Transcript Document

LONG-TERM ANALYSIS OF A PHASE III RANDOMIZED,
INTERGROUP, INTERNATIONAL TRIAL
ASSESSING THE CLINICAL ACTIVITY OF IMATINIB
AT TWO DOSE LEVELS
IN PATIENTS WITH UNRESECTABLE OR METASTATIC
GASTROINTESTINAL STROMAL TUMORS (GIST)
Paolo G. Casali, John Zalcberg, Jaap Verweij, Axel Le Cesne,
Peter Reichardt, Jean-Yves Blay, Lars Lindner, Ian R. Judson,
Elena Fumagalli, Pancras Hogendoorn, Agnes Natukunda,
Sandrine Marreaud, Saskia Litière, Winette T.A. Van Der Graaf
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Speaker’s
potential conflicts of interest
Empl
Amgen Dompé
ARIAD
Bayer
Glaxo SK
ImClone
Infinity
Janssen Cilag
Lilly
Merck SD
Molmed
Novartis
Pfizer
PharmaMar
Sanofi Aventis
Schering Plough
Cons
Stocks
Honor
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Other
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Res
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Study design
February 2001 /
February 2002
946 eligible pts:

GIST (CD117+)

metastatic and/or unresectable

WHO PS = 0-3

previous chemo accepted
imatinib 400 mg /d
R
progression
imatinib 800 mg /d
End points
 PFS
primary
 OS
 OR
 TOX
secondary
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5
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Long-term update
946 randomized
473: 400mg/day
1 did not start treatment
9 ineligible
473: 800mg/day
1 did not start treatment
9 ineligible
379 progressed
360 died
82 still alive
31 lost to follow up
358 progressed
339 died
95 still alive
39 lost to follow up
Database lock on May 27, 2013
• Median follow-up: 10.9 years (IQR: 8.1 - 11.3)
• Maximum follow up: 11.8 years
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Objective response
Treatment
A-400mg
(N=473)
N (%)
B-800mg
(N=473)
N (%)
Total
(N=946)
N (%)
33 (7.0)
32 (6.8)
65 (6.9)
PR
208 (44.0)
239 (50.5)
447 (47.3)
SD
160 (33.8)
138 (29.2)
298 (31.5)
PD
49 (10.4)
40 (8.5)
89 (9.4)
Early death
7 (1.4)
11 (2.3)
18 (1.9)
Un-evaluable
16 (3.4)
13 (2.7)
29 (3.1)
Best overall response
CR
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Progression-free survival
100
HR 0.91 (95%CL 0.80, 1.05 )
90
80
70
Overall Logrank test: p=0.202
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Median PFS:
- 400mg 1.7 years (95% CI 1.5, 2.0)
- 800mg 2.0 years (95% CI 1.9, 2.3)
50
40
30
20
10
0
0
O N
417 473
405 473
2
4
6
Number of patients at risk :
206
111
67
230
110
67
8
42
42
10
(years)
12
30
29
Treatment
A-400mg
B-800mg
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Overall survival
100
90
HR 0.93(95% CL 0.80, 1.07)
80
70
Overall Logrank test: p=0.312
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Median OS:
400mg 3.9 years (95% CI 3.3, 4.4)
800mg 3.9 years (95% CI 3.4, 4.9
50
40
30
20
10
0
0
O N
360 473
339 473
2
4
6
Number of patients at risk :
312
213
146
326
212
146
8
93
96
10
(years)
12
61
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Treatment
A-400mg
B-800mg
10
11
10-y survivors (120 pts)
946 randomized patients
473 at
400mg/day
61(12.9%) were 10-y survivors
62 censored prior to 10 years
350 dead before 10 years
473 at
800mg/day
59 (12.5%) were 10-y survivors
82 censored prior to 10 years
332 dead before 10 years
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10-y progression-free survivors (59 pts)
946 randomized patients
473 at
400mg/day
30 (6.3%) were 10-y prog-free
26 censored prior to 10 years
415 progressed before 10 years
473 at
800mg/day
29 (6.1%) were 10-y prog-free
41 censored prior to 10 years
403 progressed before 10 years
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Surgery of residual disease
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Surgery of residual disease
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Dose intensity
400 mg
800 mg
100%
100%
90%
90%
80%
80%
70%
800
70%
800
60%
600
60%
600
50%
500
50%
500
40%
400
40%
400
30%
300
30%
300
200
20%
200
20%
10%
100
0%
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months)
10%
100
0%
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45
Time (Months)
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10-y survivors
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10-y progression-free survivors
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Prognostic factor analysis
 Univariate and multivariate analyses were done using:
 Cox regression for PFS and OS
 Logistic regression for RR
 For prognostic factor analysis a full model was built and
reduced using backward selection method at a 5% significance
level
 Factors included in the full model were:










