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FOLFOXIRI/ bevacizumab ( bev ) versus FOLFIRI/ bev

2013 ASCO Annual Meeting Chicago, 31 May – 4 Jun 2013. FOLFOXIRI/ bevacizumab ( bev ) versus FOLFIRI/ bev as first-line treatment in unresectable metastatic colorectal cancer patients : Results of the phase III TRIBE ( TRI plet + BE va ) trial by GONO group.

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FOLFOXIRI/ bevacizumab ( bev ) versus FOLFIRI/ bev

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  1. 2013 ASCO Annual Meeting Chicago, 31 May – 4 Jun 2013 FOLFOXIRI/bevacizumab(bev) versus FOLFIRI/bev asfirst-line treatment in unresectablemetastatic colorectalcancerpatients: Resultsof the phase III TRIBE (TRIplet+BEva) trial by GONO group. A. Falcone, C. Cremolini, G. Masi, S. Lonardi, V. Zagonel, L. Salvatore, P. Trenta, G. Tomasello, M. Ronzoni, L. Ciuffreda, A. Zaniboni, G. Tonini, A.Buonadonna, C. Valsuani, S. Chiara, C. Carlomagno, C. Boni, L. Marcucci, L. Boni, F. Loupakis on behalf of the GONO Investigators

  2. DISCLOSURES • AdvisoryRole, Honoraria, Researchfunding: • Amgen • Merck Serono • Roche

  3. Background • Doublets plus bev are a standard of care in the first-line treatment of mCRC • Hurwitz et al. NEJM ‘04, Saltz et al. JCO ‘08 • FOLFOXIRI tripletdemonstratedsuperior RR, PFS and OS comparedto LV5FU2+CPT11 doublet in apreviousphase III trial by the GONO group • Falcone et al. JCO ‘07 • FOLFOXIRI plus bevachievedpromisingresults (median PFS 13.1 mos, RR 77%), with a safetoxicityprofile in a phaseII study (N=57) • Masi et al. Lancet Oncol ‘11

  4. Objective To confirm the superiority in the 1st- line treatment of unresectablemCRC of FOLFOXIRI tripletcompared to FOLFIRI doublet alsowhenbevacizumabisassociated to chemotherapy

  5. TRIBE Study Design PD FOLFIRI+bev (up to 12 cycles) 5-FU/LV +Bev • 508 mCRCpts • 1st line • unresectable • stratified by • center • PS 0/1-2 • adjuvant CT R 5-FU/LV +Bev FOLFOXIRI+bev (up to 12 cycles) INDUCTION MAINTENANCE

  6. FOLFOXIRI+Bev schedule Experimental ARM : FOLFOXIRI + bev oxaliplatin 85 mg/sqm irinotecan 165 mg/sqm bev 5 mg/Kg 5FU flat continuous infusion 3200 mg/sqm 48h L-LV 200 mg/sqm 2 hours 1 hour 48 hours 30 min Repeatedevery 2 weeks No prophylatic G-CSF recommended

  7. End-points / Statistics • Primary end-point • Progression free survival • to detect a HR for PFS of 0.75 in favour of FOLFOXIRI + bev • witha 2-sided type 1 error= 0.05; • power= 80% • 379 events required (approx. 450-500 patients to be rand.) • Secondary end-points • Response Rate • Secondary R0-resection rate • Overall survival • Safety profile • Biomarkers evaluation

  8. KeyEligibilityCriteria • Histologically proven adenocarcinoma • Unresectable (locally assessed) mCRCnotpre-treated for mets • Measurablediseaseaccording to RECIST 1.0 • Age 18-75 • ECOG PS ≤ 2 (ECOG PS = 0 ifage = 71-75 years) • Adjuvantoxa-containingchemotherapyallowedif more than 12 monthselapsedbetween the end of adjuvant and first relapse • Adequate bone marrow, liver and renalfunctions

  9. Patients’ characteristics – ITT population

  10. Induction treatment duration and management

  11. OverallSafety – Safetypopulation

  12. ToxicityProfile – Safetypopulation

  13. Primaryendpoint: PFS (updated) – ITT population FOLFIRI + bev FOLFOXIRI + bev Medianfollow up: 32.3 mos FOLFIRI + bev: N = 256 / Progressed= 226 FOLFOXIRI + bev: N = 252 / Progressed = 213 FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos Unstratified HR: 0.77 [0.64-0.93] p=0.006 Stratified HR: 0.75 [0.62-0.90] p=0.003 Progression-free survivalprobability F-up time (months)

