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1、Disclosures,Advisory boards for Genentech and AstraZenecaResearch support from AstraZeneca,Case#1,56 yo woman with 15 pack-year history presents with a malignant pleural effusion,mediatinal adenopathy,and a 3-4 small CNS metastases.She has been having mild headaches recently.Cytology reveals adenoca
2、rcinoma,TTF1+EGFR mutatation testing could not be performed from cell block and additional biopsy refused.,She is initially treated with stereotactic XRT for her CNS lesions and comes for systemic therapy.Which chemotherapy regimen is not supported by randomized phase III data?,Carbo/pacCarbo/pac/BV
3、Pem/cisPem/carbo/BV,Question 1,Question#1,She is initially treated with stereotactic XRT for her CNS lesions and comes for systemic therapy.Which chemotherapy regimen is not supported by randomized phase III data?Carbo/pacCarbo/pac/BVPem/cisPem/carbo/BV,Case#1,She is started on treatment with carbop
4、latin,paclitaxel,and BV x 6 cycles.She has a partial response,tolerates treatment well,and wants to be treated aggressively.,Which maintenance therapy is part of a regimen that has been shown to prolong OS in a randomized phase III study?,BV monotherapyPemetrexedBV+PemBV+erlotinibA and BA,B,and DNo
5、maintenance therapy,Question 2,Question#2,Which maintenance therapy is part of a regimen that has been shown to prolong OS in a randomized phase III study?BV monotherapyPemetrexedBV+PemBV+erlotinibA and BA,B,and DNo maintenance therapy,12 mo.24 mo.43.7%16.9%51.9%22.1%,0.0,0.2,0.4,0.6,0.8,1.0,Probabi
6、lity,PC,PCB,P=0.007,0,6,12,18,24,30,36,Months,Medians:10.2,12.5,HR:0.77(0.65,0.93),Phase III Trial of Bevacizumab in Non-Squamous NSCLC(ECOG 4599),Sandler et al,NEJM 2006,Overall survival,Does BV maintenance provide benefit in first-line NSCLC?,In ECOG4599,60.1%completed 6 cycles of CPB and 48%recei
7、ved BV maintenance.44%completed 6 cycles of CP without PD.,Sandler et al,Proc World Lung meeting 2011,poster P3.216,JMEN:Outcome in non-squamous histologypemetrexed vs BSC for NSCLC,Ciuleanu et al,Lancet,2009,PFS 4.5 vs 2.6 monthsHR 0.44P.0001,OS 15.5 vs 10.3 monthsHR 0.70P.002,ATLAS study design,Mi
8、ller VA,et al.J Clin Oncol 2009;27(Suppl 1):Abstract LBA8002,Post-progressiontherapy,Unblind at PD,1:1,Bevacizumab(15 mg/kg)+erlotinib(150 mg)to PD,Bevacizumab+Placebo to PD,Primary endpointPFS in all randomized patientsSecondary endpointsOverall survivalSafetyExploratory endpointsBiomarker analyses
9、(IHC,FISH,EGFR&K-Ras mutation),Eligibility Stage IIIB*/IV NSCLC ECOG performance status 01 Stratification factors Gender Smoking history(never vs former/current)ECOG performance status(0 vs 1)Chemotherapy regimen,*Carbo/paclitaxel;cis/vinorelbine;carbo or cis/gemcitabine;carbo or cis/docetaxel*IIIB
10、with pleural effusion,Non-PDn=768(66%),4 cycles of 1st-line chemotherapy*+bevacizumab,Chemo-naveadvanced NSCLCN=1160,ATLAS progression-free survival,Miller VA,et al.J Clin Oncol 2009;27(Suppl 1):Abstract LBA8002,373,142,58,27,15,6,3,0,370,178,81,43,20,6,3,1,No.of patients at risk:,Bev+placebo,Bev+er
11、lotinib,Progression-free survival(months),ATLAS update on overall survival,A 40%crossover rate(placebo patients to receive E once disease progressed)and underpowered design prevented trial from reaching significance for OS analysis2-month OS benefit was observed in the Bv and E maintenance arm after
