ASCO_2012_files/Masi GONO BEBYP ESMO 2012

A randomized study evaluating the continuation
of bevacizumab beyond progression in
metastatic colorectal cancer patients who
received bevacizumab as part of first-line
treatment: results of the BEBYP trial by the
Gruppo Oncologico Nord Ovest (GONO).
G. Masi1, F. Loupakis1, L. Salvatore1, L. Fornaro1, C. Cremolini1, M. Schirripa1, E. Fea2, C.
Granetto2, L. Antonuzzo3, E. Giommoni3, G. Allegrini4, S. Cupini5, C. Boni6, M. Banzi6, S.
Chiara7, C. Sonaglio7, C. Valsuani8, A. Bonetti9, L. Boni10, A. Falcone1,11
1) Pisa, Italy; 2) Cuneo, Italy; 3) Firenze, Italy; 4) Pontedera, Italy;
5) Livorno, Italy 6) Reggio Emilia, Italy; 7) Genova, Italy; 8) Lido
di Camaiore, Italy; 9) Legnago, Italy; 10) Istituto Toscano Tumori,
Firenze, Italy; 11) Università di Pisa, Italy.
www.esmo2012.org
Disclosure: Gianluca Masi
• Honoraria: Roche, Merck-Serono, Amgen
• Research Funding: Roche
www.esmo2012.org
Background
• BV plus fluoropyrimidine-based CT is a standard first-line
treatment in mCRC pts.
• Retrospective data from BRITE and ARIES studies suggested
that the continuation of BV with second line CT beyond
progression was associated with improved survival 1,2.
• A recent phase III study (AIO/AMG ML18147)
demonstrated an improved survival with BV beyond
progression 3.
1. Grothey et al. JCO 2008;26:5326-34
2. Cohn et al. JCO 2010;28(15s):Abstr 3596
3. Arnold et al. JCO 2012;30 (suppl; abstr CRA3503)
www.esmo2012.org
Study Design
I-line CT * + BV
Stratification
‐ Center
‐ PS 0/1-2
‐ CT-free interval
(> vs ≤ 3 mos)
‐ II-line CT
*
•
•
•
•
FOLFIRI
FOLFOX
FOLFOXIRI
Fluoropyrimidine mono-tx
R
A
N
D
O
M
A. Second-line CT§
B. Second-line CT§+ BV
§ • FOLFIRI
• mFOLFOX-6
• Study conducted in 19 Italian centers
• Supported by AIFA
www.esmo2012.org
Treatment schedules
FOLFIRI
• IRINOTECAN 180 mg/sqm i.v. over 1 hr on day 1 concomitantly with
• l-LV 200 mg/sqm i.v. over 2 hrs on days 1 followed by
• 5-FU 400 mg/sqm i.v. bolus on days 1 followed by
• 5-FU 2400 mg/sqm i.v. by c.i. over 46 hrs on days 1
cycles repeated every 2 weeks
mFOLFOX-6
• OXALIPLATIN 85 mg/sqm i.v. over 1 hr on day 1 concomitantly with
• l-LV 200 mg/sqm i.v. over 2 hrs on days 1 followed by
• 5-FU 400 mg/sqm i.v. bolus on days 1 followed by
• 5-FU 2400 mg/sqm i.v. by c.i. over 46 hrs on days 1
cycles repeated every 2 weeks
In pts randomized to the BV containing arm the regimens were associated with:
BEVACIZUMAB 5 mg/kg i.v. on day 1 (immediately before irinotecan or oxaliplatin)
repeated every 2 weeks
Objectives
Primary
• Progression Free Survival
Secondary
• Response Rate
• Overall Survival
• Safety
• Potential markers predictive of BV activity
www.esmo2012.org
Statistical Design / Accrual
• Original Hypothesis
• To detect a HR for PFS of 0.70 in favor of CT+BV
• Power=80%; alpha, two-sided=0.05
• Required 249 events and a total of 262 pts
• Accrual started on April 8th 2008 and was stopped
prematurely on May 11th 2012
• Press release of TML study results with OS improvement
• Slow accrual rhythm due to bevacizumab supply limitation
• Randomized 185 pts (184 pts for ITT) (1 pt randomized twice)
Main Eligibility Criteria
• Pts with histologically confirmed colorectal adenoca
• Age >18 yrs and <75 yrs
• ECOG PS 0-2
• Unresectable and measurable metastatic disease
according to RECIST criteria
• Progressive disease after or during first-line CT with
fluoropyrimidine, FOLFIRI, FOLFOX + BV or >3 mos after
the last dose of FOLFOXIRI + BV
www.esmo2012.org
Patients’ characteristics (1)
CT (92 pts)
CT + BV (92 pts)
%
%
66 yrs (38-75)
62 yrs (38-75)
75/25
57/43
82/17/1
82/16/2
24/76
23/77
Liver-only metastases
15
13
KRAS* (wt/mut/NA)
36/31/33
32/40/28
BRAF* (wt/mut/NA)
64/3/33
65/7/28
Characteristics
Age, median (range)
Sex (M/F)
ECOG PS 0/1/2
Sites of disease (single/multiple)
* By central analysis
www.esmo2012.org
