Transcript Slide 1

Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumors:
Multicenter phase II trial of the SAKK (SAKK 56/07)
M. Montemurro1, A. Cioffi2, J. Domont2, P. Rutkowski3, A. Roth4, R. von Moos5, R. Inauen6, B. Bui7, R.O. Burkhardt8, C. Knuesli9, S. Bauer10, P. Cassier11, H. Schwarb12,
A. LeCesne2, D. Koeberle6, D. Baertschi13, D. Dietrich13, C. Biaggi13, J. Prior1, S. Leyvraz1 on behalf of Swiss Group for Clinical Cancer Research SAKK13
1 Univ-Hospital Lausanne, Switzerland, 2 Institut Gustave Roussy, Villejuif, France, 3 Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland, 4 Univ-Hospital Geneva, Switzerland, 5 Kantonsspital Graubünden, Chur, Switzerland, 6 Kantonsspital St Gallen, Switzerland,
7 Institut Bergonie, Bordeaux, France, 8 Triemlispital, Zürich, Switzerland, 9 Claraspital, Basel, Switzerland, 10 West German Cancer Center, Univ-Hospital Essen, Essen, 11 Centre Léon Bérard, Lyon, France, 13 SAKK Coordinating Center, Bern, Switzerland
• Tyrosine kinase inhibitors standard of care in advanced GIST
• 1st-line Imatinib:
• mPFS: 18-23mo
mOS: 45-55mo
• CR+PR: KIT ex11= 64%
WT=38%
All=45%
•
2nd-line
6mo
65%
• oral 2nd-Gen multi-target kinase inhibitor
• inhibits BCR-ABL, SRC, PDGFR, KIT
• inhibits Imatinib-resistant PDGFRA D842V
• Dasatinib in GiST after Imatinib failure (SARC 009 trial)2
mutants1
Sunitinib:
• mPFS:
• PR+SD:
Dasatinib - Background
2
mOS: 17mo
– N= 47
(80% also sunitinib failure)
– PR= 22%
– PFS= 2months (PDGFRA subgroup PFS=10 months; n=3 )
– OS= 19months
• Can we stop progression?
2nd-Gen TKI, HSPI, pathway inhibitors, antibodies, combinations etc.
Main Exclusion Criteria
2
3
4
Pulmonary
Cough
Dyspnea
Pleural Effusion
Capillary Leak
Voice Changes
Gastrointestinal
Anorexia
Dehydration
Diarrhea
Ileus
Nausea
Vomiting
Thrombosis / Embolism
(Vascular access)
24
90
45
0
5
28
0
76
0
28
8
0
4
48
70
0
0
17
0
10
0
15
7
0
0
3
6
1
0
6
2
5
3
2
2
0
0
1
0
0
0
0
0
0
0
0
0
1
14
PET Response
CR, PR, SD
( Primary Endpoint )
• 18-F-fluorodeoxyglucose-PET at4 weeks compared tobaseline
• EORTC criterita (Young et al EJC 1999)
• CR+PR PET Response Rates
– Overall
74%
– KIT Exon 11
80%
– Wild-Type
57%
Starting dose is 70 mg BID (one cycle = 4weeks)
–Dose level -1 50mg BID
–Dose level -2 100mg QD
Continue until progression, unacceptable toxicity and up to 2years
After 2 years, decision of the physician (continue or switch)
Elective Surgery is allowed after 6 cycles if SD or better
–Adjuvant Treatment to be considered
•
DASATINIB
2x 70mg / d p.o.
1mo
PET
•
Interim analysis (response + toxicity) after n=17pts
If > 9 / 17 pts respond @ PET 4weeks  proceed
«Promising» Response Rate (CR+PR) = 70% or better
2mo
PET
0mo
PET
CT
.
3mo
PET
CT
15
Survival
IMATINIB
11
Patient Characteristics
Elective
Surgery
.
etc.
14
8
7
• Median PFS 13.6 months
• Median OS
not reached
Death
3
Other
5
• 47 pts included (of 52 pts initially planned)
• 5 pts not eligible
(n=2 not GIST; n=2 baseline PET negative on central review; n=1 no baseline CT)
Performance
Status
Mutation
at Diagnosis
• Total 460 cycles administered (median 6, min 1, max 26)
Localisation
at Diagnosis
• Median Follow-Up 47.7 months
16
( Secondary Endpoint )
Toxicity
Parameter
(early closure, slow accrual)
• 42 pts treated in 13 centres in 4 European countries
• Median Follow-Up 47.7 months
• all patients off-trial, but n=4 continue drug > 2years
Progression
Trial Population
Gender
Progression OFF-STUDY
by
18F-FDG PET/CT
10
• Trial open from 17.01.2008 – 30.11.2011
by
18F-FDG PET/CT
Elective surgery allowed after month 6
1
• Secondary objective(s)
•
•
•
 Efficacy and safety of dasatinib in GIST
 Correlation of dasatinib efficacy with mutational status
9 Dasatinib 1st-Line in GIST – Trial Design
• PET
Antacids – PPI, H-2 blockers
IV bisphosphonates
CYP 3A4 inducers/inhibitors
Medications that prolong QT
Adverse Event /
Grade
Central Review
– Center Qualification before Trial Participation
– Monitoring of Center Qualification/Calibration during Trial
– Central PET Review within 3 working days
13 Selected AE, cumulative, 460 cycles
•
•
•
•
•
•
•
•
Histologically proven diagnosis of GIST
Positive baseline PET/CT with [18F]-fluorodeoxyglucose
Measurable disease by conventional scans (CT or MRI)
WHO performance status 0-2
Age ≥ 18 years
Adequate hematological and organ function values
Written informed consent before registration.
