Transcript EORTC STBSG Prognostic factors for initial and late resistance to Imatinib in patients with advanced GIST Martine Van Glabbeke, Jaap Verweij, Paolo G.

EORTC
STBSG
Prognostic factors for
initial and late resistance to Imatinib
in patients with advanced GIST
Martine Van Glabbeke, Jaap Verweij, Paolo G. Casali, John Zalcberg,
Axel Le Cesne, Peter Reichardt, Jean-Yves Blay, Marcus Schlemmer,
Allan T. van Oosterom, Pancras Hogendoorn, Konstantin Stoitchkov,
Ian R. Judson
EORTC – ISG - AGITG
Background (1)
Imatinib in advanced / metastatic GIST
Progression free survival
Same “shape” of the
PFS curves in
100
90

Rankin et al,
ASCO 2004

Demetri et al,
NEJM 347, 2002

Verweij et al,
Lancet 364, 2004
80
70
60
50
40
30
20
Overall Logrank test: p=0.026
10
0
0
3
6
9
400 mg o.d.
12
15
18
400 mg b.i.d.
21
24
27
30 (months)
EORTC – ISG - AGITG
Background (2)

New mutations

Genomic amplification
mechanisms are

Loss of KIT expression
responsible for initial

Functional resistance
and late resistance to

J. Fletcher, ASCO 2003
imatininb

M. Debiec-Rychter,
Gastroenterology, 2004
Different biological
Different mechanisms of resistance
may be predicted by
different prognostic factors
EORTC – ISG - AGITG
Objectives of the analysis

Identify factors that may predict
initial resistance to imatininb

Identify factors that may predict
late resistance to imatininb

Explore the dose/efficacy relationship
in the important prognostic subgroups
EORTC – ISG - AGITG
Material

EORTC – ISG – AGITC trial 62005

946 patients with advanced / metastatic GIST

Randomized to imatinib


400 mg o.d.

400 mg b.i.d.
Median follow-up: 25 months
EORTC – ISG - AGITG
End-points for each objective

Initial resistance :
documented progression within 3 months

116 progressions / 934 evaluable cases

Logistic regression models

Late resistance :
time to progression after 3 months

3 months landmark period

347 progressions / 818 evaluable cases

Cox regression model
EORTC – ISG - AGITG
Investigated co-factors

Imatinib dose (randomized)

Age, gender, PS

Site of disease origin

Site and size of lesions at entry

Prior therapies

Hematological and biological parameters
Results

For each end-point: univariate and multivariate analysis

Overall TTP curve for important prognostic factors

Comparison of treatment arms in prognostic subgroups
EORTC – ISG - AGITG
Results :
Prognostic factors for initial resistance
Factor
Univariate
OR
P-value
Lung metasases
0.323
< 0.0001
Hemoglobin
1.421
< 0.0001
Granulocytes
0.926
0.0049
PS
0.734
0.0079
Platelets (/ 100)
0.845
0.0082
Albumin
1.040
0.0186
Liver metastases
1.611
0.0212
Time since diag
1.297
0.0488
EORTC – ISG - AGITG
Results :
Prognostic factors for initial resistance
Factor
Univariate
Multivariate
OR
P-value
OR
P-value
Lung metastases
0.323
< 0.0001
0.332
0.0001
Hemoglobin
1.421
< 0.0001
1.380
0.0004
Granulocytes
0.926
0.0049
0.935
0.0208
PS
0.734
0.0079
Platelets (/ 100)
0.845
0.0082
Albumin
1.040
0.0186
Liver metastases
1.611
0.0212
1.816
0.0055
Time since diag
1.297
0.0488
EORTC – ISG - AGITG
Results :
Prognostic factors for late resistance
Factor
Univariate
HR
P-value
Granulocytes
1.064
< 0.0001
Largest diameter
1.033
0.0001
WBC
1.051
0.0001
PS
1.241
0.0014
Stomach origin
0.712
0.0042
Sm.bowel origin
1.385
0.0053
Albumin
0.976
0.0095
Prior chemo
1.298
0.0184
Imatinib dose
0.779
0.0202
EORTC – ISG - AGITG
Results :
Prognostic factors for late resistance
Factor
Univariate
Multivariate
HR
P-value
HR
P-value
Granulocytes
1.064
< 0.0001
1.051
0.0009
Largest diameter
1.033
0.0001
1.023
0.0095
WBC
1.051
0.0001
PS
1.241
0.0014
Stomach origin
0.712
0.0042
0.731
0.0088
Sm.bowel origin
1.385
0.0053
Albumin
0.976
0.0095
Prior chemo
1.298
0.0184
Imatinib dose
0.779
0.0202
0.754
0.0093
EORTC – ISG - AGITG
Summary :
factors predicting resistance to imatininb
Factor
Initial
resistance
(P-value)
Late
resistance
(P-value)
Low imatinib dose
ns
0.0093
High granulocytes
0.0208
0.0009
Low hemoglobin
0.0004
ns
Large lesions
ns
0.0095
Origin outside of stomach
ns
0.0088
Lung metastases
0.0001
ns
No liver metastases
0.0055
ns
EORTC – ISG - AGITG
Lung and liver metastases at entry
Time to progression
by presence of liver and lung lesions

