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1、,Department of Thoracic/Head&Neck,Medical Oncology,Mutational Analysis in NSCLC Adenocarcinoma to Guide Therapy,Anne S.Tsao,M.D.,Associate Professor,The University of Texas,MD ANDERSON,CANCER CENTER,Director,Mesothelioma ProgramDirector,Thoracic Chemo-XRT Program,Outline:NSCLC,Lung Cancer,During 201
2、3,228,190 new cases and 159,480 deaths are expected in the United StatesSecond most common cancer and leading cause of cancer death,American Cancer Society.Cancer Facts and Figures 2013.Atlanta,GA:American Cancer Society;2013;Siegel.CA Cancer J Clin.61(4):212.,Stage at Diagnosis,Localized(stage I/II
3、)15%,Distant(stage IV)56%,Regional(stage III)22%,5-Year Relative Survival Rateby Stage at Diagnosis,Survival(%),Localized,Distant,Regional,53%,24%,4%,0,10,20,30,40,50,60,70,80,90,100,2004 WHO Classification of Lung Tumors,American Cancer Society.Cancer Facts and Figures 2008.Atlanta:American Cancer
4、Society;2008;Travis,ed.WHO Pathology 374(9699):1432.,Emerging data indicate that specific regimens show greater benefit depending on tumor histology.,BAC=bronchioloalveolar carcinoma;LCC=large cell carcinoma;LCNEC=large cell neuroendocrine carcinoma;SCC=squamous cell carcinoma;SCLC=small cell lung c
5、ancer;WHO=World Health Organization.,Lung Cancer Mutation ConsortiumOrganization,Headquarters:University of Colorado Paul Bunn,Principal Investigator14 Sites:SPORE,P01,NCI Intramural ProgramsPlan:Genotype 1000 patients with advanced lung adenocarcinoma,2009-2011Assay 10“driver”mutations in CLIA-cert
6、ified laboratories:EGFR,KRAS,BRAF,HER2,AKT1,NRAS,PIK3CA,MEK1,EML4-ALK,MET amp,Johnson et al on behalf of LCMC investigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506,LCMC Objectives,Characterize 1000 tumor specimens from patients with lu
7、ng adenocarcinoma for KRAS,EGFR,BRAF,HER2,PIK3CA,AKT1,NRAS,MEK1,and EML4-ALK,and MET amplification To use the information in real time to either select erlotinib with EGFR mutations or recommend a clinical trial of an agent targeting the specific mutation identified,Johnson et al on behalf of LCMC i
8、nvestigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506,Lung Cancer Mutation ConsortiumIncidence of Mutations Detected(n=516),A driver mutation was found in 54%(280/516)oftumors completely tested(CI 50-59%),HER 2,Johnson et al on behalf o
9、f LCMC investigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506,Lung Cancer Mutation Consortium Conclusions,An actionable driver mutation in 54%of patients with lung adenocarcinoma23%KRAS mutations2%BRAF mutations18%EGFR mutations2%PIK3CA
10、 mutations9%EML4-ALKEGFR mutations correlate with younger age,female gender,and never smokersKRAS mutations correlate with older age and smoking history Plans are underway to expand the scope of the LCMC when ARRA funding ends-LCMC 2.0,Johnson et al on behalf of LCMC investigators,WLCC July 2011 Abs
11、tract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506,Outline:NSCLC,NSCLC PATIENT,Platinum-doublet-bevacizumabPlatinum-pemetrexed+bevacizumabNon-platinum or platinum based doubletSwitch Maintenance:pemetrexed,erlotinib(E4599,AVAiL,Pointbreak,SATURN,JMEN),Tsao Algorit
12、hm:Histology and Molecular Profiling,EGFR mutations,Found in 10%-15%of all lung cancer patients and 85%who clinically respond to EGFR TKIsFound more commonly in never-smokers,adenocarcinomas,BAC,women,AsiansPredominantly located in EGFR exons 19-21 EGFR mutations are not the same.There are sensitive
13、 mutations and acquired resistance mutations(T790M).85%of EGFR mutations are either deletion exon 19 or L858 mutation.,Pao,Miller.J Clin Oncol.2005;23:2556-2568;Wu et al.J Thorac Oncol.2007;2:430-439.,Patient with EGFR mutation deletion exon 19,Patient with L858 EGFR mutation,EGFR T790M:Frequently F
