1 / 27

D i sc l o s u re: S e b a st i a n St i ntz i n g

R a ndo m i z e d c o m p ar i s o n o f F O LF I R I p l u s cet u x i m a b vers u s F O LF I R I p l u s b evac i z u m a b as f ir st - li n e treat m e n t o f KRA S w il d - t y p e m etasta t i c c o l o recta l ca n cer: G er m a n A I O st u d y K RK -0306 ( F I R E -3).

matthias-xylon
Télécharger la présentation

D i sc l o s u re: S e b a st i a n St i ntz i n g

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Randomized comparison ofFOLFIRIpluscetuximab versusFOLFIRIplusbevacizumab asfirst-linetreatmentofKRASwild-typemetastaticcolorectal cancer:German AIO studyKRK-0306(FIRE-3) V.Heinemann,L.FischervonWeikersthal,T.Decker, A.Kiani,U. Vehling-Kaiser, S.AlBatran,T.Heintges, C.Lerchenmüller,C. Kahl,G. Seipelt,F.Kullmann, M. Stauch,W. Scheithauer,J.Hielscher,M. Scholz,S. Müller, B. Schaefer,D.P.Modest,A.Jung,S.Stintzing

  2. Disclosure:SebastianStintzing • Consultant /advisoryboard: Merck Serono,Hoffmann-La Roche,Amgen • Honoraria: Merck Serono,Hoffmann-La Roche,Amgen • Researchfunding: Merck Serono,GermanCancerAid Presentedby:SStintzing

  3. Phase IIIstudy design FOLFIRI + Cetuximab mCRC 1st-linetherapyKRASwild-type N=592 2 C e t u x i m a b : 4 0 0 m g / m i . v . 1 2 0 m i n i n i t i a l d o s e i . v . 6 0 m in q 1 w 2 5 0 m g / m 2 Randomize1:1 FOLFIRI+Bevacizumab Bevacizumab:5mg/kgi.v. 30-90minq2w B e v a c i z u m a b : 5 m g / k g i . v . 3 0 - 9 0 m i n q 2 w • FOLFIRI:5-FU:400mg/m2(i.v.bolus);folinicacid:400mg/m2 • irinotecan:180mg/m2 5-FU:2,400mg/m2(i.v.46h) • Keyinclusioncriteria • Patients ≥18yearswith histologicallyconfirmeddiagnosisofmCRC • ECOGPS 0-2 • prioradjuvantchemotherapy allowed ifcompleted >6 month before inclusion • AmendmentinOctober 2008 to include onlyKRASwildtype patients • 150 active centersin Germany and Austria

  4. Statisticalconsiderations FOLFIRI + Cetuximab mCRC 1st-linetherapyKRASwild-type N=592 2 C e t u x i m a b : 4 0 0 m g / m i . v . 1 2 0 m i n i n i t i a l d o s e i . v . 6 0 m in q 1 w 2 5 0 m g / m 2 Randomize1:1 FOLFIRI+Bevacizumab Bevacizumab:5mg/kgi.v. 30-90minq2w B e v a c i z u m a b : 5 m g / k g i . v . 3 0 - 9 0 m i n q 2 w FOLFIRI:5-FU:400mg/m2(i.v.bolus);folinicacid:400mg/m2 irinotecan:180mg/m2 5-FU:2,400mg/m2(i.v.46h) • Primary objective:Overall response rate (ORR) • Designed to detecta difference of12% in ORR induced byFOLFIRI+ cetuximab (62%)ascompared to FOLFIRI+bevacizumab (50%) • 284 evaluablepatientsperarmneeded to achieve 80% powerforan one-sided Fisher‘s exacttestatan alpha level of2.5%

  5. Endpoints • Primaryendpoint • ORR (mRECIST1.0,investigators‘ read) • Secondaryendpoints • Progression-free survival (PFS) • Overall survival (OS) • Time tofailureofstrategy(time to failure of 1st-line therapy)(TFS) • Deepnessofresponse (percentoftumorshrinkage compared to baseline) • Secondaryresectionsoflivermetastaseswith potentiallycurative intention • Safetyand tolerabilityaccording to NCI-CTCAE criteria • analyseswereperformedintheITTand assessableforresponsepopulation

