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

14th World Congress on Gastrointestinal Cancer

San Francisco, CA January 24-26 2013

Disclosures

Bayer, Consultant

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

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

Study Design

R1:1

1st lineunresectable

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 gg13

• 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 gg13*both repeated every 2 wks for a max of 12 cycles followed by maintenance with 5FU/bev until PD

Treatment schedule

5FU flat continuous infusion3200 mg/sqm 48h

L-LV 200 mg/sqm

oxaliplatin 85 mg/sqm

irinotecan165 mg/sqm

bev5 mg/Kg

Experimental ARM : FOLFOXIRI + bevExperimental ARM : FOLFOXIRI + bev

1 hour 2 hours 48 hours30 min

Endpoints

Primary end-point

Progression free survival

Secondary end-points

• Response Rate

• Secondary R0-resection rate

• Overall survival

• Safety profile

• Biomarkers evaluation

Statistical considerations

379 events required

(approximately 450-500 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%

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 = 71-75 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

Patients’ demographics – ITT population

N=508

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

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 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

Median follow up: 26.6 mos

FOLFIRI + bev: N = 256 / Progressed = 225FOLFOXIRI + bev: N = 252 / Progressed = 199

FOLFIRI + bev, median PFS : 9.7 mosFOLFOXIRI + bev, median PFS : 12.2 mos

Unstratified HR: 0.73 [0.60-0.88]p=0.0012

Stratified HR: 0.71 [0.59-0.86] p=0.0006

Primary endpoint: PFS – ITT population

FOLFIRI/bev 256 198 93 42 22 10 3 0 0 0

FOLFOXIRI/bev 252 203 125 64 27 15 8 3 1 0

Pro

gre

ssio

n-f

ree

surv

ival

pro

bab

ility

F-up time (months)

FOLFIRI + bev

FOLFOXIRI + bev

PD-free rateat 2 years: 11.4% vs

20.3%

Subgroup analyses of PFS

0.5 1 1.5 2

Experimental better Control Better

Secondary endpoint: Response rate (ITT population)

Best Response, %

FOLFIRI + bev

N = 256

FOLFOXIRI + bev

N = 252p

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%

Target lesions shrinkage: waterfall plots

FOLFIRI + BEV

FOLFOXIRI + BEV

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%

Toxicity Profile – Safety population

G3/4 adverse events,

% patients

FOLFIRI + bev

N=254

FOLFOXIRI + bev

N=250p

Nausea 3 3 1.000

Vomiting 3 4 0.492

Diarrhea 11 19 0.012

Stomatitis 4 9 0.048

Neutropenia 20 50 <0.001

Febrile neutropenia 6 9 0.315

Neurotoxicity 0 5 <0.001

Hypertension 2 5 0.157

Venous Thrombosis 6 7 0.593

Arterial Thrombosis 2 1 1.000

Bleeding 1 1 1.000

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%

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

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

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