WCLC肺癌—奥希替尼AURA研究结果公布ppt课件.pptx

Presented by VA Papadimitrakopoulou at the World Conference on Lung Cancer 2016Plenary Session:PL03 Presidential Symposium(abstract PL03.03)Vassiliki A Papadimitrakopoulou1,Yi-Long Wu2,Myung-Ju Ahn3,Suresh S Ramalingam4,Marina Chiara Garassino5,Hye Ryun Kim6,Frances A Shepherd7,Hiroaki Akamatsu8,Willemijn SME Theelen9,Chee Khoon Lee10,Martin Sebastian11,Alison Templeton12,Marcelo Marotti12,Serban Ghiorghiu12,Tony Mok13Randomised Phase III study of osimertinib vs platinum-pemetrexed for EGFR T790M-positive advanced NSCLC(AURA3)1Department of Thoracic/Head and Neck Medical Oncology,The University of Texas MD Anderson Cancer Center,Houston,TX,USA;2Guangdong Lung Cancer Institute,Guangdong General Hospital&Guangdong Academy of Medical Sciences,Guangzhou,China;3Samsung Medical Center,Seoul,Republic of Korea;4Emory University,Winship Cancer Institute,Atlanta,GA,USA;5Medical Oncology Department,Thoracic Oncology Unit,Fondazione IRCCS Istituto Nazionale dei Tumori,Milan,Italy;6Department of Internal Medicine,Division of Medical Oncology,Yonsei University College of Medicine,Seoul,Republic of Korea;7Princess Margaret Cancer Centre,Toronto,Canada;8Third Department of Internal Medicine,Wakayama Medical University,Wakayama,Japan;9Department of Thoracic Oncology,The Netherlands Cancer Institute,Amsterdam,The Netherlands;10St George Hospital,Clinical Research Unit,Division of Cancer Services,Pitney Clinical Sciences Building,Kogarah,New South Wales,Australia;11University Hospital Frankfurt,Goethe University,Frankfurt am Main,Germany;12AstraZeneca,Cambridge,UK;13Key Laboratory of South China,Department of Clinical Oncology,The Chinese University of Hong Kong,Sha Tin,Hong KongDisclosuresVassiliki A Papadimitrakopoulou:consultancy for AstraZeneca,ARIAD,BMS,Genentech,Biothera,Janssen,Clovis,Merck,Eli Lilly;grants/research support from AstraZeneca,Genentech,Merck,BMS,Novartis,Janssen,ACEA Biosciences,Celgene,Clovis;honoraria from prIME Oncology,Imedex,CancerNet,CECYi-Long Wu:honoraria/speaker fees from AstraZeneca,Roche,Eli Lilly,Pfizer,SanofiSuresh S Ramalingam:consultancy for Amgen,Abbvie,AstraZeneca,BMS,BI,Celgene,Merck,Lilly,GenentechFrances A Shepherd:consultancy for AstraZeneca,Roche;stock shareholder in and honoraria from AstraZenecaHiroaki Akamatsu:honoraria from AstraZeneca,Eli Lilly,Chugai pharmaceuticals,BI,Merck,Pfizer,Ono pharmaceutical,Taiho pharmaceutical,NovartisChee Khoon Lee:honoraria from AstraZenecaMartin Sebastian:consultancy for and honoraria from Roche,BI,AstraZeneca,Novartis,PfizerAlison Templeton,Marcelo Marotti,Serban Ghiorghiu:employed by and stock shareholder in AstraZenecaTony Mok:employed by The Chinese University of Hong Kong;speakers bureau for AstraZeneca,Roche/Genentech,Pfizer,Eli Lilly,BI,MSD,Amgen,Janssen,Clovis Oncology,GSK,Novartis,BMS,PrIME Oncology;grants/research support from AstraZeneca,BI,Pfizer,Novartis,SFJ,Roche,MSD,Clovis Oncology,BMS;consultancy for AstraZeneca,Roche/Genentech,Pfizer,Eli Lilly,BI,Merck Serono,MSD,Janssen,Clovis Oncology,BioMarin,GSK,Novartis,SFJ Pharmaceutical,ACEA Biosciences,Inc.,Vertex Pharmaceuticals,Aveo&Biodesix,BMS,geneDecode Co.,Ltd.,OncoGenex Technologies Inc.,Celgene;stock shareholder in Sanomics Ltd.;honoraria for AstraZeneca,Roche/Genentech,Pfizer,Eli Lilly,BI,Merck Serono,MSD,Janssen,Clovis Oncology,BioMarin,GSK,Novartis,SFJ Pharmaceutical,ACEA Biosciences,Inc.,Vertex Pharmaceuticals,BMS,AVEO&Biodesix,Prime Oncology,Amgen,OncoGenex Pharmaceuticals,Inc.,CelgeneMarina Chiara Garassino:consultancy for AstraZeneca,Roche,Eli LillyMyung-Ju Ahn,Hye Ryun Kim,Willemijn SME Theelen:none declaredIntroductionOsimertinib is an