Loss of significance in
the subgroup of
patients with
confirmed GIST

Misdiagnosed
patients ???
100
90
80
70
60
50
40
30
20
10
0
0
4
None
8
12
16
Liver
20
24
Lung
28
32
Both
(months)
36
EORTC – ISG - AGITG
Hemoglobin
Time to progression
by initial hemoglobin level (mmol/l)

Also a PF in CML

Influences PK

Advanced disease
(mucosal ulceration,
bleeding)
100
90
80
70
60
50
40
30
20
10
0
0
6
<7
< 11.27
12
7-8
11.27 - 12.88
18
24
8 - 8.8
12.88 - 14.17
30
> 8.8
> 14.17
(months)
36
mg/100 ml
EORTC – ISG - AGITG
Granulocytes

Time to progression
by initial granulocyte count (10**9/l)
100
90
Inflammatory
reaction in
aggressive types of
tumors ?
80
70
60
50
40
30
20
10
0
0
6
<4
12
4-5
18
24
5 - 6.5
30
> 6.5
(months)
36
EORTC – ISG - AGITG
Largest tumor size

Tumor size is a PF for
primary disease

Advanced stage of
disease ?

Increasing risk rate ?
Time to progression
by largest tumor size (cm)
100
90
80
70
60
50
40
30
20
10
0
0
6
<4
12
4-8
18
24
8 - 12
30
> 12
(months)
36
EORTC – ISG - AGITG
Largest tumor size – logarithmic scale

Increased risk of
progression

At +/- 18 months

In large tumors

Delayed mechanism
of resistance ?
Time to progression
by largest tumor size (cm)
100
90
80
70
60
50
40
30
20
10
0
6
<4
12
4-8
18
24
8 - 12
30
> 12
(months)
36
EORTC – ISG - AGITG
Site of origin of disease
Time to progression
by original tumor site

