duffaud f et al. asco 2009; abstract 10508. (oral presentation)

Time to Secondary Resistance (TSR) After Interruption of Imatinib: Updated Results of the Prospective French Sarcoma Group Randomized Phase III Trial on Long Term Survival

Duffaud F et al.ASCO 2009; Abstract 10508. (Oral Presentation)

Introduction

85%-90% of patients with GIST experience tumor control with imatinib (IM)

Previous studies suggest that IM therapy should be administered continuously until disease progression or intolerance and not interrupted in responding patients

The impact of IM re-introduction at disease progression on time to secondary resistance (TSR) remains unknown

Current study objectives (N = 432):– Assess the impact on PFS and TSR of interrupting first-line IM

therapy after 1, 3 and 5 years in responding patients with advanced or metastatic GIST

Source: Blay JY et al. J Clin Oncol 2007;25(9):1107-13.

Source: Duffaud F et al. ASCO 2009; Abstract 10508.

BFR14 Phase III Trial Design

Evaluate for Randomization at 1 yr, 3 yrs, 5 yrs

Advanced/metastatic

GIST on imatinib

Stable Disease or better

ContinueImatinib

400 mg daily

StopImatinib

DiseaseProgression

RestartImatinib400 mg

daily

ContinueImatinib

and Follow-up

Surgery possible if resectable

R

1 Year Randomization Group

3 Year Randomization Group

CONT (n = 26)

STOP (n = 32)

CONT (n = 25)

STOP (n = 25)

PFS 1 Year 85% 31% 92% 32%

PFS 2 Year — — 78% 16%

Median TTP31.4 mos 7.3 mos

Not reached

9.4 mos

Rate of Secondary Resistance (SR)1-2

Rate of SR at 1 Year 85% 84% — —

Rate of SR at 2 Years 62% 63% 78% 87%

1 Rate of SR after randomization to IM = first progression in the CONT arm and second progression in the STOP arm2 Five year randomization group insufficient data to report


Effect of IM Treatment Interruption on PFS

Rate of Secondary Resistance in Patients That Have Interrupted

IM Treatment

Source: With permission from Duffaud F et al. ASCO 2009; Abstract 10508.

Rate of Relapse-2 Year Follow Up 1 Year Randomization Group: 40%

3 Year Randomization Group: <20%

00.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12 18 24 30 36 42 48 54 60 66 72

Months

Su

rviv

al p

rob

ab

ilit

y

The rate of secondary resistance appearsto decrease with longer duration of imatinib treatment

Log-rank p-value = 0.129

1 year STOP arm:15 evts/32 patients2 years PFS: 63% CI95 = [43 - 78]

3 years STOP arm:6 evts/25 patients2 years PFS: 87% CI95 = [64 - 96]

Summary and Conclusions

Interruption of IM treatment in patients with GIST who have achieved stable disease or better results in rapid disease progression

- 1-Year Randomization: Median TTP CONT = 31.4 mos vs STOP = 7.3 mos- 3-Year Randomization: Median TTP CONT = Not reached vs STOP =

9.4 mos Re-introduction of IM treatment to patients in the STOP arms after a new

progression allowed for tumor control - 92% of patients (23/25) in the 1 year group- 100% of patients (20/20) in the 3 year group

Interruption of IM treatment does not hasten development of secondary resistance upon re-introduction of treatment

Rate of secondary resistance appears to decrease with longer duration of IM treatment

Results with patients randomized to interrupt IM after 5 years of therapy will be available for ASCO 2010


Outcome of Patients with Advanced GIST Achieving a Complete Remission (CR) with Imatinib (IM) Before Interruption: Pooled Analysis of Two Consecutive Prospective Randomizations of the French Sarcoma Group BFR14 Phase III Trial

Chevreau C et al.ASCO 2009; Abstract 10549. (Poster)

Source: Chevreau C et al. ASCO 2009; Abstract 10549.

Introduction

Optimal duration of IM treatment is unknown, but treatment interruption in responding patients after 1-3 years leads to high risk of rapid progression within a few months (See Duffaud ASCO 2009;Abstract 10508)

Current study objectives:

– Determine PFS of patients in the STOP group achieving a CR or a significant PR (residual tumor < 10 millimeters by CT scan) before IM interruption compared to the outcome of patients in the STOP group who experienced other patterns of response

Median PFS of Patients With Interrupted IM Treatment

STOP Group Median PFS, months p-value

Responders* Non-Responders —

1 Year IM Treatment(n = 32)

9.4 (n = 9) 6.0 (n = 23) 0.298

3 Year IM Treatment(n = 25)

14.1 (n = 10) 5.0 (n = 15) 0.0084

All IM Treatment Groups Combined(n = 65)1

12.0 (n = 23) 5.9 (n = 41) 0.019


1 Includes patients for five-year IM treatment group (four responders, three nonresponders)

* Responders = Patients who achieved CR or significant PR (residual tumor <10mm by CT scan)

Relapse Events in Patients With Interrupted IM Treatment


STOP Group Relapse Events Observed

Responders* Non-Responders

1 Year IM Treatment (n = 32) 7/9 22/23

3 Year IM Treatment (n = 25) 7/10 14/15

All IM Treatment Groups Combined (n = 65)1

15/23 (65%)

36/41 (88%)

1 Includes patients for five-year IM treatment group (four responders, three nonresponders)


Absence of Liver Involvement CorrelatesTo Patients Achieving Response to

IM Treatment Prior to Randomization

Responders*(n = 24†)

Non-Responders(n = 41)

Liver alone involvement N % N % P-value

Yes 6 25 25 610.009

No 18 75 16 39


† Includes one additional responder from five-year IM treatment group not included in progression analyses


Summary and Conclusions

CR obtained under IM treatment is a prerequisite for prolonged disease-free survival in advanced GIST

– 35% of all responding patients (CR or significant PR with residual tumor <10mm by CT scan) that interrupted IM treatment remained relapse-free versus only 12% of the non-responders

Longer period of IM treatment prior to treatment interruption may delay the onset of first progression

– Median PFS in the responders for one-year versus three-year treatment groups (9.4mo versus 14.1mo, respectively)

Absence of liver invasion may serve as a marker for favorable response to IM treatment

– Absence of liver invasion was statistically correlated (p = 0.009) with complete or significant partial response to IM in this study


duffaud f et al. asco 2009; abstract 10508. (oral presentation)

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