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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).

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

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  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

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