Download Sarcoma.Ray-Coquard.10032

Risk of relapse with imatinib (IM) at 5
years in advanced GIST patients:
Results of the prospective BFR14
randomized phase III study comparing
interruption versus continuation of IM at 5
years of treatment:
A French Sarcoma Group study.
I. Ray-Coquard, N. Bin Bui, A. Adenis, M. Rios,
F. Bertucci, S. Chabaud, D. Pérol,
J. Y. Blay, A. Le Cesne
for the French Sarcoma Group
STUDY DESIGN
RC
RP
SD
Advanced/
metastatic
GIST
R
A
N
D
O
M
I
S
A
T
I
O
N
STOP
PD
GLIVEC
400 mg
Surgery possible if resectable
1 yr,
3 yrs,
5 yrs
Follow-up
GLIVEC
400 mg
Objectives
Main endpoint
Progression-free survival (PFS)
Secondary endpoints
Overall survival (OS)
Response to imatinib re-start in the STOP arm
Time to secondary resistance (TSR) in both arms
Summary of study steps
• 1 year randomization
From May 03 to March 04, 58 patients were randomized (32 in the STOP
group).
STOP group: 1-year PFS: 31% [CI95% , 16-47]
CONT group: 1-year PFS: 85% [CI95%, 64-94]
•
3 years randomization
From June 05 to May 07, 50 patients were randomized (25 in the STOP
group).
STOP group : 1-years PFS : 32% [CI95% ; 15-50]
CONT group : 1-years PFS : 92% [CI95% ; 72-98]
•
May 2007: amendment to address similar question
after 5 years of imatinib treatment.
5 years randomization,
statistical methods
Since, Nov 07, 24 patients have been randomized (13 in the STOP group).
Statistical consideration: in order to stop the study earlier ASAP in case
of excess of relapses in the Stop arm :
a Bayesian approach (study endpoint every 3 months)
Bayesian Principle:
Progression rate considered as a random parameter.
Distribution updated at each analysis conditionally to previous data
Probability of progression rate > in the STOP arm vs. CONT arm is
estimated.
If Prob (STOP > CONT) > 0.95 : progression rate in STOP
group is considered as statistically higher than in the CONT group.
Adamina, M., G. Tomlinson, and U. Guller. "Bayesian statistics in oncology: a
guide for the clinical investigator"; Cancer 115.23 (2009): 5371-81.
Berry, D. A. "Bayesian clinical trials"; Nat.Rev.Drug Discov. 5.1 (2006): 27-36.
Results (1)
434 GIST patients included between
May 2005 and December 2009
191 patients with
follow-up < 5 year
243 patients included
since more than 5
years
(before May 2005)
219 patients non
randomized
24 patients randomized
Stop Imatinib:
13 patients I arm
Continuous Imatinib:
11 patients C arm
Randomization not done,
Randomization STOP at 1 year, n=32
Randomization STOP at 3 years, n=25
Death before 5 years, n=78
Progression before 5 years, n=48
Other, n=36
Results (2)
•Density probability
function
•Date
6
•Feb 2009:
Probability density Function
•STOP group: 1 prog / 6
•CONT group: 0 prog / 4
5
STOP (1 prog / 6)
4
CONT (0 prog / 4)
3
2
1
•Prob (STOP > CONT): p = 0.641
0
•Aug 2009:
10
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0.7
0.8
0.9
1
0.7
0.8
0.9
1
9
Probability density Function
•STOP group: 3 prog / 10
•CONT group: 0 prog / 8
0
•Prob (STOP > CONT): p = 0.887
8
STOP (3 prog / 10)
7
CONT (0 prog / 8)
6
5
4
3
2
1
0
0
12
•STOP group: 7 prog / 11
•CONT group: 0 prog / 10
10
Probability density Function
•May 2010:
0.1
0.2
0.3
0.4
0.5
0.6
STOP (5 prog / 11)
8
CONT (0 prog / 10)
6
4
2
•Prob (STOP > CONT): p =
0.987
0
0
0.1
0.2
0.3
0.4
0.5
0.6
Results (3)
Median follow-up : 11.9 months
1.0
CONT group
0 evt / 12 patients
0.9
Survival probability
0.8
0.7
0.6
0.5
0.4
STOP group
7 evts / 13 patients
median PFS : 12.6 months
(CI95% = 8.6;21.6)
0.3
0.2
0.1
0.0
0
6
12
18
24
Months
STOP group : median PFS : 12.6 months
CONT group : median not reached
Log-rank test: p value = 0.0317
(CI95% = 8.6;21.8)
Conclusions
1.
Imatinib stop at 5 yrs resulted in a higher rate of progression than imatinib
maintenance in patients with advanced GIST in response or stabilized
with imatinib.
2.
Imatinib has to be given continuously until PD or intolerance in the
population of non progressing advanced or metastatic GIST.