12、 occurrence of 57%eventsBiomarker analysis data of ATLAS study are expected soon,Kabbinavar FF,et al.J Clin Oncol 2010;28:15s(suppl;abstr 7526),*25 patients were randomized after cut-off for main analysis of PFS,ECOG5508:Phase III trial of BV,Pem,or BV+Pem as maintenance therapy in advanced NSCLC,Ca
13、rbo/pac/BVQ3w x 4 cycles,Eligibility-BV eligible-non-squam-chemonaive-no CNS mets,PI:S.Ramilingam;clinictrials.gov;trial NCT01107626,R,Non-PD,BV,Induction,Maintenance,Pem,BV+Pem,Primary endpoint:OSSecondary:PFS,S130 trial:Phase III trial of CP+BvBv vs PemCarbo+BvPem in first line NSCLC,Eligibility-B
14、V eligible-non-squam-chemonaive-treated brain mets,Sponsor:Lilly;from clinictrials.gov;trial NCT00948675,R,Carboplatinpaclitaxel+BV(15mg/kg)q3w,BV,Pem,Carboplatinpemetrexed,Induction,Maintenance,Primary endpoint:PFS without grade 4 toxicitySecondary:PFS,ORR,DCR,toxicity,Point Break:phase III trial o
15、f CP+BvBv vs PemCarbo+BvPem+BV(Sandler vs Patel)in first line NSCLC,Eligibility-BV eligible-non-squam-chemonaive-treated brain mets,PI J.Patel;Patel et al,Clin Lung Cancer,2009,R,Carboplatinpaclitaxel+BV(15mg/kg)q3w,BV,BV+Pem,Carboplatinpemetrexed+BV(15mg/kg)q3w,Induction,Maintenance,N900Primary end
16、point:OS(superiority)Secondary:PFS,ORR,toxicity,AVAPERL1:Phase III BV+Pem as maintenance after cis/pem/BV induction as 1st line therapy,CisplatinPemetrexedBV(7.5 mg/kg)Q3w x 4 cycles,Eligibility-BV eligible-non-squam-chemonaive-no CNS mets,Sponsor:Hoffman-LaRoche;clinictrials.gov;trial NCT00961415,R
17、,Non-PD,BV(7.5 mg/kg),Induction,Maintenance,BV(7.5 mg/kg)+Pemetrexed,Primary endpoint:PFSSecondary:RR,DCR,duration of response,OS,Case#1 continued,She eventually developed shortness of breath from a recurrent pleural effusion,and is found to have mediastinal adenopathy.A biopsy confirmed the presenc
18、e of adenocarcinoma.Mutation testing demonstrated an exon 19 deletion in EGFR.,She is given a prescription for erlotinib,but asks whether BV should be restarted as well.Which of the following is true?,In phase III testing,the addition of BV to erlotinib prolonged PFS and improved response rates but
19、did not improve OS.Patients with mutant EGFR appear to derive greater relative benefit from BV+erlotinib(compared to erlotinib alone)than those with wt EGFR.Both A and B.None of the above.,Question 3:Second-line treatment,Question#3:second-line treatment,She is given a prescription for erlotinib,but
20、 asks whether BV should be restarted as well.Which of the following is true?In phase III testing,the addition of BV to erlotinib prolonged PFS and improved response rates but did not improve OS.Patients with mutant EGFR appear to derive greater relative benefit from BV+erlotinib(compared to erlotini
21、b alone)than those with wt EGFR.Both A and B.None of the above.,Randomized phase III study comparing BV+erlotinib vs erlotinib(BeTa),Herbst et al,Lancet 377:1846-54,2011,N=636;peripheral squamous,treated CNS mets allowedDid not prolong OS(primary endpoint),Randomized phase III study comparing BV+erl
22、otinib vs erlotinib(BeTa),Herbst et al,Lancet 377:1846-54,2011,PFSHR=0.62,OSHR=0.97P=0.76,Randomized phase III study comparing BV+erlotinib vs erlotinib(BeTa):greater benefit for BV in EGFR mutants?,Herbst et al,Lancet 377:1846-54,2011,HR EGFR mutant:0.44HR wt EGFR:1.11,Elevated MET and HIF-1a level
23、s in cell lines with mutated EGFR,Xu et al,Oncogene,2010,Regulation of HIF and MET by EGFR,Xu et al,Oncogene,2010,A549,HCC827,H1975,H3255,Differential Regulation of VEGF Secretion in Human NSCLC Cells by EGFR Inhibition,M F F F,Xu et al,Oncogene,2010,Phase III study of BV+erlotinib vs erlotinib in E
