周彩存：肺癌的精準(zhǔn)治療

1、Caicun ZhouShanghai Pulmonary Hospital,Shanghai Tongji University, P.R.China腫瘤學(xué). 同濟(jì)大學(xué)出版社 2010年1月第一版:P276.J Clin Oncol 2008:3543-35517.88.17.48.18.18.86.99.59.8 9.98.0 8.010.111.39.410.310.310.411.80.02.04.06.08.010.012.014.0PTX+DDPGEM+DDPDOC+DDPPTX+CBPPTX+DDPGEM+DDPGEM_PTXNVB+DDPGEM+DDPPTX+CBPPTX+CB

2、PNVB+DDPNVB+DDPDOC+DDPDOC+CBPGEM+DDPPEM+DDPGEM+DDPPEM+DDPSchillerE1594Van MeerbeckEORTCScagliottiILCPKellyS9509TAX-326JMDBITT非鱗癌21%22%17% 17%31%36%27%30% 30%32%25%28%25%32%24%28.20%30.60%0%10%20%30%40%123456789101112131415161718192021222324Precision Medicine in Advanced NSCLCClinical Lung Cancer Gen

3、ome Project and Network Genomic Medicine, Science Transl. Med. 2013Target therapy(1st, 2nd, and 3rd generation)New targets Increase of biomarker testing Immunotherapy 1 50% Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo actionabledriver mutationAvastinChemo Non-squamous NSCLC Adeno CaS

4、quamous Ca.SCLCNOSLarge cell PFS in IPASS 048121620240.00.20.40.60.81.0Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)Probabilityof PFSEGFR M+ HR (95% CI) 0.48 (0.36, 0.64), p0.0001EGFR M- HR (95% CI) 2.85 (2.05, 3.98),

5、 p0.0001Primary Cox analysis with covariates; ITT population; HR 1 implies a lower risk of progression on gefitinibTreatment by subgroup interaction test, p5060%) is T790M mutation. Kadoaki et al. JCO, 2013T790M mutation is sensitive to the third-generation EGFR-TKIsRociletinib(CO1686)AZD9291EGFR-TK

6、Is resistance with T790M mutationORR61%59%DCR95%93%mPFS12 months8.0 monthsSequist JV, et al. N Eng J Med 2015; Janne PA, et al. N Eng J Med 2015AZD9291 80mg 每日一次 (n=175)每6周進(jìn)行RECIST 1.1 評(píng)估指導(dǎo)出現(xiàn)疾病進(jìn)展基于最近一次治療后進(jìn)展的腫瘤標(biāo)本經(jīng)中心實(shí)驗(yàn)室檢測(cè)出T790M突變陽(yáng)性EGFRm+的局部晚期或轉(zhuǎn)移性 NSCLC 患者，且T790M突變陽(yáng)性作為2線治療508作為3線或以上治療10017中國(guó)患者(n=150)非中

7、國(guó)患者(n=25)依據(jù)既往治療分入兩個(gè)隊(duì)列設(shè)計(jì)：本研究預(yù)計(jì)入組225例患者，其中包括180例中國(guó)患者 （占總?cè)虢M人數(shù)80%）主要終點(diǎn): ORR次要終點(diǎn): PFS, OSConfidential for AZD9291. Internal Use only. Not for internal or external distribution期待2016WCLC結(jié)果！PI: Caicun ZhouPresented By Tetsuya Mitsudomi at 2016 ASCO Annual MeetingCrizotinib in ALK positive NSCLC Phase III t

8、rials comparing crizotinib with chemotherapyin ALK+ lung cancer (PROFILE 1007 and 1014)Presented By Tetsuya Mitsudomi at 2016 ASCO Annual MeetingLimitations of crizotinib Low brain penetrance CSF/plasma ratio=0.03* inactive against secondary mutations of the ALK genePreviously untreated for BM (n=10

9、9)Previously treated for BM (n=166)No BM detected (n=613)nOutcomenOutcomenOutcomeTarget lesions only,n(%)49%813%5221%Non-Target lesions or New lesions(n=43)(n=54)(n=201)Intracranial/Brain,n(%)3070%3972%5125%Lung,n(%)37%611%2512%Bone,n(%)49%815%2512%Liver,n(%)25%36%4723%Presented By Shirish Gadgeel a