age
PS
sex
time delay between diagnosis and registration
prior surgery
prior chemotherapy
prior radiotherapy
primary site of disease
KIT mutation
initial tumor load and diameter of longest lesion
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Multivariate model
Factor
Age
40-50 vs. <40 yrs.
50-60 vs. <40 yrs.
60-70 vs. <40 yrs.
>70 vs. <40 yrs.
Prior chemotherapy
yes vs. no
HR
Reduced model after
selection
95% CI HR
backward
p-value
1.48
1.27
1.44
2.66
1.04
0.92
1.04
1.70
2.09
1.77
1.99
4.16
<.001
1.30
1.07
1.60
0.007
Objective response
Reduced model
Factor
Diameter of longest lesion
Initial tumor load
KIT mutation
Exon 9 vs. exon11
Wild type vs. exon 11
Other vs. exon 11
OR
0.81
1.08
0.29
0.38
0.40
95% Confidence
Limits
0.78
0.84
1.06
1.09
0.15
0.26
0.15
0.57
0.53
1.09
P value
<0.0001
<0.0001
<0.0001
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Progression-free survival
Covariates
Reduced model
Hazard Ratio (95% CI)
P-Value
1.08(1.06,1.09)
<.0001
Diameter of longest lesion
Per 10mm increase
Initial tumor load
Per 10mm increase
0.99(0.98,0.99)
0.0005
Prior chemo
yes vs. No
1.19(1.02,1.39)
0.028 (df=1)
Performance status
1 vs. 0
1.12(0.96, 1.31)
0.048(df=3)
2 vs. 0
1.29(1.00, 1.67)
3 vs. 0
1.54(1.05, 2.26)
Kit mutation
exon 9 vs. exon11
1.45 (1.06, 1.99)
Wild type vs. exon 11
1.08(0.91, 1.27)
Other vs. exon 11
2.63(1.65, 4.19)
<.0001(df=3)
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Overall survival
Reduced model
Covariates
Age
Performance status
Gender
Prior chemotherapy
Hazard Ration(95% CI)
P-Value
40-50 vs. <40 yrs.
1.18(0.82,1.70) <.0001 (df=4)
50-60 vs. <40 yrs.
1.41(0.99, 2.01)
60-70 vs. <40 yrs.
1.26 (0.89, 1.78)
>70 vs. <40 yrs.
1.97 (1.38, 2.83)
1 vs. 0
1.48(1.25, 1.76)
2 vs. 0
1.68 (1.28, 2.20)
3 vs. 0
2.27 (1.52, 3.39)
female vs. male
0.83 (0.71, 0.97)
0.023 (df=1)
yes vs. No
1.31 (1.10, 1.55)
0.002 (df=1)
1.05(1.04, 1.06)
<.0001
1.46 (1.04, 2.06)
1.18(0.98, 1.41)
2.61 (1.62, 4.22)
0.0002 (df=3)
Diameter of largest lesion Per 10mm increase
Exon 9 vs. exon11
Kit mutation
Wild type vs. exon 11
Other vs. exon 11
<.0001 (df=3)
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Conclusions
 A large trial in a rare cancer, carried out on a wide inter-group
basis at the beginning of the imatinib learning curve
 At a median FU of 10 yrs, less than 10% and 15% of pts,
respectively, were long-term progression-free and overall
survivors
 No difference between 400 and 800 mg /d, though the
subgroup of exon 9 mutated pts was already shown
separately to benefit from the higher dose
 Mutational status and initial tumor burden were prognostic
factors also on a long follow-up
 An even longer follow-up and «high-resolution» assessments
needed to characterize long-term progression-free survivors
either as a specific subset biologically, or just the expression
of stochastic processes leading to secondary resistance
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Participating institutions
Institution
Country
Institution
Country
Fondazione IRCCS Istituto Nazionale dei Tumori
IT
Centre Oscar Lambret
FR
Institut. Gustave Roussy
FR
Herlev Hospital University Copenhagen
DN
Charite Universitaetmedizin Berlin - Buch
DE
Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Napoli
IT
Centre Leon Berard
FR
National Cancer Center
SG
Ludwig Maximilians Universitaet Muenchen Klinikum Grosshadern
DE
Sir Charles Gairdner Hospital
AU
Royal Marsden Hospital
UK
Western Infirmary Glasgow
UK
Universitair.Ziekenhuis. Gasthuisberg
BE
CH
Ospedale Gradenigo Torino
IT
Centre Hospitalier Universitaire Vaudois
FR
St George Hospital.
AU
Institut Bergonie
Medizinische.Hochschule.Hannover
DE
University Medical Center Groningen
NL
Hospital De La Santa Creu
ES
Wesley Clinic
AU
Ashford Cancer Center
AU
Weston Park Hospital Sheffield
UK
Instituto Europeo Di Oncologia Milano
IT
Royal Prince Alfred Hospital.
AU
Universitair.Ziekenhuis.Rotterdam
NL
Royal Brisbane Hospital.
AU
Netherlands Cancer Institute – Antoni Van Leeuwenhoekziekenhuis Amsterdam
NL
University Medical Center Leiden
NL
Aarhus University.Hospital.
DK
Maria Sklodowska Curie Memorial Cancer Centre Warsaw
PL
Bankstown-Lidcombe Hospital
AU
Fondazione del Piemonte per l’Oncologia-Institue for Cancer Research and Treatment
Candiolo
IT
Universitair.Ziekenhuis. Antwerpen
BE
Hospital Uno,versotarop Central De Asturias
ES
Assistance Publique – Hôpitaux de Marseille La Timone
FR
Instituto Valenciano De Oncologia
ES
Christie Manchester
UK
Royal Melbourne Hospital
AU
Wellington Hospital
NZ
AU
Centre Claudius Regaud
FR
The Geelong Hospital
Prince Of Wales Hospital
AU
Westmead Hospital
AU
University College hospital
UK
Flinders Medical Center
AU
Hospital Universitario 12 Octubre
ES
Launceston Hospital
AU
St James'S Leeds
UK
Nottingham University Hospitals
UK
Universitaets.Krankenhaus.Eppendorf
DE
Royal Perth Hospital
AU
Peter Maccallum Cancer Institute
AU
Princess Alexandra Hospital – University of Queensland
AU
Centro Di.Riferimento Oncologico Aviano
IT
Royal North Shore Hospital
AU