  6. ConsortDiagram N=752 KRASmutant : 100 KRASunknown: 43 Notreatment: 17 160 N=592 KRASwild-typeITTpopulation N=297 N = 2 9 7 N=295 FOLFIRI +Bevacizumab N = 2 9 5 FOLFIRI + Cetuximab F O L F I R I + F O L F I R I + B e v a c i z u m a b C e t u x i m a b 42 24 Earlydeath: 4 Otherreasons: 20 Earlydeath: 1 Allergicreaction: 13 Otherreasons: 28 N=526 Assessableforresponse* N=255 N = 2 5 5 N=271 FOLFIRI +Bevacizumab N = 2 7 1 FOLFIRI + Cetuximab F O L F I R I + F O L F I R I + B e v a c i z u m a b C e t u x i m a b *predefined perprotocol: 3cycles of chemotherapyandoneCTscanfollowing baseline

  7. Follow-uptime FOLFIRI + CetuximabN=297 FOLFIRI + BevacizumabN=295 P Medianfollow-uptime(months) (95% CI,months) 33.0 39.0 0.540 29.0 – 39.5 31.7 – 41.2 p=two-sidedlog-rank test

  8. PatientDemographics FOLFIRI +CetuximabN=297 FOLFIRI +BevacizumabN=295 Characteristic Sex, male,% Age,median,years 72.1 64.0 66.4 65.0 Age<65,% Age≥65,%Age>70,% ECOG PerformanceStatus,% 0 1 2 Leukocytecount ≥8,000/µl,% AlkalinePhosphatase 53.2 46.8 30.3 54.2 45.8 23.4 51.9 45.8 2.4 53.6 45.1 1.4 43.4 40.0 ≥300U/L,% 13.5 13.2

  9. Tumor related patient characterists FOLFIRI +CetuximabN=297 FOLFIRI +BevacizumabN=295 Characteristic Siteofprimarytumor,% ColonRectum Colon+Rectum Livermetastasisonly,% Yes Numberofmetastatic sites,% 1site ≥2sites Priortreatment,% Surgery AdjuvantchemotherapyRadiotherapy pretreatment 56.6 38.7 3.0 60.0 35.9 4.1 31.3 31.9 40.1 59.9 41.7 58.3 83.8 22.1 13.1 85.4 18.9 13.4

  10. Treatment duration FOLFIRI +CetuximabN=297 Median,months Cycles, n FOLFIRI +BevacizumabN=295 p 4.8 0.0 – 31.3 5.3 0.0 – 33.0 0.112 10 1 – 63 12 1 – 72 0.014 treatment with all3substances;two-sidedWilcoxontest

  11. EvaluationofORR FOLFIRI +Cetuximab FOLFIRI +Bevacizumab Odds ratio p 1.18 0.85-1.64 0.183 Assessableforresponse (N=526) 1.52 1.05-2.19 72.2 63.1 0.017 66.2 – 77.6 57.1 – 68.9 p= Fisher´s exact test (one-sided)

  12. Evaluationofresponse FOLFIRI +CetuximabN=297 FOLFIRI +BevacizumabN=295 RECIST, n (%) Completeresponse 13 (4.4)* 4(1.4)* Partialresponse 171 (57.6) 167 (56.6) Stabledisease 53 (17.5)* 85 (28.8)* Progressivedisease 21 (7.1) 16 (5.4) Notevaluable 39 (13.1) 23 (7.8) *significantdifferencesinresponse; p=two-sidedFisher´exact test

  13. Progression-freesurvival Median (months) 10.0 Events 95%CI n/N(%) 1.0 ―FOLFIRI+Cetuximab 250/297 8.8 – 10.8 (84.2%) ―FOLFIRI+Bevacizumab 242/295 10.3 9.8 – 11.3 0.75 (82.0%) HR1.06(95% CI0.88–1.26) Probabilityofsurvival Log-rankp= 0.547 0.50 0.25 0.0 48 12 60 36 24 72 monthssincestart of treatment 297 numbers 10 6 3 19 15 5 4 100 99 atrisk 295