10、t 2016 ASCO Annual MeetingJ-ALEX: Study DesignKey criteriaStage IIIB/IV or recurrent ALK-positive NSCLC ALK centralized testing(IHC and FISH or RT-PCR)ECOG PS 0-2Measurable target lesionTreated/asymptomatic brain metastases allowed1prior chemotherapyAlectinib 300mg BID PO, 28-day cycle(N=100)Crizoti

11、nib 250mg BID PO, 28-day cycle(N=100)End-pointsPrimaryPFS assessed by IRFSecondaryOS,ORRPKQOLCNS PFSSafetyR1:1Stratification factors: Clinical Stage(IIIB/IV vs. Recurrent) Prior chemotherapy(0 vs.1) ECOG PS(0/1 vs.2); Not stratified by Brain Mets StatusPresented By Shirish Gadgeel at 2016 ASCO Annua

12、l MeetingPrimary Endpoint:PFS by IRF(ITT Population)Presented By Tetsuya Mitsudomi at 2016 ASCO Annual Meeting3rd Generation ALKi: LoratinibEfficacy results for ALK+ patientsnORR (%) (95% CI)PFS (mo) (95% CI)1 prior ALK TKI1457(29-82)13.5(6-NR)2 prior ALK-TKI2642(23-63)9.2(1.5-NR)Total ALK4146(31-63

13、)11.4(3.4-16.6)How to improve efficacy ? Application sequence: 1st vs new generation TKI Selection of population Bim SNP Abundance Mutation of other genesWhat is the best Sequence?TodayEGFR mut1st generation TKIProgression T790M-ChemotherapyDeathEGFR mut1st generation TKIProgression T790M+Third gene

14、ration TKIPDChemotherapyDeathTomorrowEGFR mutThird generation TKIChemotherapyPDPFS1PFS2PFS1+PFS2: 17.2 to 27.5 monthsPFS=PFS1+PFS2Multiple mechanisms have been elucidated in human samples and preclinical models The most common acquired resistance mutation (5060%) is T790M mutation. Kadoaki et al. JC

15、O, 2013Primary endpointPFS by independent reviewSecondary endpointsOSORRDCRResponse duration1:1l Stage IIIB/IV or recurrent NSCLCl Non-squamous histologyl EGFR Mut+ exon 19 deletion / L858R*l No prior treatmentl ECOG PS 01(n=152)RStratified by: gender, stage,smoking status, EGFR Mut typePDPDBevacizu

16、mab15mg/kg i.v. q3w + erlotinib 150mg/dayErlotinib 150mg/day Exploratory endpointsBiomarkersJO25567 phase II study of 1L erlotinib bevacizumab in EGFR Mut+ NSCLC QoLSafetyBev + erlotinib(n=75)Erlotinib(n=77)Median age, years67.067.050% Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo act

17、ionabledriver mutationAvastinChemo Non-squamous NSCLC Adeno CaSquamous Ca.SCLCNOSLarge cell E4599：Bevacizumab + Taxol/carbo ECOG 4599HR=0.66, p0.001 (95% CI: 0.570.77)0 6 12 18 24 304.56.21.00.80.60.40.20PFSAvastin + ChemotherapyChemotherapy 1098765432100 6 12 18 24 30 36 42OSHR=0.79(0.670.92)P=0.00

18、312.310.3Sandler, et al. N Engl J Med 2006 Avastin+ ChemoptherapyChemotherapyHRPPFS (months)6.24.50.660.0016-month PFS55%33%1-year PFS15%6%OS (months)12.310.30.790.003ORR35%15%Avastin + ChemotherapyChemotherapy BEYOND：Bevacizumab + Chemotherapy in Chinese NSCLC Placebo MaitainenaceStage IIIB/IV, Non