24、GFR mut+patients(CALGB31002/CHUGAI A+T),First-line chemo-nave NSCLCStage IIIB/IVPresence of EGFR mutation(L858R/exon 19)Treated brain mets ok,BV+Erlotinib,Erlotinib,Primary endpoint:PFS(IRF)Secondary endpoints:PFS(Inv),ORRQoL,Randomization,Schema presented by R.Lilenbaum,Astro Chicago Lung Symposium
25、 2010,Case#1:third line treatment,She eventually develops PD after treatment with erlotinib.She is treated with pemetrexed but develops renal insufficiency.Docetaxel is recommended.She wants to know if there is any role of adding a VEGF inhibitor to docetaxel.,Which of the following has been found t
26、o be true in phase III testing in 2nd/3rd line NSCLC?,BV prolongs PFS,ORR,and OS in combination with docetaxel.No VEGF inhibitor has been shown to prolong overall survival in combination with docetaxel.No VEGF inhibitor has been shown to provide clinical benefit in combination with docetaxel in phas
27、e III testing.Both B and C,Question 4:third-line treatment,Question#4:third line treatment,Which of the following has been found to be true in phase III testing in 2nd/3rd line NSCLC?BV prolongs PFS,ORR,and OS in combination with docetaxel.No VEGF inhibitor has been shown to prolong overall survival
28、 in combination with docetaxel.No VEGF inhibitor has been shown to provide clinical benefit in combination with docetaxel in phase III testing.Both B and C,Recurrent(stage IIIB/IV)NSCLC afterfailure of first-line chemotherapyTotal recruitment=1391 patients,Vandetanib 100 mg/d+docetaxel 75 mg/m2(max
29、six 21-day cycles)n=694,Placebo+docetaxel 75 mg/m2(max six 21-day cycles)n=697,ZODIAC,Vandetanib 100 mg/d+pemetrexed 500 mg/m2(every 21 days)n=256,Placebo+pemetrexed 500 mg/m2(every 21 days)n=278,Locally advanced or metastatic NSCLC(stage IIIB/IV)after failure of first-line treatment n=534,ZEAL,ZEST
30、,Vandetanib 300 mg/dn=623,Erlotinib 150 mg/dn=617,Recurrent(stage IIIB/IV)NSCLCafter failure of at least one previous chemotherapyPrior treatment with cetuximab or bevacizumab was permittedn=1240,De Boer R,et al.J Clin Oncol 2009;27(Suppl 15):Abstract 8010;Natale RB,et al.J Clin Oncol 2009;27(Suppl
31、15):Abstract 8009;Herbst R,et al.J Clin Oncol 2009;27(Suppl 15):Abstract CRA 8003,1:1 RANDOMIZE,1:1 RANDOMIZE,1:1 RANDOMIZE,Phase III randomized vandetanib trials in NSCLC,PFS in ZODIAC trial,Herbst R,et al,Lancet Oncol 2010;11:604,Time(months),0,Progression-free survival,0,0.1,0.2,0.3,0.4,0.5,0.6,0
32、.7,0.8,0.9,1.0,3,6,9,12,15,18,21,24,HR=0.79(0.700.90);P0.001Median PFS(m):Van 4.0;Placebo 3.2ORR:Van 17%;Placebo 10%,P0.001,Vandetanib 100 mg+docetaxelPlacebo+docetaxel,Vandetanib in NSCLC,De Boer R,et al.J Clin Oncol 2009;27(Suppl 15):Abstract 8010;Natale RB,et al.J Clin Oncol 2009;27(Suppl 15):Abs
33、tract 8009;Herbst R,et al.Lancet Oncol 2010;11:604;Herbst R,et al.J Clin Oncol 2009;27(Suppl 15):Abstract CRA 8003,Summary,BV maintenance is indicated for maintenance therapy after CP+BV although benefits of maintenance BV have not been established in randomized phase III trialsBV+Pem being tested a
34、s maintenanceMultiple trials comparing BV,pem,or combination in maintenance setting are ongoingNo OS benefit established to date for combinations of VEGF inhibitors with chemo or erlotinib in platinum-refractory NSCLC although additional trials ongoingPFS benefit observed in ZODIAC and BeTaBV may provide greater relative benefit in EGFR mut+;randomized phase III testing is in progress,
