EORTC STBSG

EORTC – ISG - AGITG

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

EORTCEORTCSTBSGSTBSG


Background (1)

Progression free survival

0 3 6 9 12 15 18 21 24 27 30

0

10

20

30

40

50

60

70

80

90

100

400 mg o.d. 400 mg b.i.d.

Overall Logrank test: p=0.026

(months)

Same “shape” of the PFS curves in

Rankin et al, ASCO 2004

Demetri et al,NEJM 347, 2002

Verweij et al, Lancet 364, 2004

Imatinib in advanced / metastatic GIST


Background (2)

New mutations

Genomic amplification

Loss of KIT expression

Functional resistance

J. Fletcher, ASCO 2003

M. Debiec-Rychter,Gastroenterology, 2004

Different biological

mechanisms are

responsible for initial

and late resistance to

imatininb

Different mechanisms of resistance may be predicted by

different prognostic factors


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


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


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


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


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

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




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




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


Albumin 0.976 0.0095


Imatinib dose 0.779 0.0202 0.754 0.0093


Summary : factors predicting resistance to imatininb

FactorInitial

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


Lung and liver metastases at entry

(months)

0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

None Liver Lung Both

Time to progressionby presence of liver and lung lesions

Loss of significance in the subgroup of patients with confirmed GIST

Misdiagnosed patients ???


Hemoglobin

Also a PF in CML

Influences PK

Advanced disease (mucosal ulceration, bleeding)

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

< 7 7 - 8 8 - 8.8 > 8.8

Time to progressionby initial hemoglobin level (mmol/l)

< 11.27 11.27 - 12.88 12.88 - 14.17 > 14.17 mg/100 ml


Granulocytes

Inflammatory reaction in aggressive types of tumors ?

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

< 4 4 - 5 5 - 6.5 > 6.5

Time to progressionby initial granulocyte count (10**9/l)


Largest tumor size

Tumor size is a PF for primary disease

Advanced stage of disease ?

Increasing risk rate ?

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

< 4 4 - 8 8 - 12 > 12

Time to progressionby largest tumor size (cm)


(months)

0 6 12 18 24 30 36

10

20

30

40

50

60708090

100

< 4 4 - 8 8 - 12 > 12

Time to progressionby largest tumor size (cm)

Largest tumor size – logarithmic scale

Increased risk of progression

At +/- 18 months

In large tumors

Delayed mechanism of resistance ?


Site of origin of disease Stomach vs

small bowel

PF for primary disease

% benign/malignant- high in stomach- low in sm.bowel

Correlation with mitotic index ?

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

Retro-int.abd. Stomach Small bowel Other GI

Extra abd.

Time to progressionby original tumor site


Impact of initial imatininb dose on TTP : subgroup analysis

Subgroup Total FailuresHazard

ratioP-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


Patients with high granulocytes

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

400 mg o.d. 400 mg b.i.d.

Time to progressionPatients with high granulocytes count (> 5.10**9/l)


Tumors of “other” GI origin

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

400 mg o.d. 400 mg b.i.d.

Time to progressionTumors of GI origin outside stomach and small bowel

Duodenal 89 Omentum 47 Rectum 44 Colon 23 Esophag. 11 …. 25


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


Material : EORTC-ISG-AGITG phase III trial

Eligibility criteria 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

Randomization 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%


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




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





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


Albumin 0.976 0.0095


Imatinib dose 0.779 0.0202 0.754 0.0093


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 ?

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

Stomach Sm.bowel Other

Time to progression

EORTC STBSG

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