驯化肿瘤微环境-西方视角课件.ppt
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- 驯化 肿瘤 环境 西方 视角 课件
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1、Lung Cancer:Targeting the micro-environmentAngiogenic and immune check-points inhibitorsI provided consultations for Astra-Zeneca,Bristol-Myers Squibb,BoehringerIngelheim,Clovis Oncology,Eli Lilly Oncology,F.HoffmannLa Roche Ltd,Novartis,Merck,MSD,Pierre Fabre and Pfizer.Multidisciplinary Oncology&T
2、herapeutic InnovationsINSERM U911 CRO2Marseille-FranceDisclosure slideMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceWhats in tumors?Adapted from Thierry A,2014OutlineOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-France Angiogen
3、ic inhibitors Antibodies TKIs Immune Checkpoints Inhibitors Pre-treated patients Naive patientsOutlineOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-France Angiogenic inhibitors Antibodies TKIs Immune Checkpoints Inhibitors Pre-treated patients Naive patientsMulti
4、disciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceAngiogenics inhibitors:antibodiesClement-Duchene C&Wakelee H,J Thorac Oncol 2010Multidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-France1L,Cx+Bevacizumab:metanalysisSoria JC et al,Ann Oncol 20131L,
5、Cx+Bevacizumab:Beyond resultsMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceCritresBv+CP(n=136)Pl+CP(n=133)Median PFS,months9,26,5P-value0,0001ORR(95%CI)54%(45,462,9)26%(19,234,8)P-value0,0001DCR(95%CI)95%(89.,397,7)89%(81,893,3)Duration of response,months(95%CI)8.
6、0(6,99,4)5.3(4,46,0)5101520Months00.00.250.751.0PFS(%)0.50Pl+CPBv+CP6.59.2Zhou et al,WCLC 20131L,Cx+Bevacizumab:ALK patientsMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FrancePatients at RiskDuruisseaux M et al,presented CPLF 2017Temps(mois)Probabilit de Survie sans pr
7、ogressionPFSpCT-BEVA(N=60)pCT(N=184)Evnements,n(%)60(100)184(100)Median(95%CI),mois8.6(7.3-12.0)5.8(4.7-7.7)Log-rank p-value=0.0261L,TKI+Bevacizumab:EGFRm patientsMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FrancePatients at RiskSeto T et al,Lancet Oncol 2014EB groupE
8、 groupMedian(months)HR0.54(95%CI:0.360.79)P value*7572696460534938302013844077665744392924211812105210001.0EEBNumber at riskTime(months)4812261014182226162024280.20.40.60.8PFS probability9.716.0EBE Median PFS Bev+Pem:7.4mBev:3.7mHR:0.48;p 2 cycles ofbevacizumabmaintenancen=600Gridelli,et al.Clin Lun
9、g Cancer 2011*SOC2:labelled agents for second-line treatment of NSCLC SOC3 and beyond:choice of labelled agents is the investigator s choiceMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceOptimizing dosing&schedulesLignet F(Benzekry S)et al,J Theoretical Biol 2012;M
10、ollard S et al,AACR 2014;Ciccolini et al(MARS team),PNAS 2015;Ciccolini J&Benzekry S(to be submitted)Bevacizumab(lung cancer model)Target vascular normalization destruction Adequate timing for antiangiogenics/drug(s)?32 days52 days75 daysOutlineOncologie Multidisciplinaire&Innovations ThrapeutiquesI
11、NSERM UMR 911 CRO2Marseille-France Angiogenic inhibitors Antibodies TKIs Immune Checkpoints Inhibitors Pre-treated patients Naive patientsImmune checkpointsOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceMHCTCRTCRActivation(cytokines,lysis,proliferation,migra
12、tion to tumour)CTLA-4 pathwayPD-1 pathwayAnti-CTLA-4Anti-PD-1/PD-L1PeripheryTumour microenvironment Anti-PD-12L,Nivolumab:OSMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceBrahmer J et al.N Engl J Med 2015;Borghaei H et al.N Engl J Med 20152L,Nivolumab:DoROncologie
13、Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceBarlesi F et al.ESMO 20162L,Nivolumab:AEsOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceBarlesi F et al.ESMO 20162L,Pembrolizumab:OS(PD-L1 1%)Multidisciplinary Oncology&Therapeuti
14、c InnovationsINSERM U911 CRO2Marseille-FranceHerbst RS et al.Lancet 2015HR 0.61(95%CI 0.49-0.75)p0.0001HR 0.71(95%CI 0.58-0.88)p=0.00810.412.78.52L,Atezolizumab:OAK designOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceAtezolizumab 1200 mg IV q3wPD or loss of
15、 clinical benefitDocetaxel 75 mg/m2 q3w Locally Advanced or Metastatic NSCLC12 prior lines of chemo including at least 1 platinum basedAny PD-L1 statusN=1,225 enrolledaPDR 1:1Stratification factorsPD-L1 expressionHistology Prior chemotherapy regimensPrimary Endpoints(first 850 enrolled patients):OS
16、in the ITT populationOS in patients with PD-L1 expression on 1%TC or ICSecondary Endpoints:ORR,PFS,DoR,SafetyBarlesi F et al.ESMO 2016Oncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceBarlesi F et al.ESMO 20162L,Atezolizumab:OSAtezolizumabDocetaxelMedian 9.6 mo
17、(95%CI,8.6,11.2)Median 13.8 mo(95%CI,11.8,15.7)Overall Survival(%)MonthsHR,0.73a(95%CI,0.62,0.87)P=0.0003Minimum follow up=19 monthsOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceBarlesi F et al.ESMO 20162L,Atezolizumab:OS(PD-L1 1%)HR,0.74a(95%CI,0.58,0.93)P
18、=0.0102Median 10.3 mo(95%CI,8.8,12.0)Median 15.7 mo(95%CI,12.6,18.0)Overall Survival(%)AtezolizumabDocetaxelMonthsMinimum follow up=19 monthsOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceBarlesi F et al.ESMO 20162L,Atezolizumab:OS(PD-L1 1%)AtezolizumabDocet
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