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FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev as 1st-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial.

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Presentation on theme: "FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev as 1st-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial."— Presentation transcript:

1 FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev as 1st-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev as 1st-line treatment of metastatic colorectal cancer: results of the phase III randomized TRIBE trial Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Trenta P, Tomasello G, Ronzoni M, Ciuffreda L, Zaniboni A, Tonini G, Buonadonna A, Valsuani C, Chiara S, Carlomagno C, Boni C, Marcucci L, Boni L, Falcone A on behalf of the GONO Investigators 14 th World Congress on Gastrointestinal Cancer San Francisco, CA January

2 Disclosures Bayer, Consultant

3 Background FOLFOXIRI plus bev achieved promising results (median PFS 13.1 mos, RR 77%), with a safe toxicity profile in a phase II study (N=57) Masi et al. Lancet Oncol ‘11 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 demonstrated superior RR, PFS and OS compared to FOLFIRI in a previous phase III trial by the GONO group Falcone et al. JCO ‘07

4 Objective To confirm the superiority in the 1st- line treatment of unresectable mCRC of FOLFOXIRI triplet compared to FOLFIRI doublet also when bevacizumab is associated to chemotherapy

5 Study Design R 1:1 1st line unresectable mCRC pts stratified by center PS 0/1-2 adjuvant CT FOLFIRI + bev* FOLFOXIRI + bev* Bev 5 mg/kg ev g1 Irinotecan 180 mg/sqm ev g1 L-LED 200 mg/sqm ev g1 5-FU 400 mg/sqm ev g1 bolus 5-FU 2400 mg/sqm ev gg1  3 Bev 5 mg/kg ev g1 Irinotecan 165 mg/sqm ev g1 Oxaliplatin 85 mg/sqm ev g1 L-LED 200 mg/sqm ev g1 5-FU 3200 mg/sqm ev gg1  3 *both repeated every 2 wks for a max of 12 cycles followed by maintenance with 5FU/bev until PD

6 Treatment schedule 5FU flat continuous infusion 3200 mg/sqm 48h L-LV 200 mg/sqm oxaliplatin 85 mg/sqm irinotecan 165 mg/sqm bev 5 mg/Kg Experimental ARM : FOLFOXIRI + bev 1 hour 2 hours 48 hours 30 min

7 Endpoints Primary end-point Progression free survival Secondary end-points Response Rate Secondary R0-resection rate Overall survival Safety profile Biomarkers evaluation

8 Statistical considerations 379 events required ( approximately patients to be randomized ) Assuming a median PFS for FOLFIRI plus bev of 11 months (Kozloff et al. JCO ’09, Sobrero et al. Oncology ‘09) to detect a HR for PFS of 0.75 in favour of FOLFOXIRI plus bev with a 2-sided type 1 error: 0.05; power: 80%

9 Key Eligibility Criteria  Histologically proven adenocarcinoma  Unresectable mCRC not previously treated for metastatic disease  At least one measurable lesion according to RECIST 1.0  Age  ECOG PS ≤ 2 (ECOG PS = 0 if age = years)  Adjuvant oxa-containing chemotherapy allowed if more than 12 months elapsed between the end of adjuvant and first relapse  Adequate bone marrow, liver and renal functions

10 Patients’ demographics – ITT population N=508 Characteristic, % patients FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Sex (M / F) 61 / 3960 / 40 Median Age (range) 60 (29 – 75)61 (29 – 75) ECOG PS (0 / 1-2) 89 / 1190 / 10

11 Baseline disease characteristics – ITT population Characteristic, % patients FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Synchronous Metastases (Y / N) 81 / 1979 / 21 Prior Adjuvant CT (Y / N) 12 / 88 Primary Tumor Site (right / left / NE) 24 / 70 / 635 / 60 / 5 Number Metastatic Sites (1 / >1) 24 / 7631 / 69 Liver Only Disease (Y / N) 18 / 8223 / 77 R esected Primary (Y / N) 65 / 3569 / 31 Kohne score (low / interm / high / NE) 41 / 44 / 11 / 443 / 44 / 7 / 6

