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
19、axelMonthsHR,0.75a(95%CI,0.59,0.96)P=0.0205bMedian 8.9 mo(95%CI,7.7,11.5)Median 12.6 mo(95%CI,9.6,15.2)Overall Survival(%)Minimum follow up=19 monthsOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceGadgeel et al.,WCLC 20162L,Atezolizumab:EGFRmEGFR status Wild
20、type(N=628)EGFR status Mutant (N=85)Baseline characteristicsAtezo(n=318)Doc(n=310)Atezo(n=42)Doc(n=43)Median age,y63.564.562.060.0Male 61.6%61.9%31.0%37.2%Nonsquamous/squamous81.4%/18.6%83.5%/16.5%97.6%/2.4%93.0%/7.0%TC3 or IC317%15%14%7%TC1/2/3 or IC1/2356%54%50%35%TC0 and IC043%45%50%65%1L,Nivolum
21、ab:CM026 designOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceNivolumab3 mg/kg IV Q2Wn=271Randomize 1:1Key eligibility criteria:Stage IV or recurrent NSCLCNo prior systemic therapy for advanced diseaseNo EGFR/ALK mutations sensitive to available targeted inh
22、ibitor therapy1%PD-L1 expressionaCNS metastases permitted if adequately treated at least 2 weeks prior to randomizationChemotherapy(histology dependent)bMaximum of 6 cyclesn=270Disease progression or unacceptable toxicity Disease progressionCrossover nivolumabc(optional)Tumor scans Q6W until wk 48 t
23、hen Q12WaDako 28-8 validated;archival tumor samples obtained 6 months before enrollment were permitted;PD-L1 testing was centralizedbSquamous:gemcitabine 1250 mg/m2+cisplatin 75 mg/m2;gemcitabine 1000 mg/m2+carboplatin AUC 5;paclitaxel 200 mg/m2+carboplatin AUC 6;Non-squamous:pemetrexed 500 mg/m2+ci
24、splatin 75 mg/m2;pemetrexed 500 mg/m2+carboplatin AUC 6;option for pemetrexed maintenance therapycPermitted if crossover eligibility criteria met,including progression confirmed by independent radiology reviewSocinski MA et al.ESMO 2016Primary endpoint:PFS(5%PD-L1+)dSecondary endpoints:PFS(1%PD-L1+)
25、d OS ORRd Stratification factors at randomization:PD-L1 expression(5%vs 5%)a Histology(squamous vs non-squamous)1L,Nivolumab:PFS(PD-L1 5%)Oncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceSocinski MA et al.ESMO 2016No.of patients at risk:Nivolumab21110471493524
26、6310Chemotherapy212144744728218100NivolumabChemotherapyMonthsPFS(%)2421181512963271008060400200Nivolumab n=211Chemotherapyn=212Median PFS,months(95%CI)4.2(3.0,5.6)5.9(5.4,6.9)1-year PFS rate,%23.623.2All randomized patients(1%PD-L1+):HR=1.17(95%CI:0.95,1.43)HR=1.15(95%CI:0.91,1.45),P=0.25111L,Pembro
27、lizumab:KN024 designMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceReck M et al.ESMO&N Engl J Med 20161L,Pembrolizumab:PFSMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-FranceReck M et al.ESMO&N Engl J Med 2016ICI monotherapy for high P
28、DL1 expressors?Oncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceCourtesy JC Soria1L,Cx+Pembrolizumab:KN021G designOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceLanger C et al,ESMO 20161L,Cx+Pembrolizumab:ORROncologie
29、Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceLanger C et al,ESMO 20161L,Cx+Pembrolizumab:PFSOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceLanger C et al,ESMO 2016Whats next?Oncologie Multidisciplinaire&Innovations Thrapeuti
30、quesINSERM UMR 911 CRO2Marseille-France PD-L1 testing?Next combinations?PD-L1 AssessmentOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceNivolumabPembrolizumabAtezolizumabDurvalumabDetection antibody28-8122C31SP1423SP2634IHC platformDako1Dako1Ventana1Ventana4C
31、ell types scored for NSCLCTC1TC1IC and TC1,3TC1Cut-off definitions for NSCLCPDL1-selected as 5%of TCs exhibiting positive membrane PD-L1 staining at any intensityPDL1-selected as 50%(treatment-nave)or 1%(previously treated)of viable TCs showing partial or complete membrane PD-L1 expression*TC3 or IC
32、3:50%of TCs or 10%of ICsTC2/3 or IC2/3:5%of TCs or ICsTC1/2/3 or IC1/2/3:1%of TCs or ICsTC0 and IC0:1%of TCs and ICs(proportion of cells stained at any intensity)PDL1-selected as 25%of TCs with membrane PD-L1 stainingEstimated PD-L1 prevalence in NSCLC*For the 22C3 assay,the proportion of viable tum
33、our cells showing partial or complete membrane PD-L1 staining is termed the tumour proportion score(TPS)1.Kerr,et al.J Thorac Oncol 2015;2.Hui,et al.ASCO 2016;3.Vansteenkiste,et al.ECC 2015;4.Rebelatto,et al.ASCO 2015;5.Rizvi,et al.ASCO 201537%68%16%TPS 1%TPS 149%TPS 50%1L22L2TC 5%TC 5%2L154%46%TC 5
34、0%PDL1+Keynote 024Q2 2016MYSTIC2017Durvalumab tremelimumabvs SoCPembrolizumab+platinium/pemetrexed(non-squamous)Keynote 189Q3 2017Avelumab monovs Pt doublet PD-L1+JAVELIN lung100 Q1 2018Atezolizumab+chemobevacizumabvs chemo+bevacizumabIMpower 150Q1 2017Nivolumab mono vsNiv+IpivsNiv+Pt doublet vs Pt
35、doubletCheckMate-227Q1 2018Pembrolizumabmonotherapy1%PDL1+Keynote 042Q2 2018Atezolizumabmonotherapyall histologiesPDL1+Impower 110Q2 2018 Atezolizumab+chemoIMpower 130(non-SCC)Impower 131(SCC)Q3 2018Durvalumabtremelimumab vs SoCNEPTUNEQ4 2018Ipilimumab+paclitaxel+carboplatinsquamousCA184-153Q3 2019P
36、D1/PDL1 MonotherapyCTLA4+PD1PD1 or PDL1CT ComboLegendCourtesy JC SoriaCombine IO+antiangiogenics:GO 29436Oncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2Marseille-FranceESMO guidelines/Personal choicesOncologie Multidisciplinaire&Innovations ThrapeutiquesINSERM UMR 911 CRO2M
37、arseille-FranceNovello S et al,Ann Oncol 2016Multidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-France Bevacizumab has demonstrated activity in first line and in maintenance treatment In second line Immune Checkpoints inhibitors have efficacy In first-line(highly selected population)In second line Lack of predictive biomarker(s)is true for bothConclusionsMultidisciplinary Oncology&Therapeutic InnovationsINSERM U911 CRO2Marseille-France
