folfoxiri/ bevacizumab ( bev ) versus folfiri/ bev as first-line treatment in unresectable...
DESCRIPTION
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 ( TRI plet + BE va ) trial by GONO group . - PowerPoint PPT PresentationTRANSCRIPT
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