12 Median follow up: 26.6 mos FOLFIRI + bev: N = 256 / Progressed = 225 FOLFOXIRI + bev: N = 252 / Progressed = 199 FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.2 mos Unstratified HR: 0.73 [ ] p= Stratified HR: 0.71 [ ] p= Primary endpoint: PFS – ITT population FOLFIRI/bev FOLFOXIRI/bev Progression -free survival probability F-up time (months) FOLFIRI + bev FOLFOXIRI + bev PD-free rate at 2 years: 11.4% vs 20.3%

13 Subgroup analyses of PFS Experimental betterControl Better

14 Secondary endpoint: Response rate (ITT population) Best Response, % FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 p Complete Response3%4% Partial Response50%61% Response Rate53%65%0.006 Stable Disease32%24% Progressive Disease5%2% Not Assessed10%9%

15 Target lesions shrinkage: waterfall plots FOLFIRI + BEV FOLFOXIRI + BEV

16 Overall Safety – Safety population Patients, % FOLFIRI + bev N = 254 FOLFOXIRI + bev N = 250 Serious AEs19.7%20.4% Fatal AEs3.5%2.8% Treatment-related deaths1.6%2.4% Early deaths (within 60 days from random) 2.7%3.6%

17 Toxicity Profile – Safety population G3/4 adverse events, % patients FOLFIRI + bev N=254 FOLFOXIRI + bev N=250 p Nausea Vomiting Diarrhea Stomatitis Neutropenia 2050<0.001 Febrile neutropenia Neurotoxicity 05<0.001 Hypertension Venous Thrombosis Arterial Thrombosis Bleeding

18 Treatment duration and management FOLFIRI + bev N = 254 FOLFOXIRI + bev N = 250 Induction CT cycles, median (range) 12 (1-25)11 (1-21) Delayed cycles 6%16% Cycles with dose reduction 8%21% 5-FU relative dose intensity 83%73% Irinotecan relative dose intensity 84%74% Oxaliplatin relative dose intensity NA75%

19 Summary FOLFOXIRI plus bev compared to FOLFIRI plus bev: significantly increased response rate (65% vs 53%, p=0.005) increased the incidence of grade 3-4 diarrhea, stomatitis and neutropenia, but not of febrile neutropenia, serious adverse events and treatment related deaths significantly reduced the risk of progression (HR=0.73, p=0.0012) and PFS benefit was consistent among all analyzed subgroups

20 Conclusions The trial achieved its objective of confirming the superiority of FOLFOXIRI vs FOLFIRI in terms of PFS, also in combination with bev Based on these results FOLFOXIRI plus bev represents a new option for the treatment of mCRC patients selected according to the eligibility criteria of this study Secondary resections, post-progression treatments and overall survival analyses are ongoing (follow-up still immature) Translational biomarker analyses are ongoing FOLFOXIRI plus bev compared to FOLFIRI plus bev moderately increases specific side effects but the overall safety profile is acceptable

21 Acknowledgements PATIENTS INVESTIGATORS and THEIR 33 CENTERS all over Italy ANCONA: Cascinu AOSTA: Numico AREZZO: Bracarda AVIANO: Frustaci BRESCIA: Zaniboni CALTANISSETTA: Vitello CREMONA: Passalacqua CUNEO: Merlano FIRENZE: Ribecco GENOVA IST: Chiara GENOVA GALLIERA: De Censi LECCE: Lorusso LEGNAGO: Bonetti LIVORNO: Cappuzzo LUCCA: Baldini MILANO NIGUARDA: Siena MILANO HSR: Villa MIRANO: Vinante MONZA: Bidoli NAPOLI: Tortora PARMA: Ardizzoni PADOVA: Zagonel PISA: Falcone, Ricci PIOMBINO: Dargenio PONTEDERA: Allegrini PRATO: Di Leo REGGIO EMILIA: Boni ROMA GEMELLI: Barone ROMA UMBERTO I: Cortesi ROMA Campus Biomedico: Tonini SONDRIO: Bertolini TORINO: Ciuffreda VERSILIA: Amoroso Special thanks go to: Dr. CREMOLINI Chiara, Dr. BONI Luca, Dr. MASI Gianluca Roche


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