  14. Overallsurvival Eventsn/N(%) Median (months) 28.7 95%CI 1.0 ―FOLFIRI+Cetuximab 158/297 24.0 – 36.6 (53.2%) 0.75 ―FOLFIRI+Bevacizumab 185/295 25.0 22.7 – 27.6 Probabilityofsurvival (62.7%) HR0.77(95% CI:0.62–0.96) Log-rankp= 0.017 0.50 0.25 0.0 48 12 60 36 24 72 monthssincestart of treatment 297 numbers 9 2 111 111 29 18 218 214 atrisk 295

  15. Subsequentanticancer therapy FOLFIRI +CetuximabN=297 Any2nd-linetherapy,% 2nd-linebevacizumab,% 2nd-lineanti- EGFR,% FOLFIRI +BevacizumabN=295 p 65.7 61.7 0.347 48.2 17.6 42.9 14.4 p=two-sidedFisher´s exacttestp

  16. ExploratorysubgroupanalysisforOS HR(95% CI) 0.73(0.56–0.94) Gender:male 0.88(0.61–1.29) female 0.75(0.56–1.01) Age: ≤65 0.80(0.58–1.09) > 65 0.88(0.67–1.16) Localization: colon 0.62(0.43– 0.89) rectum 1 Numberofmetastatic sites: 0.78(0.56–1.09) >1 0.77(0.58–1.02) Liverlimiteddisease: no 0.79(0.61–1.02) yes 0.74(0.50–1.10) Synchronousmets: yes 0.75(0.59–0.97) no 0.83(0.54–1.25) < 8/nl Leukocytes: 0.68(0.51–0.90) ≥8/nl 0.92(0.66–1.28) 0.1 FOLFIRI+cetuximab 1 10 FOLFIRI+bevacizumab favors:

  17. Hematologicaltoxicity FOLFIRI +CetuximabN=297 FOLFIRI +BevacizumabN=295 p p= Fisher´s exact test

  18. Non-hematologicaltoxicity FOLFIRI + Cetuximab N= 297 FOLFIRI + Bevacizumab N= 295 p grade≥3 0.066 0.414 0.473 0.458 0.835 0.449 0.401 0.037 0.030 significant differences inanygradetoxicity: *p=0.0005; **p= 0.03, ***p=0.0002, p= Fisher´s exacttest p

  19. Non-hematologicaltoxicity FOLFIRI + Cetuximab N= 297 FOLFIRI + Bevacizumab N= 295 p grade≥3 0.066 0.414 0.473 0.458 0.835 0.449 0.401 0.037 0.030 significant differences inanygradetoxicity: *p=0.0005; **p= 0.03, ***p=0.0002, p= Fisher´s exacttest p

  20. Non-hematologicaltoxicity FOLFIRI + Cetuximab N= 297 FOLFIRI + Bevacizumab N= 295 p grade≥3 0.066 0.414 0.473 0.458 0.835 0.449 0.401 0.037 0.030 significant differences inanygradetoxicity: *p=0.0005; **p= 0.03, ***p=0.0002, p= Fisher´s exacttest p

  21. Adverseevents ofspecial interesttocetuximab FOLFIRI +CetuximabN=297 anygradegrade≥3 FOLFIRI +BevacizumabN=295 anygradegrade≥3 pgrade≥3 Toxicity,% significant differences inanygradetoxicity: *p<0.0001**p=0.0003, p= Fisher´s exact test p

  22. Adverseevents ofspecial interesttobevacizumab FOLFIRI + Cetuximab N= 297 anygrade grade≥3 FOLFIRI + Bevacizumab N= 295 anygrade grade≥3 p grade≥3 Toxicity,% significant differences inanygradetoxicity: *p<0.001; **p=0.046, #p=0.006, p= Fisher´s exact test p

  23. Adverseevents ofspecial interesttobevacizumab FOLFIRI + Cetuximab N= 297 anygrade grade≥3 FOLFIRI + Bevacizumab N= 295 anygrade grade≥3 p grade≥3 Toxicity,% significant differences inanygradetoxicity: *p<0.001; **p=0.046, #p=0.006, p= Fisher´s exact test p