14、ound inTumor Cells From Patients With Acquired Resistance to EGFR TKIs,Pao W,et al.PLoS Med.2005;2:e73;Balak MN,et al.Clin Cancer Res.2006;12:6494-6501.,T790M blocks erlotinib binding and leads to a resistant phenotype,Michalczyk et al.Bioorganic April 2008,IPASS:Phase III Trial of Gefitinib vs Carb
15、oplatin/Paclitaxel in Selected PatientsWith Advanced NSCLC,Never or lightex-smoker*withadenocarcinomahistologyPS 0-2Stage IIIB or IVchemotherapy-nave NSCLCN=1217,RANDOMIZE,Gefitinib(250 mg/day)Offered carboplatin/paclitaxel on progression,Carboplatin(AUC 5 or 6)+Paclitaxel(200 mg/m2)3 times weekly u
16、p to 6 cycles,Primary endpoint:PFS(noninferiority)Secondary endpoints:ORR,OS,QOL,disease-related symptoms,safety,and tolerabilityExploratory:biomarkers EGFR mutation,gene copy number,and protein expression,Mok.N Engl J Med.2009;361:947.,*Never smoker=smoked 100 cigarettes in lifetime;light ex-smoker
17、=stopped 15 years ago and smoked 10 pack-years.,0,4,8,12,16,20,24,Time From Randomization(Months),0.0,0.2,0.4,0.6,0.8,1.0,Probability of PFS,Gefitinib EGFR M+(N=132)Gefitinib EGFR M(N=91)Carboplatin/paclitaxel EGFR M+(N=129)Carboplatin/paclitaxel EGFR M(N=85),HR 1 implies a lower risk of progression
18、 in the M+group compared with the M group.,IPASS:PFS by EGFR Mutation Status Within Treatment Arms,Gefitinib,HR=0.19;P0.0001Carboplatin/paclitaxel,HR=0.78;P=0.1103,Adapted with permission from Mok.N Engl J Med.2009;361:947;Mok.ESMO.2008(abstr LBA2).,M=mutation.,IPASS:PFS and OS by EGFR Mutation Stat
19、us,Gefitinib EGFR M+,Gefitinib EGFR M-,C/P EGFR M+,C/P EGFR M-,OS(2010),PFS(2008),1.0,0.8,0.6,0.4,0.2,0.0,0,4,8,12,16,20,24,Mos,Probability of Survival,28,32,36,40,44,48,52,Mutation+,Mutation-,Reproduced with permission from Fukuoka.J Clin Oncol.2011;29(21):2866.Reproduced with permission from Yang.
20、ESMO.2010(LBA2).,EURTAC:Phase III Study of Erlotinib vs Chemotherapy in Patients with EGFR Mutations,*Cisplatin/docetaxel,cisplatin/gemcitabine,carboplatin/docetaxel,or carboplatin/gemcitabine.,Primary endpoint:PFSSecondary endpoints:ORR,OS,site of progression,safety,and QOLStratification:mutation t
21、ype and ECOG PS,Rosell.ASCO.2011(abstr 7503).,Eligibility:Chemo naveStage IIIB/IV NSCLCEGFR exon 19 deletion or exon 21 L858R mutation ECOG PS 0-2(n=174),R A N D O MIZE,Erlotinib 150 mg/day,Platinum-based doublet chemotherapy q3w 4 cycles*,PD,PD,Response and PFS in ITT,Rosell et al.ASCO 2011 Abstrac
22、t 7503,OS in ITT,Rosell et al.ASCO 2011 Abstract 7503,Summary EURTAC,EURTAC is the first Caucasian front-line EGFR TKI vs chemotherapy study performed in EGFR-mutation positive patients.The PFS(HR 0.37)was consistent with prior studies and favored the erlotinib arm with no new safety signals.OS rema
23、ins immature with high level of crossover.,TITLE,Yang et al.ASCO 2012 Abstract LBA7500,Yang et al.ASCO 2012 Abstract LBA7500,Phase III Lung LUX-3 Trial,1269 screened,452 EGFR mutation(+)=345 randomized,TITLE,Yang et al.ASCO 2012 Abstract LBA7500,ORR favored afatinib,Yang et al.ASCO 2012 Abstract LBA
24、7500,PFS favored afatinib,Yang et al.ASCO 2012 Abstract LBA7500,PFS Independent Review Subgroup Analysis,Yang et al.ASCO 2012 Abstract LBA7500,PFS Common Mutants(Del 19/L858R),Yang et al.ASCO 2012 Abstract LBA7500,QOL:EORTC QLQ C-30,Yang et al.ASCO 2012 Abstract LBA7500,Summary LUNG LUX-3,Front-line
25、 afatinib improved QOL,RR,DCR,and median PFS over cisplatin-pemetrexed in both the overall EGFR mutation population and in the common EGFR mutation(del19/L858)patients.Subgroup analysis showed benefit across most of the subgroups.No new safety signals with diarrhea and rash as the most frequent AEs.
