FOLFOXIRI/ bevacizumab ( bev ) versus FOLFIRI/ bev as first-line treatment in unresectable metastatic

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

2013 ASCO Annual MeetingChicago, 31 May – 4 Jun 2013

DISCLOSURES

Advisory Role, Honoraria, Research funding:

AmgenMerck SeronoRoche

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 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

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

TRIBE Study Design

R

508 mCRC pts1st lineunresectablestratified by center PS 0/1-2

adjuvant CT

FOLFIRI+bev(up to 12 cycles)

FOLFOXIRI+bev

(up to 12 cycles)

5-FU/LV +Bev

5-FU/LV +Bev

PD

INDUCTION MAINTENANCE

FOLFOXIRI+Bev 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 + bev

1 hour 2 hours 48 hours30 min

Repeated every 2 weeksNo prophylatic G-CSF recommended

End-points / StatisticsPrimary 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. 450-500 patients to

be rand.)

Secondary end-points

Response Rate Secondary R0-resection rate Overall survival Safety profile Biomarkers evaluation

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 = 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’ characteristics – ITT population

N=508

Characteristic, % patientsFOLFIRI + bev

N = 256FOLFOXIRI + 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 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

Induction treatment duration and management

FOLFIRI + bevN = 254

FOLFOXIRI + bevN = 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%

Overall Safety – Safety population

Patients, %

FOLFIRI + bevN = 254

FOLFOXIRI + bevN = 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%

Toxicity Profile – Safety population

G3/4 adverse events, % patients

FOLFIRI + bevN=254

FOLFOXIRI + bevN=250 p

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

Median follow up: 32.3 mos

FOLFIRI + bev: N = 256 / Progressed = 226FOLFOXIRI + bev: N = 252 / Progressed = 213

FOLFIRI + bev, median PFS : 9.7 mosFOLFOXIRI + 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

Primary endpoint: PFS (updated) – ITT population

FOLFIRI/bev 256 203 94 46 26 14 7 3 0 0

FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1

Prog

ress

ion-

free

sur

viva

l pro

babi

lity

F-up time (months)

FOLFIRI + bevFOLFOXIRI + bev

Factor N HR p

0.5 1 1.5 2

Subgroup analyses of PFS (updated) – clinical characteristics

Experimental better Control Better

Molecular characteristics – centralized analyses

Characteristic, % patients

FOLFIRI + bevN = 201*

FOLFOXIRI + bevN = 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

Subgroup analyses of PFS – molecular characteristics

0.4 0.6 0.8 1

Experimental better Control Better

Factor N HR p

Masi et al. Lancet Oncol ‘10

Previous evidences of FOLFOXIRI+Bev in BRAF mut

Median PFS: 9.2 months(95%CI 5.1-13.3)

Phase II prospective trial of FOLFOXIRI plus bev in BRAF

mutant mCRC patients

Salvatore et al. ASCO Ann Meet ‘12

Secondary endpoint: Response rate (updated) - ITT population

Best Response, %

FOLFIRI + bevN = 256

FOLFOXIRI + bevN = 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% 4%

Secondary endpoint: Resection of Metastases

FOLFIRI + bevArm A N = 256

FOLFOXIRI + bevArm BN = 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

Secondary surgery with radical intent 41% 39% 1.000

R0 secondary surgery 28% 32% 0.823

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%

Secondary endpoint: OS (preliminary) – ITT population

FOLFIRI/bev 256 233 216 172 109 69 36 15 5 0

FOLFOXIRI/bev 252 234 205 175 119 70 35 15 4 0

Ove

rall

surv

ival

pro

babi

lity

F-up time (months)

FOLFIRI + bevFOLFOXIRI + bev

Median follow up: 32.3 mos

FOLFIRI + bev: N = 256 / Died = 155FOLFOXIRI + bev: N = 252 / Died = 131

FOLFIRI + bev, median OS : 25.8 mosFOLFOXIRI + bev, median OS : 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

Summary

FOLFOXIRI plus bev compared to FOLFIRI plus bev:

significantly increased the incidence of grade 3-4 neurotoxicity, diarrhea, stomatitis and neutropenia, but not of febrile neutropenia, serious AEs and treatment related deaths

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)

may reduce the risk of death, but OS data are still immature

Conclusions The trial achieved its primary 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 standard option in the treatment of mCRC pts selected according to the eligibility criteria of this study (particular interest in BRAF mut)

FOLFOXIRI moderately increases specific side effects, but the overall safety profile remains acceptable

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

Acknowledgements

PATIENTS

INVESTIGATORS and THEIR 33 CENTERS all over ItalyANCONA: 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