oral,irreversible,CNS-active,EGFR-TKI selective for both sensitising(EGFRm)and EGFR T790M resistance mutations1,2Previous global Phase II studies showed osimertinib 80 mg QD provides clinically meaningful efficacy with minimal side effects in patients with EGFR T790M-positive NSCLC,whose disease had progressed on EGFR-TKI therapy3,4AURA extension(N=201):ORR(by BICR)was 62%,median PFS 12.3 months and median DoR 15.2 monthsAURA2(N=210):ORR(by BICR)was 70%,median PFS 9.9 months and median DoR 11.4 monthsAURA3 is the first randomised Phase III study to compare an EGFR T790M-selective EGFR-TKI(osimertinib)against platinum-based doublet chemotherapy in patients with centrally-confirmed EGFR T790M-positive advanced NSCLC whose disease had progressed on first-line EGFR-TKI therapy1.Cross et al.Cancer Discov 2014;4:104661;2.Ballard et al.Clin Cancer Res 2016;22:513040;3.Yang et al.AURA extension manuscript in preparation;4.Goss et al.Lancet Oncol 2016 ePub ahead of printAURA extension:NCT01802632;AURA2:NCT02094261;AURA3:NCT02151981BICR,Blinded Independent Central Review;CNS,central nervous system;DoR,duration of response;EGFR,epidermal growth factor receptor;ORR,objective response rate;NSCLC,non-small cell lung cancer;PFS,progression-free survival;QD,once daily;TKI,tyrosine kinase inhibitorAURA3 study designKey eligibility criteria18 years(20 years in Japan)Locally advanced or metastatic NSCLCEvidence of disease progression following first-line EGFR-TKI therapyDocumented EGFRm and central confirmation of tumour EGFR T790M mutation from a tissue biopsy taken after disease progression on first-line EGFR-TKI treatmentWHO performance status of 0 or 1No more than one prior line of treatment for advanced NSCLCNo prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior to starting first EGFR-TKI treatmentStable*asymptomatic CNS metastases allowedR 2:1Osimertinib(n=279)80 mg orally QDPlatinum-pemetrexed(n=140)Pemetrexed 500 mg/m2+carboplatin AUC5 or cisplatin 75 mg/m2Q3W for up to 6 cycles+optional maintenance pemetrexed#Optional crossoverProtocol amendment allowed patients on chemotherapy to begin post-BICR confirmed progression open-label osimertinib treatmentEndpointsPrimary:PFS by investigator assessment(RECISTv1.1)Secondary and exploratory:Overall survival Objective response rate Duration of response Disease control rate Tumour shrinkageBICR-assessed PFSPatient reported outcomesSafety and tolerabilityPatients were stratified at randomisation based on ethnicity(Asian/Non-Asian)RECISTv1.1 assessments performed every 6 weeks until objective disease progression;patients could receive study treatment beyond RECISTv1.1 defined progression as long as they experienced clinical benefitWith 221 events of progression or death,the study would have 80%power to reject the null hypothesis of no significant difference in duration of PFS between the two treatment groups,assuming a treatment effect HR of 0.67 at 5%two-sided significance*Defined as not requiring corticosteroids for 4 weeks prior to study treatment;#For patients whose disease had not progressed after 4 cycles of platinum-pemetrexedHR,hazard ratio;Q3W,every 3 weeks;R,randomisation;RECIST,Response Evaluation Criteria In Solid Tumors;WHO,World Health OrganizationCharacteristicOsimertinib(n=279)Platinum-pemetrexed(n=140)Sex,%:male/female38/6231/69Age,median(range),years62(2585)63(2090)Race,%:White/Asian/other*32/65/332/66/2Smoking status,%:never/current/former68/5/2767/6/27CNS metastases#,%3336EGFR mutations,%:T790M/Ex19del/L858R/other99/68/30/299/62/32/4Number of previous anti-cancer regimens,%:1/2/396/3/1*96/4/0Well balanced demographics and characteristics across AURA3 treatment groups419 