26、On July 12,2013,the FDA approved afatinib for front-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21(L858R)as detected by an FDA-approved test.,Yang et al.ASCO 2012 Abstract LBA7500,Front-line EGFR TKI,EGFR TKI monotherapy in NSCLC patients with sensitive EGFR mutations impr
27、oves PFS over chemotherapy.However,EGFR TKI monotherapy should not be given to patients without EGFR mutations,i.e.EGFR wild-type(WT).EGFR WT patients need front-line chemotherapy.It is unclear which EGFR TKI should be used front-line.It is unclear whether EGFR TKI+chemo or chemo then maintenance er
28、lotinib would improve survival for EGFR mutation patients.CALGB 30406 frontline study(ASCO 2010)FAST-ACT(intercalating EGFR TKI with chemo)await results.There are concerns over combining erlotinib-chemo as erlotinib arrests the cancer cells in the G1 checkpoint and chemo usually works best in the mi
29、totic phase.SATURN showed that EGFR mutation patients had significant survival improvement with maintenance erlotinib after 4 cycles of chemo.,Outline:NSCLC,ALK anaplastic lymphoma kinaseEML 4 echinoderm microtubule associated protein like 4 Found Primarily in adenocarcinoma patients who are never-o
30、r light former smokers,EGFR and KRAS WT,and younger All adenocarcinomas:9%EML4-ALKIf EGFR WT,Caucasian never-smoker,adenocarcinoma:10-20%EML4-ALKEML4-ALK-positive tumors are a distinct entity among lung adenocarcinomas and usually do not respond to EGFR TKIs.EML 4 ALK is a negative prognostic factor
31、 ALK(+)NSCLC treated with 2nd/3rd line crizotinib have longer OS than those who are not treated with crizotinib.,EML4-ALK Fusion Gene,Koivunen et al.CCR 14(13):2008;Shaw et al.ASCO 2011 Abstract 7507;Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506,Crino et al.ASCO 2011 Abs
32、tract 7514,Phase II crizotinib in ALK-positive NSCLC,Crino et al.ASCO 2011 Abstract 7514,Best responseORR 51.1%SD 34%DCR week 6 85%week 12 74%PD7.5%,Tumor response,Crizotinib was FDA approved for usein pre-treated EML4 ALK patients.,ALK Inhibitor Efficacy in EML4-ALK NSCLC,Baseline 2 months of PF-02
33、341066,Kwak EL.J Clin Oncol 2009;27(suppl):Abstract 3509,Crizotinib ASCO 2010 Plenary,Treatment with crizotinib resulted in impressive clinical activity in patients with ALK-positive advanced NSCLCORR:57%DCR at 8 weeks:87%PFS probability at 6 months:72%Crizotinib was well tolerated Most frequent AEs
34、:mild/moderate GI events and mild visual disturbancesFor patients with ALK-positive NSCLC,crizotinib may offer a potential new standard of care.,ROS1 is an oncogene homologous to ALK and LTK within the Insulin Receptor Superfamily,v-ros initially discovered as the oncogene in the avian sarcoma RNA t
35、umor virus,UR2Expression restricted to epithelial cellsNormally expressed in kidney,small intestine,lungs,heart and male reproductive organsOrphan receptor with no known ligands,Bergethon et al.J Clin Oncol.2012;30(8):863-870,Doebele.IASLC Targeted Therapy 2012,Screening for ROS1 gene fusions reveal
36、s 1%incidence in NSCLC,RT-PCR(Li et al.PLoS One 2011)2/202(1%)East Asian Never Smokers with adenocarcinoma assaying for SLC34A2-or CD74-ROS1 fusions2/2 CD74-ROS1FISH(Bergethon et al.JCO 2012)18/1073(1.7%)6/18 confirmed by RT-PCR5 CD74-ROS11 SLC34A2-ROS1FISH(Davies et al.,accepted AACR 2012)5/428(1.2
37、%)surgically resected 5/5 confirmed by RT-PCR2 CD74-ROS12 SLC34A2-ROS11 SDC4-ROS11/48 patients screened at U.of Colorado SDC4-ROS1,Doebele.IASLC Targeted Therapy 2012,Clinical tumor responses in ROS1+NSCLC treated with crizotinib,pre-crizotinib,post-crizotinib(56 days),pre-crizotinib,post-crizotinib
38、(12 weeks),Bergethon et al.JCO 2012Davies et al.AACR 2012Doebele IASLC Targeted Therapy 2012,ROS1,ROS1 gene fusions involved in multiple cancer typesIncidence across multiple studies in NSCLC is approximately 1%ROS1 mutant patients are younger and more likely to be never smokers with higher grade ad
39、enocarcinoma histology Clinical responses are seen in ROS1 mutant patients with crizotinibOngoing clinical trial for ROS1 NSCLC patients using crizotinib,Bergethon et al.J Clin Oncol.2012;30(8):863-870,Doebele.IASLC Targeted Therapy 2012,2nd generation ALK inhibitors,NSCLC PATIENT,Platinum-doublet-b
40、evacizumabPlatinum-pemetrexed+bevacizumabNon-platinum or platinum based doubletSwitch Maintenance:pemetrexed,erlotinib(E4599,AVAiL,Pointbreak,SATURN,JMEN),Tsao Algorithm:Histology and Molecular Profiling,Adenocarcinoma,crizotinib,Platinum-doublet-bevacizumabPlatinum-pemetrexed+bevacizumabNon-platinum or platinum based doubletSwitch Maintenance:pemetrexed,erlotinib(E4599,AVAiL,Pointbreak,SATURN,JMEN),Potential Future of NSCLC-Molecular Profiling,Met inhibition,KRAS mutant,MEK inhibitor combination,Resistance rebiopsyNovel Agent,