Patients’ characteristics (2)
Characteristics
CT (92 pts)
CT + BV (92 pts)
• Fluoropyrimidine
4%
1%
• FOLFIRI
58%
59%
• FOLFOX
25%
24%
• FOLFOXIRI
13%
16%
First-line PFS, median
10.3 mos
10.3 mos
CT-free interval > 3 mos
66%
66%
Beva-free interval > 3 mos
43%
50%
First-line CT
www.esmo2012.org
Second-line CT on the basis of first-line CT
CT (92 pts)
Second-line CT
CT + BV (92 pts)
FOLFOX
FOLFIRI
FOLFOX
FOLFIRI
66%
34%
66%
34%
First-line fluoropyrimidine (N=5)
75%
25%
100%
0%
First-line FOLFIRI (N=107)
98%
2%
98%
2%
First-line FOLFOX (N=45)
0%
100%
5%
95%
First-line FOLFOXIRI (N=27)
50%
50%
47%
53%
All pts (N=184)
www.esmo2012.org
Primary Objective - PFS
CT (85 events) median PFS = 4.97 mos
CT+ B (87 events) median PFS = 6.77 mos
HR=0.65 (95%CI 0.48-0.89)
p=0.0062
Median follow up 18.0 mos
Subgroup Analysis of PFS
*
* Test of interaction
Response Rate
CT (N=92)
CT + BV (N=92)
Complete Response (CR)
2%
0%
Partial Response (PR)
16%
21%
Overall Response Rate (RR)*
18%
21%
Stable Disease (SD)
44%
50%
Disease Control Rate (DCR)**
62%
71%
Progressive Disease
30%
24%
Not Evaluable
8%
5%
* p not statistically significant (0,71)
** p not statistically significant (0,21)
Overall Safety
CT
(92 pts)
CT + BV
(92 pts)
8
9
Any grade AE
93%
94%
Grade 3-4 AEs
43%
44%
Serious AEs
7%
7%
Toxic Deaths
0%
1%*
Median number of cycles
* CNS ischemia
www.esmo2012.org
Maximum Toxicities per patient (CT related)
CT (n=92)
CT + BV (n=92)
Any G
G 3-4
Any G
G 3-4
Vomiting
30 %
2%
30 %
2%
Diarrhea
41 %
5%
49 %
7%
Stomatitis
34 %
0%
38 %
3%
Neutropenia
49 %
27 %
47 %
24 %
3%
Febrile Neutropenia
4%
Thrombocytopenia
36 %
2%
36 %
1%
Neurotoxicity
47 %
5%
45 %
9%
Maximum Toxicities per patient (Beva-related)
CT (n=92)
CT + BV (n=92)
Any G
G 3-4
Any G
G 3-4
Hypertension
3%
1%
25 %
2%
Bleeding
3%
1%
21 %
0%
Venous thrombosis
3%
3%
2%
1%
Arterial thrombosis
0%
0%
1%
1%
GI perforation
0%
0%
0%
0%
Proteinuria
0%
0%
30 %
4%
Ematuria
0%
0%
7%
1%
Subsequent anti-cancer therapies
CT
(92 pts)
CT + BV
(92 pts)
Pts who received ≥ 1 subsequent line
70%
69%
Subsequent BEVA therapy
1%
3%
Subsequent anti-EGFR therapy
46%
32%
www.esmo2012.org
Overall Survival
• OS data are still immature
• After a median follow up of 18 months we
observed 52 events in arm A (CT) and 46
events in arm B (CT+BV)
www.esmo2012.org
Summary
• Bevacizumab beyond progression significantly improved PFS
→ CT vs CT+BV: mPFS 4.97 vs 6.77 months
→ HR=0.65 (95% CI 0.48-0.89), p=0.0062
• Data from subgroup analyses for PFS consistent with overall
population
• No significant differences in RR and DCR
• OS data still immature
• Safety profile consistent with previously reported data
www.esmo2012.org
Conclusions
• Second randomized trial investigating the impact of
BV continuation beyond first progression
• Our results are in line with those of TML
• The prosecution of BV in combination with secondline CT represents a new treatment option
www.esmo2012.org
Acknowledgements
• Patients and their caregivers
• AIFA
• Dr. Luca Boni Centro Coordinamento Sperimentazioni Cliniche, Istituto Toscano Tumori
• Investigators
‐ Pisa (A. Falcone, G. Masi, F. Loupakis, L. Salvatore, C. Cremolini, ‐
M. Schirripa, L. Fornaro)
‐
‐ Cuneo (M. Merlano, C. Granetto, E. Fea)
‐
‐ Livorno (F. Cappuzzo, S. Cupini, C. Barbara)
‐
‐ Firenze (F. Di Costanzo, L. Antonuzzo, E. Giommoni)
‐ Reggio Emilia (C. Boni, M. Banzi, R. Gnoni)
‐
‐ Genova IST (P. Pronzato, S. Chiara, C. Sonaglio)
‐
‐ Versilia (D. Amoroso, C. Valsuani)
‐
‐ Pontedera (G. Allegrini, L. Marcucci, S. Lucchesi)
‐
‐ Legnago (A. Bonetti, F. Greco)
‐
‐ Piombino (F. Dargenio, V. Safina)
Biella (M. Clerico)
Lecce (V. Lorusso, A. Gambino)
Novara (O. Alabiso)
Siena (S. Crispino, S. Biancanelli, A.
Martignetti)
Fabriano (RR Silva, E. Galizia)
Pesaro (V. Catalano)
Caltanissetta (S. Vitello)
Empoli (G. Fiorentini)
Parma (A. Ardizzoni)
www.esmo2012.org