patients were randomised to treatment(osimertinib,n=279;platinum-pemetrexed,n=140)Population:intent-to-treat*Including:Black or African American and American Indian or Alaska Native;#CNS metastases determined programmatically from baseline data of CNS lesion site,medical history,and/or surgery,and/or radiotherapy;EGFR mutation identified by cobas EGFR Mutation Test(by biopsy taken after confirmed progression on most recent treatment regimen);Six patients without centrally confirmed T790M mutation-positive status.Three patients subsequently found to be tumour T790M mutation-positive;Other includes G719X,S768I and Exon 20 insertion;*One patient had three previous anti-cancer regimens;Ex19del,Exon 19 deletionAnalysis of PFS by BICR was consistent with the investigator-based analysis:HR 0.28(95%CI 0.20,0.38),p0.001;median PFS 11.0 vs 4.2 months.Population:intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death.Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data;CI,confidence intervalAURA3 primary endpoint:PFS by investigator assessment1.00.80.60.40.200369121518Probability ofprogression-free survivalNo.at riskOsimertinibPlatinum-pemetrexedMonths2791402409316244881750713100Median PFS,months(95%CI)HR(95%CI)10.1(8.3,12.3)0.30(0.23,0.41)p0.001 4.4(4.2,5.6)Osimertinib Platinum-pemetrexedSubgroupOverall(n=419)Cox proportional hazardsLog rank(primary)Ethnicity Asian(n=274)Non-Asian(n=145)SexMale(n=150)Female(n=269)Age at screening65(n=242)65(n=177)EGFR-TKI sensitising mutation status prior to start of study Exon 19 deletion(n=279)L858R(n=128)Duration of prior EGFR-TKI6 months(n=24)6 months(n=395)CNS metastasesYes(n=144)No(n=275)Smoking historyEver(n=136)Never(n=283)PFS benefit with osimertinib observed across all subgroups in AURA3Population:intent-to-treatHR 1 implies a lower risk of progression on osimertinib 80 mg.Cox proportional hazards model includes randomised treatment,the subgroup covariate of interest,and the treatment by subgroup interaction.Size of circle is proportional to the number of events.Overall population analysis was performed using a Cox proportional hazards model and the primary analysis(U and V statistics)from stratified log-rank test.If there were 20 events in a subgroup then the analysis was not performed;NC,non-calculableHazard ratio(95%CI)0.37(0.29,0.48)0.30(0.23,0.41)0.32(0.24,0.44)0.48(0.32,0.75)0.43(0.28,0.65)0.34(0.25,0.47)0.38(0.28,0.54)0.34(0.23,0.50)0.34(0.24,0.46)0.46(0.30,0.71)NC0.39(0.30,0.51)0.32(0.21,0.49)0.40(0.29,0.55)0.40(0.27,0.62)0.36(0.26,0.49)0.10.20.30.40.50.70.9 1.00.60.8PFS benefit in AURA3 patients with CNS metastases at baselineWith CNS metastasesWithout CNS metastasesPopulation:intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death.Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data.CNS metastases determined programmatically from baseline data of CNS lesion site,medical history,and/or surgery,and/or radiotherapy.Probability ofprogression-free survival1.00.80.60.40.20No.at riskOsimertinibPlatinum-pemetrexed0369121518935180324692741424000MonthsOsimertinib(n=93)Platinum-pemetrexed(n=51)Median PFS,months(95%CI)8.5(6.8,12.3)4.2(4.1,5.4)HR 0.32(95%CI 0.21,0.49)Probability ofprogression-free survival1.00.80.60.40.20036912151818689160611163561133659100MonthsOsimertinib(n=186)Platinum-pemetrexed(n=89)Median PFS,months(95%CI)10.8(8.3,12.5)5.6(4.2,6.8)HR 0.40(95%CI 0.29,0.55)Durable response to osimertinib in AURA3Osimertinib(n=279)Platinum-pemetrexed(n=140)ORR(95%CI)71%(65,76)31%(24,40)Odds ratio*(95%CI)5.39(3.47,8.48);p0.001 Complete response,n(%)Partial response,n(%)Stable disease 6 weeks,n(%)Progression,n(%)Not evaluable,n(%)4(1)193(69)63(23)18(6)1(1 favours osimertinib 80 mg.The p-value was calculated based on the likelihood ratio test which compared two models(one model with ethnicity covariate only and the other model with both treatment factor and ethnicity covariate).