19、-squamous NSCLCTreatment nave, Aged 18 yrs old ECOG PS 0-1n=276Bevacizumab 15 mg/kg d1 Carbo AUC6 d1 Taxol 175 mg/m2 d1 Every 3wks , n=138Up to 6 cycles RPD*Placebo d1+Taxol/Carbo q3wks , n=1381:1PDBeva Maitainenace Primary endpoint ：PFS Secondary endpoints：OS，ORR，safety,exploratory biomarker analys

20、is (VEGF-A，VEGFR-2)Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.CharacteristicsBev+CP (n=138)Pl+CP (n=138)ECOG PS, n (%) 034 (25)27 (20) 1104 (75)111 (80)Histoloty, n (%) Adenocarcinoma137 (99)136 (98)Stage, n (%) Recurrent 4 (3)3 (2) IIIB8 (6)9 (7) IV126 (91)125 (91) Unknown0 (0.0)1 (1)EGFR stati

21、s, n (%)85 66 EGFR mutation, n (%)23 (27)17 (26) EGFR wild-type, n (%)62 (73)50 (74)nDesignBEYOND：PFS and OS improvedPFS (主要終點(diǎn))PFS 9.2 vs 6.5 HR 0.40 (95% CI 0.290.54) p0.0011.00.80.60.40.206121824Beva +Taxol/Carbo (n=138)Taxol/Carbo (n=138)Time (months)9.2月 6.5月2.7Time (Months)1.00.80.60.40.2061218

22、243036總生存Beva+Taxol/Carbo (n=138)Taxol+Carbo (n=138)OS 24.3 vs 6.5HR 0.68 (95% CI 0.500.93)p=0.015424.3月17.7月6.6數(shù)據(jù)截止時(shí)間 2013年1月27日Z(yǔ)hou C, et al. J Clin Oncol 2015; 33:2197-2204.Bev+CP (n=136)Pl+CP (n=133)ORR, %(95% CI)54 (45.462.9)26 (19.234.8) P value0.0001DCR, %(95% CI)95 (89.397.7)89 (81.893.3)Dur

23、ation of response, Months (95% CI)8.0 (6.99.4)5.3 (4.46.0)Bevacizumab + platinum doublet (no pemetrexed)66% ATLAS1Bevacizumab + pemetrexed/cisplatin67% AVAPERL3Gemcitabine/carboplatin53% Doc maintenance7Pemetrexed/cisplatin57% PARAMOUNT8Bevacizumab + cisplatin/gemcitabine64% AVAiL*2Cisplatin/gemcita

24、bine59% AVAiL control arm2Gemcitabine/carboplatin49% Gem maintenance6Bevacizumab + carboplatin/pemetrexed66% POINTBREAK4Bevacizumab + carboplatin/paclitaxel67% POINTBREAK4Platinum doublet46% SATURN5Median OS (months)24126018Pac + carbo + bevPac + carbo+ bevbev + pl bevPem + cis bev + erl bev + pemE4

25、5991POINTBREAK2PARAMOUNT3ATLAS4AVAPERL5Chemo + bevPem + cis + bevbevbevpem + bevpem + BSCPem + carbo+ bev17.015.717.716.918.915.919.816.9First-line(randomised at induction)Maintenance(randomised at maintenance)Carboplatin backboneChemo at investigators discretionCisplatin backboneRamucirumab 10mg/kg

26、+Docetaxel 75mg/m2,q3wN=628PD or intolerable toxicityStaged IVNSCLCTreated with 1st line platinum-based chemotherapy +/-maintenance therapyECOG PS 0/1Previous bevacizumab allowed N=1253R1:1Placeno+Docetaxel 75mg/m2, q3wN=6251st endpoint：OS3.04.59.110.59.711.18.29.50.02.04.06.08.010.012.0PL+DOC RAM+DOCPL+DOC RAM+DOCPL+DOC RAM+DOCPL+DOC RAM+DOCHR=0.76; P50% Mutation load200 Squamous Carcinoma Smoking adenocarcinomaNo actionabledriver mutationAvastinChemo Non-squamous NSCLC Adeno CaSquamous Ca.SCLCNOSLarge cell Activity in pretreated patientsNivolumabPembrolizumabAtezolizumabDurvalum