1. FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev
14th World Congress on Gastrointestinal Cancer
San Francisco, CA January
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
Slides based on TRIBE report v1.3 Jan

2. Disclosures
Bayer, Consultant

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 demonstrated superior RR, PFS and OS compared to FOLFIRI in a previous phase III trial by the GONO group
Falcone et al. JCO ‘07
FOLFOXIRI vs FOLFIRI RR: 66 vs 41
PFS 9.8 vs 6.9
OS 22.6 vs 16.7
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

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. FOLFIRI + bev* FOLFOXIRI + bev*
Study Design
FOLFIRI + 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
1st line
unresectable
mCRC pts
stratified by
center
PS 0/1-2
adjuvant CT R
1:1
FOLFOXIRI + bev*
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. Experimental ARM : FOLFOXIRI + bev
Treatment schedule
Experimental ARM : FOLFOXIRI + bev
bev
5 mg/Kg
irinotecan
165 mg/sqm
oxaliplatin
85 mg/sqm
L-LV
200 mg/sqm
5FU flat continuous infusion
3200 mg/sqm 48h
30 min
1 hour
2 hours
48 hours

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

8. (approximately 450-500 patients to be randomized)
Statistical considerations
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%
AVIRI median PFS: 11.1
ARIES median PFS: 10.2
BRiTE median PFS: 10.8
379 events required
(approximately patients to be randomized)

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 18-75
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
Characteristic, % patients
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252
Sex (M / F)
61 / 39
60 / 40
Median Age (range)
60 (29 – 75)
61 (29 – 75)
ECOG PS (0 / 1-2)
89 / 11
90 / 10

11. Baseline disease characteristics – ITT population
Characteristic, % patients
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252
Synchronous Metastases (Y / N)
81 / 19
79 / 21
Prior Adjuvant CT (Y / N)
12 / 88
Primary Tumor Site (right / left / NE)
24 / 70 / 6
35 / 60 / 5
Number Metastatic Sites (1 / >1)
24 / 76
31 / 69
Liver Only Disease (Y / N)
18 / 82
23 / 77
Resected Primary (Y / N)
65 / 35
69 / 31
Kohne score (low / interm / high / NE)
41 / 44 / 11 / 4
43 / 44 / 7 / 6

12. Primary endpoint: PFS – ITT population
FOLFIRI + bev
FOLFOXIRI + bev
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=0.0012
Stratified HR: 0.71 [ ]
p=0.0006
Progression-free survival probability
PD-free rate
at 2 years:
11.4% vs 20.3%
F-up time (months)
FOLFIRI/bev
256
198 93 42 22 10 3
FOLFOXIRI/bev
252
203
125 64 27 15 8 1

13. Subgroup analyses of PFS
0.5 1
1.5 2
Experimental better
Control Better

14. Secondary endpoint: Response rate (ITT population)
Best Response, %
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252 p
Complete Response 3% 4%
Partial Response
50%
61%
Response Rate
53%
65%
0.006
Stable Disease
32%
24%
Progressive Disease 5% 2%
Not Assessed
10% 9%
Vd ppgg del report

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 AEs
19.7%
20.4%
Fatal AEs
3.5%
2.8%
Treatment-related deaths
1.6%
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 3
1.000
Vomiting 4
0.492
Diarrhea 11 19
0.012
Stomatitis 9
0.048
Neutropenia 20 50
<0.001
Febrile neutropenia 6
0.315
Neurotoxicity 5
Hypertension 2
0.157
Venous Thrombosis 7
0.593
Arterial Thrombosis 1
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 NA
75%

19. Summary FOLFOXIRI plus bev compared to FOLFIRI plus bev:
significantly reduced the risk of progression (HR=0.73, p=0.0012) and PFS benefit was consistent among all analyzed subgroups
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

20. Conclusions
The trial achieved its objective of confirming the superiority of FOLFOXIRI vs FOLFIRI in terms of PFS, also in combination with bev
FOLFOXIRI plus bev compared to FOLFIRI plus bev moderately increases specific side effects but the overall safety profile is acceptable
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

21. REGGIO EMILIA: Boni ROMA GEMELLI: Barone ROMA UMBERTO I: Cortesi
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
Roche
Special thanks go to:
Dr. CREMOLINI Chiara, Dr. BONI Luca, Dr. MASI Gianluca