#Calculated using Kaplan-Meier approach.Probability of remaining in responseNo.at riskOsimertinibPlatinum-pemetrexed0369121518197441632996125642113000MonthsOsimertinibPlatinum-pemetrexed1.00.80.60.40.20AURA3 safety summaryAE any*,n(%)Osimertinib(n=279)Platinum-pemetrexed(n=136)Any AE273(98)135(99)Any AE Grade 363(23)64(47)Any AE leading to death4(1)1(1)Any serious AE50(18)35(26)Any AE leading to discontinuation19(7)14(10)AE,possibly causally related#,n(%)Any AE231(83)121(89)Any AE Grade 316(6)46(34)Any AE leading to death1(1)1(1)Any serious AE8(3)17(13)Any AE leading to discontinuation10(4)12(9)Population:safety analysis set(all patients who received at least one dose of study drug and for whom post-dose data were available)*Patients with multiple events in the same category counted only once in that category.Patients with events in more than one category counted once in each of those categories;#As assessed by the investigator.Includes AEs with an onset date on or after the date of first dose and up to and including 28 days following the date of last dose of study medication;AE,adverse eventAll causality adverse events*in AURA3N(%)15%cut-offOsimertinib(N=279)Platinum-pemetrexed(N=136)Any gradeGrade 3Any gradeGrade 3Any AE273(98)63(23)135(99)64(47)Diarrhoea113(41)3(1)15(11)2(1)Rash#94(34)2(1)8(6)0Dry skin#65(23)06(4)0Paronychia#61(22)02(1)0Decreased appetite50(18)3(1)49(36)4(3)Cough46(16)019(14)0Nausea45(16)2(1)67(49)5(4)Fatigue44(16)3(1)38(28)1(1)Stomatitis41(15)021(15)2(1)Constipation39(14)047(35)0Vomiting31(11)1(1)27(20)3(2)Thrombocytopenia#28(10)1(1)27(20)10(7)Neutropenia#22(8)4(1)31(23)16(12)Leukopenia#22(8)020(15)5(4)Anaemia#21(8)2(1)41(30)16(12)Asthenia20(7)3(1)20(15)6(4)Select adverse eventsInterstitial lung disease#10(4)1(1)1(1)1(1)QT prolongation10(4)1(1)1(1)0Population:safety analysis set(all patients who received at least one dose of study drug and for whom post-dose data were available)*Includes AEs with an onset date on or after the date of first dose and up to and including 28 days following discontinuation of randomised treatment or the day before first administration of cross-over treatment.Some patients had more than one AE.#Grouped term:if a patient has multiple preferred term level events within a specific grouped term AE,then the maximum CTCAE grade across those events is counted.ConclusionsAURA3 is the first randomised,Phase III study of a third-generation EGFR-TKI(osimertinib)vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive NSCLCOsimertinib demonstrated statistically superior clinically-meaningful efficacy over platinum-pemetrexed:PFS HR 0.30(95%CI 0.23,0.41)p0.001Investigator-assessed median PFS:10.1 vs 4.4 months(BICR:11.0 vs 4.2 months)ORR:71%vs 31%,odds ratio 5.39(95%CI 3.47,8.48);p0.001 Osimertinib benefit observed in patients with and without CNS metastases at baselineOsimertinib was associated with lower rates of grade 3 AEs compared with platinum-pemetrexedPlanned overall survival analysis will be reported separatelyOsimertinib is the new standard of care for patients with EGFR T790M-positive NSCLC following disease progression with first-line EGFR-TKI therapyAcknowledgementsThanks to all the patients and their familiesThanks to the staff and investigators at all sitesThis study was sponsored by AstraZeneca,ClinicalTrials.gov identifier:NCT02151981Medical writing support was provided by Natasha Cary,BSc of iMed Comms,an Ashfield company,and funded by AstraZeneca