  14. Subgroupanalyses of PFS (updated) – clinicalcharacteristics FactorN HR p Experimentalbetter Control Better

  15. Molecularcharacteristics – centralizedanalyses • * Patientswhosesampleswerecentrallyanalyzed • KRAScodon 12, 13 and 61 and BRAFcodon 600 mutationswereassessed by pyrosequencing

  16. Subgroupanalyses of PFS – molecularcharacteristics FactorN HR p Experimentalbetter Control Better

  17. Previousevidences of FOLFOXIRI+Bev in BRAF mut Phase II prospective trial of FOLFOXIRI plus bev in BRAFmutantmCRCpatients Median PFS: 9.2 months (95%CI 5.1-13.3) Masi et al. Lancet Oncol‘10 Salvatore et al. ASCO AnnMeet ‘12

  18. Secondaryendpoint: Response rate (updated) - ITT population

  19. Secondaryendpoint: Resection of Metastases

  20. OverallSurvival: estimatedpower for the analysis • Based on the presentnumber of events (deaths= 286), accrualduration (34 mos) and median follow-up (32 mos) • Assuming an expectedmedian OS for FOLFIRI+Bev of 24 mos • With a 2-sided type I error= 0.05 the powerof the analysis to demonstrate a significantreduction in the risk of deathin the range of 20-25% isapproximately35-55%

  21. Secondaryendpoint: OS (preliminary) – ITT population FOLFIRI + bev FOLFOXIRI + bev Medianfollow up: 32.3 mos FOLFIRI + bev: N = 256 / Died = 155 FOLFOXIRI + bev: N = 252 / Died= 131 FOLFIRI + bev, medianOS : 25.8 mos FOLFOXIRI + bev, medianOS : 31.0 mos Unstratified HR: 0.83 [0.66-1.05] p=0.125 Stratified HR: 0.79 [0.63-1.00] p=0.054 Overallsurvivalprobability F-up time (months)

  22. Summary FOLFOXIRI plus bevcompared to FOLFIRI plus bev: • significantlyreduced the risk of progression (HR=0.77, p=0.006) • (with a significantinteraction with the priorexposure to adjuvant CT) • significantlyincreasedresponse rate (65% vs 53%, p=0.006), butnot R0 resection rate (15% vs 12%, p=0.327) in thisunselectedpopulation for conversion(see OLIVIA studyabst. #3619) • significantlyincreasedthe incidence of grade 3-4 neurotoxicity, diarrhea, stomatitis and neutropenia, butnot of febrile neutropenia, seriousAEs and treatment relateddeaths • may reduce the risk of death, but OS data are still immature

  23. Conclusions • The trial achieveditsprimaryobjective of confirmingthe superiority of FOLFOXIRI vs FOLFIRI in terms of PFS, also in combination with bev • FOLFOXIRI moderatelyincreasesspecific side effects, but the overallsafetyprofileremainsacceptable • Based on theseresults FOLFOXIRI plus bevrepresents a new standard option in the treatment of mCRCptsselectedaccording to the eligibilitycriteria of thisstudy(particularinterest in BRAF mut) • Finallytheseresultssupport the hypothesisthat an upfrontintensive approach for fewmonthsassociated with a greatertumorshirinkage(followedby maintenance) mayhave a favourable impact in later PFS, and perhaps OS, also in a palliative settingindependently from an increase in resections

  24. Acknowledgements • PATIENTS • Roche • INVESTIGATORS and THEIR 33 CENTERS all over Italy • ANCONA: CascinuAOSTA: Numico AREZZO: BracardaAVIANO: FrustaciBRESCIA: ZaniboniCALTANISSETTA: Vitello CREMONA: Passalacqua CUNEO: Merlano FIRENZE: Ribecco • GENOVAIST: ChiaraGENOVAGALLIERA: De CensiLECCE: LorussoLEGNAGO: Bonetti • LIVORNO: CappuzzoLUCCA: Baldini MILANONIGUARDA: SienaMILANOHSR: Villa • MIRANO: VinanteMONZA: BidoliNAPOLI: TortoraPARMA: ArdizzoniPADOVA: Zagonel • PISA: Falcone, Ricci PIOMBINO: DargenioPONTEDERA: AllegriniPRATO: Di Leo • REGGIOEMILIA: BoniROMAGEMELLI: BaroneROMAUMBERTOI: Cortesi • ROMA Campus Biomedico: ToniniSONDRIO: Bertolini TORINO: CiuffredaVERSILIA: Amoroso

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