Stomach vs
small bowel

PF for primary
disease

% benign/malignant
- high in stomach
- low in sm.bowel

Correlation with
mitotic index ?
100
90
80
70
60
50
40
30
20
10
0
(months)
0
6
12
18
Retro-int.abd. Stomach
Extra abd.
24
Small bowel
30
36
Other GI
EORTC – ISG - AGITG
Impact of initial imatininb dose on
TTP : subgroup analysis
Total
Failures
Hazard
ratio
P-value
All patients
946
463
0.801
0.017
Granulocytes < 5 109/l
514
207
0.874
0.3368
Granulocytes > 5 109/l
432
256
0.678
0.0020
Largest diam. < 12 cm
728
336
0.793
0.0337
Largest diam. > 12 cm
218
127
0.796
0.2025
Stomach origin
316
131
0.836
0.3077
Small bowel origin
238
130
1.025
0.8886
Other GI origin
239
121
0.576
0.0029
Subgroup
EORTC – ISG - AGITG
Patients with high granulocytes
Time to progression
Patients with high granulocytes count (> 5.10**9/l)
100
90
80
70
60
50
40
30
20
10
0
0
6
400 mg o.d.
12
18
400 mg b.i.d.
24
30
(months)
36
EORTC – ISG - AGITG
Tumors of “other” GI origin
Time to progression
Tumors of GI origin outside stomach and small bowel
100
90

80

70

60

50

40

Duodenal
Omentum
Rectum
Colon
Esophag.
….
89
47
44
23
11
25
30
20
10
0
0
6
400 mg o.d.
12
18
400 mg b.i.d.
24
30
(months)
36
EORTC – ISG - AGITG
Conclusions

Initial and late resistance are predicted by different
factors

Initial imatinib dose has
No impact on initial resistance
Impact on late resistance



In patients with high GRA
In tumors of “unusual” GI origin
Not in patients with small bowel origin

Hypotheses to be confirmed by immunohistochemical
/ molecular parameters

The models should be externally validated
EORTC – ISG - AGITG
EORTC – ISG - AGITG
Material : EORTC-ISG-AGITG phase III trial

Eligibility criteria




Randomization



Advanced or metastatic GIST; c-KIT positive
PS 0-3; no upper age limit; any prior therapy
HGB > 9 g/dl (5.6 mmol/l) - transfusion allowed
Imatinib, 400 mg od; cross-over if PD
Imatinib, 400 mg bid (800 mg/day)
Data set


946 patients randomized
Median follow-up: 25 months; 1 year: 98%; 2 years: 58%
EORTC – ISG - AGITG
Analyzed end-points

Initial resistance : progression within 3 months





3 months: includes 1st eval. / excludes 2nd eval.
Binary variable: 116 PD / 818 no PD
Exclude 11 early deaths (no PD) and 1 lfu (ineligible)
Logistic model
Late resistance : progression after 3 months





3 months landmark period
Time to event variable (event = progression)
Deaths without progression censored
347 events – 24 death no PD – 447 alive & prog.free
Cox model
EORTC – ISG - AGITG
Results :
Prognostic factors for initial resistance
Factor
Univariate
Multivariate
OR
P-value
OR
P-value
Lung metastases
0.323
< 0.0001
0.332
0.0001
Hemoglobin
1.421
< 0.0001
1.380
0.0004
Granulocytes
0.926
0.0049
0.935
0.0208
PS
0.734
0.0079
Platelets (/ 100)
0.845
0.0082
Albumin
1.040
0.0186
Liver metastases
1.611
0.0212
1.816
0.0055
Time since diag
1.297
0.0488
EORTC – ISG - AGITG
Results :
Prognostic factors for late resistance
Factor
Univariate
Multivariate
HR
P-value
HR
P-value
Granulocytes
1.064
< 0.0001
1.051
0.0009
Largest diameter
1.033
0.0001
1.023
0.0095
WBC
1.051
0.0001
PS
1.241
0.0014
Stomach origin
0.712
0.0042
0.731
0.0088
Sm.bowel origin
1.385
0.0053
Albumin
0.976
0.0095
Prior chemo
1.298
0.0184
Imatinib dose
0.779
0.0202
0.754
0.0093
EORTC – ISG - AGITG
Site of origin of disease

Stomach vs
sm. bowel

PF for primary
disease

% benign/malignant
- high in stomach
- low in sm.bowel

Correlation with
mitotic index ?
Time to progression
100
90
80
70
60
50
40
30
20
10
0
0
6
Stomach
12
18
Sm.bowel
24
Other
30
(months)
36
EORTC – ISG - AGITG