  24. EfficacySummary • ORRfavoredFOLFIRI pluscetuximab(62%vs58%, p= 0.183), but didnot reachthelevelof significancewithintheITT population • ORRwassignificantlyhigherinpatientsreceivingFOLFIRI pluscetuximab(72.2%vs63.1%, p= 0.017)inpatientsassessableforresponse • NodifferenceinPFS betweenbotharmscouldbeobserved (HR1.06,p= 0.547) • OS wassignificantlylonger(HR0.77, p= 0.017)inpatientstreatedwithFOLFIRI pluscetuximabcomparedtoFOLFIRI plus bevacizumab

  25. Deepnessofresponsecorrelateswithpost-progression survival • Data fromthe CRYSTALtrialindicate thattumorsize reduction ismore predictive forOS than PFS • Mansmannetal, • ASCO 2013 abstract#3630 Cetuximab +FOLFIRI (n=315) FOLFIRI (n=348) p Median DpR (95%CI) Median OS (95%CI) 50.9 (18.4- 78.6) 33.3 (8.0- 58.0) p<0.0001 23.5 (21.2- 26.3) 20.0 (17.4- 21.7) p<0.0093 adoptedfromMansmannetal,ASCOGI2013abstract#427 • Central,independentreview ofFIRE-3CTscans isongoingtoanalyze tumor volumechanges (secondaryendpointofFIRE-3study)

  26. Conclusions • FIRE-3isthefirsthead-to-head comparison of FOLFIRI plus cetuximabversusFOLFIRI plusbevacizumabinKRAS wild-typemCRCpatients • First-linetreatmentwithFOLFIRI pluscetuximabresultedinaclinicallymeaningful differenceinmedian OSof3.7months(HR0.77)whencomparedtoFOLFIRI plusbevacizumab • Toxicityprofileswereasexpected and manageableforboth combinations

  27. Acknowledgement Patientsandtheirfamilies FIRE-3studyinvestigators Germany:FischervonWeikersthal, Decker,Jäger, Al-Batran, Vehling-Kaiser,Heintges, Kiani, Lerchenmüller,Kahl,Kullmann, Seipelt, Stauch, Müller(Ansbach), Hielscher, Scholz,Niederle, Schäfer,Lindig,Möhler, Höffkes,Rost,Reeb, Geißler, Denzlinger,Kubin,Maschmeyer,Burckhard, Knorrenschild, Ketzler,Schmits, Siebler, Schepp,Schneider,Harich, Bohle, Mergenthaler, Eggers, Puchtler, Uhlig, Römmele,Schmidt(München),Raßmann, Engel,Zimber,Link, Gehbauer,Lerch, Hebart,Königsmann, Kiehl, Kempf,Wolff, Fleck,Meiler, Schwittay,Herrmann, Schlimock, Spes, Bair,Pihusch, Stötzer/Salat,Lambertz,Müller(Osnabrück), Schwella,Michl, Breunig, Schlag, Behringer, Demandt, Gassmann,Schneider-Kappus,Quitzsch,Weiß,Siveke, Respondek,Sölling, Prügl, Haberl, Schulze, Feder,Schmidt(Bochum), Peuser,Schulz-Abelius,Walther, Fauth, Dürk, Hagen,Truckenbrodt,Constantin, Slawik,Hitz,vonWichert,Koch, Abele,Horndasch,Schanz, Hoffmann(Ludwigshafen), Holtmann,Hoffmann(Weimar),Fries,Erhardt,Luhn, Pfeiffer,Porschen, Rummel,Perker,Mittermüller, Matzdorff,Kappauf, Greif, Pohl,Post,Pistorius, Buschmann, Holtkamp, Zöller,Hartnack,Kreibich,Winkelmann,Jakobs,Müller(Leer), Cordes,Weber, Fischinger,vonSchilling,Losem, Kindler, Hegewisch-Becker, Abendhardt Austria:Scheithauer, Samonig,Dittrich,Ziebermayr, Andel,Thaler,Ludwig,Ulrich-Pur

More Related