1. 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 (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 Amgen Merck Serono Roche
Advisory Role, Honoraria, Research funding:
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 triplet demonstrated superior RR, PFS and OS compared to LV5FU2+CPT11 doublet in a previous phase III trial by the GONO group
Falcone et al. JCO ‘07
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. TRIBE Study Design R FOLFIRI+bev FOLFOXIRI+bev INDUCTION 5-FU/LV +BevPD
508 mCRC pts
1st line
unresectable
stratified by
center
PS 0/1-2
adjuvant CT
FOLFIRI+bev
(up to 12 cycles)
5-FU/LV +Bev R
FOLFOXIRI+bev
(up to 12 cycles)
5-FU/LV +Bev
INDUCTION
MAINTENANCE

6. Experimental ARM : FOLFOXIRI + bev
FOLFOXIRI+Bev 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
Repeated every 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
with a 2-sided type 1 error= 0.05;
power= 80%
379 events required (approx patients to be rand.)
Secondary end-points
Response Rate
Secondary R0-resection rate
Overall survival
Safety profile
Biomarkers evaluation

8. Key Eligibility Criteria
Histologically proven adenocarcinoma
Unresectable (locally assessed) mCRC not pre-treated for mets
Measurable disease 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

9. Patients’ characteristics – 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
Synchronous Metastases (Y / N)
81 / 19
79 / 21
Prior Adjuvant CT (Y / N)
13 / 87
Primary Tumor Site (right / left / NR)
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

10. Induction 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%

11. 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)
2.3%
3.2%

12. 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

13. Primary endpoint: PFS (updated) – ITT population
FOLFIRI + bev
FOLFOXIRI + bev
Median follow 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 [ ]
p=0.006
Stratified HR: 0.75 [ ]
p=0.003
Progression-free survival probability
F-up time (months)
FOLFIRI/bev
256
203 94 46 26 14 7 3
FOLFOXIRI/bev
252
208
125 74 35 21 11 5 2 1

14. Subgroup analyses of PFS (updated) – clinical characteristics
Factor N HR p
0.5 1
1.5 2
Experimental better
Control Better

15. * Patients whose samples were centrally analyzed
Molecular characteristics – centralized analyses
Characteristic, % patients
FOLFIRI + bev
N = 201*
FOLFOXIRI + bev
N = 205*
KRAS (wt / mut / not evaluable)
49 / 48 / 3
46 / 51 / 3
BRAF (wt / mut / not evaluable)
91 / 6 / 3
89 / 8 / 3
* Patients whose samples were centrally analyzed
KRAS codon 12, 13 and 61 and BRAF codon 600 mutations were assessed by pyrosequencing

16. Subgroup analyses of PFS – molecular characteristics
Factor N HR p
0.4
0.6
0.8 1
Experimental better
Control Better

17. Masi et al. Lancet Oncol ‘10 Salvatore et al. ASCO Ann Meet ‘12
Previous evidences of FOLFOXIRI+Bev in BRAF mut
Phase II prospective trial of FOLFOXIRI plus bev in BRAF mutant mCRC patients
Median PFS: 9.2 months
(95%CI )
Masi et al. Lancet Oncol ‘10
Salvatore et al. ASCO Ann Meet ‘12

18. Secondary endpoint: Response rate (updated) - ITT population
Best Response, %
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252 p
Complete Response 3% 5%
Partial Response
50%
60%
Response Rate
53%
65%
0.006
Stable Disease
32%
25%
Progressive Disease
11% 6%
Not Assessed 4%

19. Secondary endpoint: Resection of Metastases
FOLFIRI + bev
Arm A
N = 256
FOLFOXIRI + bev
Arm B
N = 252 p
Secondary surgery with radical intent
21%
26%
0.210
R0 secondary surgery
12%
15%
0.327
Liver-only subgroup
N = 46
N = 59
41%
39%
1.000
28%
32%
0.823

20. Overall Survival: estimated power for the analysis
Based on the present number of events (deaths= 286), accrual duration (34 mos) and median follow-up (32 mos)
Assuming an expected median OS for FOLFIRI+Bev of 24 mos
With a 2-sided type I error = 0.05
the power of the analysis to demonstrate a significant reduction in the risk of death in the range of 20-25% is approximately 35-55%

21. Secondary endpoint: OS (preliminary) – ITT population
FOLFIRI + bev
FOLFOXIRI + bev
Median follow up: 32.3 mos
FOLFIRI + bev: N = 256 / Died = 155
FOLFOXIRI + bev: N = 252 / Died = 131
FOLFIRI + bev, median OS : 25.8 mos
FOLFOXIRI + bev, median OS : 31.0 mos
Unstratified HR: 0.83 [ ]
p=0.125
Stratified HR: 0.79 [ ]
p=0.054
Overall survival probability
F-up time (months)
FOLFIRI/bev
256
233
216
172
109 69 36 15 5
FOLFOXIRI/bev
252
234
205
175
119 70 35 4

22. Summary FOLFOXIRI plus bev compared to FOLFIRI plus bev:
significantly reduced the risk of progression (HR=0.77, p=0.006)
(with a significant interaction with the prior exposure to adjuvant CT)
significantly increased response rate (65% vs 53%, p=0.006), but not R0 resection rate (15% vs 12%, p=0.327) in this unselected population for conversion (see OLIVIA study abst. #3619)
significantly increased the incidence of grade 3-4 neurotoxicity, diarrhea, stomatitis and neutropenia, but not of febrile neutropenia, serious AEs and treatment related deaths
may reduce the risk of death, but OS data are still immature

23. Conclusions
The trial achieved its primary objective of confirming the superiority of FOLFOXIRI vs FOLFIRI in terms of PFS, also in combination with bev
FOLFOXIRI moderately increases specific side effects, but the overall safety profile remains acceptable
Based on these results FOLFOXIRI plus bev represents a new standard option in the treatment of mCRC pts selected according to the eligibility criteria of this study (particular interest in BRAF mut)
Finally these results support the hypothesis that an upfront intensive approach for few months associated with a greater tumor shirinkage (followed by maintenance) may have a favourable impact in later PFS, and perhaps OS, also in a palliative setting independently from an increase in resections

24. REGGIO EMILIA: Boni ROMA GEMELLI: Barone ROMA UMBERTO I: Cortesi
Acknowledgements
PATIENTS
Roche
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