.3
19、60.60)未知132580.79 (0.521.20)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 recepto
20、r0.250.512Favors durvalumabFavors placebo*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 b
21、etween 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 durvalumabBICR, blinded independent
22、central review; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; RR, relative riskP0.001(24.2832.89)(11.3121.59)(RR 95% CI): 1.78 (1.272.51)*A patient may have had more than one new lesion site. Includes lesions in: abdominal wall, biliary tract, breast, chest wal
23、l, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum, retroperitoneum, skin, spleen, uterus and other (unspecified).BICR, blinded independent central review; ITT, intention-to-treat1.00.90.80.70.60.50.40.30.20.10.0136912151821242730Probability of death or distant metastasisTime from
24、 randomization (months)PlaceboDurvalumabNo. at riskDurvalumabPlacebo4764073362881739146224102371841291066332165400DurvalumabPlacebo14.6 (10.618.6)23.2 (23.2NR)Median time (95% CI),monthsBICR, blinded independent central review; ITT, intention-to-treat分层分层HR, 0.52 (95% CI, 0.390.69)Two-sided P11% of
25、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 spon
26、sor.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 Safety analysis set (all-causality). *Pneumonitis/radiation pneumonitis was assessed by investig
27、ators 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 leas
28、t one dose of durvalumab and were considered part of the durvalumab arm for safety reporting. 1. Antonia SJ, et al. Poster presented at the 41st European Society for Medical Oncology Annual Meeting, Copenhagen, October 711, 2016.DoR, duration of response; HR, hazard ratio; ORR, overall response rate
29、; PFS, progression-free survivalIII期不可切除的非小细胞肺癌患者完成同步放化疗后，Durvalumab巩固治疗是一种令人鼓舞的新治疗选择研究目的：检验并确立一种基于血液学的检测方法，用以测定血液中TMB的含量，并以此评估 bTMB和Atezolizumab的疗效相关性bTMB和Atezolizumab的疗效相关性在之后依据POPLAR和OAK验证研究进行分析，以bTMB16作为界值BEP: bio-marker evaluable population； HR： hazard rate；ITT: intention to treatBEP: bio-marke
30、r evaluable population； HR： hazard rate；ITT: intention to treatBEP: bio-marker evaluable population； HR： hazard rate；ITT: intention to treatSLD: 最大直径总和影响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
31、=0.62bTMB=16亚组中 19.2%为TC3 or IC3TC3 or IC3的患者中29.1%为bTMB=16 N=126 N=30 N=73bTMB=16TC3 or IC3Enriqueta 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
32、,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,
33、 Meldola, Italy; 4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 5Hospital De Madrid, Norte Sanchinarro, Madrid, Spain; 6Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 7Instituto Nacional de Cancerologa, Mexico City, Mexico;8Fundacin Jimnez Daz, Mad
34、rid, Spain; 9Centro Internacional de Estudios Clinicos, Santiago, Chile; 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
35、;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, USA1.ChampiatS.etal.ClinCancerRes.2017;23(8):1920-1928;2.Sada-
36、BouzidE,etal.AnnOncol.2017;3.KatoS.etal.ClinCancerRes.2017;4.LahmarJ.etal.AnnOncol2016,27(suppl_6):1222P;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HP
37、D患者的PFS和OSGomez-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.结 果结果-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. 结 果排除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 结 论