3) Stroobants et al. Eur J Cancer 2003; 4) Antoch et al. J Nucl Med 2004; 5) Goldstein et al Oncology 2005;
6) Goerres et al. Eur J Nucl Med Mol Imaging 2005; 7) Young et al. EJC 1999; 8) Shankar et al J Nucl Med 2006
Van den Abbeele et al. Eur J Cancer 2002; Gayed et al. J Nucl Med 2004; Choi et al. AJR 2004
– Central Pathology Review and Mutational Analysis
• Avoid / not permitted:
–
–
–
–
• Primary objective
6
Dasatinib Trial - Overview
5
• Recommendations for PET use exist (EORTC7; NCI8)
• Pathology
• Concurrent medical condition, incl. pleural or pericardial effusion, coagulation or
platelet function disorder, ongoingsignificant gastro-intestinal bleeding, nausea,
vomiting or malabsorption syndrome
Objectives
 Efficacy of dasatinib assessed by fusion PET/CT-scan
• PET response predicts PFS3,6 and OS6
1) Dewaele et al. Clin Cancer Res 2008
2) Trent et al ASCO 2011
8
• Previous therapy against GIST with TKI
• Previous malignancy within 5 years
• Clinically significant cardiovascular disease
• allows early response prediction 3
• predicts later CT responses3,4
• PET response precedes CT by 2-6 months3,5
4
(* 18-F-FluoroDeoxyGlucose -Positron Emission Tomography)
Demetri et al. JCO 2006, Blanke et al JCO 2008; Heinrich et al. JCO 2008; MetaGist JCO 2010
7
3 Early FDG-PET* in GIST - Background
2 years
completed
5
Disease Extension
at trial start
17
SummarySurvival
Progression-free
1.0
Variable
Female
Male
0
1
Kit Exon 11
Kit Exon 9
Wild-Type
N.A.
Gastric
Small Intestine
N
18
24
29
13
25
1
7
15
11
14
%
43
57
69
31
60
2
16
35
26
33
N.A.
Localized
Metastatic
N.A.
18
4
33
6
42
9
77
14
12
•
•
•
•
/
/
/ / /
non-progression) and resolved prior death; no autopsy )
18
• This multicenter Phase II trial of the Swiss Group for Clinical
Cancer Research SAKK investigated first-line Dasatinib, starting
dose 70mg BID, in TKI-naïve patients with GIST
• FDG-PET response was primary, Survival secondary endpoint
//
/
/
0.8
/
/// / /
/
0.6
/
/
/
0.4
/ /
/
/
/
/
//
0.8
/
/
Treatment was interrupted in 32 patients (76%%)
Dosage was reduced or interrupted in 25% of cycles
Treatment was stopped due to toxicity in 7 pats (17%)
48% of pts experienced a G3, 5% a G4 toxicity
• Clinical deterioration
• GIST tumor bleeding
• Cardiac arrest ( hospitalised due to an intestinal occlusion (CT confirmed
1.0
/
Safety / Toxicity
• 3 deaths occurred
Overall Survival
Proportion surviving
GIST - Background
Proportion without progression/death
1
Abstract:
0.000
Main Inclusion Criteria
///
/
/ /// / /
//
/ ///
0.6
/
• 42 eligible patients evaluated, median Follow-Up is 47.7 months
0.4
• 48% of pts experienced Grade 3 and 5% Grade 4 toxicity
0.2
0.2
• Responses (CR+PR) were 74% overall (80% KIT Exon 11; 57% WT)
0.0
0.0
• Median PFS is 13.6 months, overall survival still not reached yet.
0
6
12
No. at risk
42
25
14
18
7
24
30
36
Time (months)
5
3
2
42
1
48
1
54
1
60
0
0
6
12
No. at risk
42 39 39
18
39
24
36
30 36 42
Time (months)
31
23
17
48
54
60
66
• Dasatinib shows promising efficacy in this small group of patients.
15
5
Email Author: [email protected]
5
1
www.sakk.ch