Transcript GIST Research at Fox Chase Cancer Center

GIST Research at
Fox Chase Cancer Center
Margaret von Mehren, MD
Survival Following Recurrence
or Metastases in GIST
1.0
Survival Probability
0.9
0.8
0.7
0.6
DFCI Data,
1995-2000
0.5
0.4
0.3
0.2
0.1
0
10
20
30
Time from Recurrence to Death (Months)
TOTAL DEAD ALIVE MEDIAN
23.0
39
33
72
Time to Progression with
Chemotherapy in GIST
0
2
4
6
8
Time to Progression (Months)
Demetri, G
10
Ligand-dependent Activation
of Wild-type c-kit
SLF
P
P
P
P
SLF
P
P
Ligand-independent Activation of
Mutant KIT (Exon 11)
In frame mutation of
exon 11
P
P
P
P
P
P
Randomized Phase II Trial of STI571
in Metastatic GIST
S
C
R
E
E
N
R
E
G
I
S
T
E
R
400 mg/day
Progression
Treat Daily
x 24
months
600 mg/day
Serial Correlative Studies
Imaging and Biopsies
Response
Best response
400 mg
600 mg
Partial response (%)
50
68
Stable disease (%)
27
24
Progression (%)
21
5
All pts
(95% CI)
59 (47-69)
26 (12-39)
13 (7-23)
Pre- and Post-STI571
8/16/00
2/6/01
PET Before and after STI571
12/7/00
1/9/01
Histology
Pre-treatment
7 Days Post-treatment
Progression free survival
Hazard ratio
100
0.89
Median PFS (months)
19 / 23
P-value
0.04
90
3 years
estimate (%)
Median PFS (months)
30
/ 34
19 / 23
80
Hazard
ratio
3 years
estimate (%)
0.89
30
/ 34
70
P-value (logrank test)
0.04
60
Estimated hazard ratio:
0.89 in both studies
50
40
30
20
10
0
(years)
0
1
400 mg
2
800 mg
3
4
5
6
Overall survival
100
90
80
70
60
50
40
Median OS (months)
49 / 49
30
3 years estimate (%)
60 / 61
20
Hazard ratio
1.00
10
P-value (logrank test)
0.97
0
(years)
0
1
400 mg
2
800 mg
3
4
5
6
Mutation status
Progression free survival
Overall survival
100
100
90
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
(years)
0
1
2
3
4
5
0
(years)
0
1
2
3
4
5
KIT exon 11 mutants – KIT exon 9 mutants – Wild types - Other
Median PFS (months)
26 / 13 / 16 / 11
Median OS (months)
60 / 31 / 43 / 17
3 years estimate (%)
38 / 11 / 27 / 9
3 years estimate (%)
69 / 44 / 57 / 34
Overall survival
KIT exon 9 mutants
100
90
Median OS (months)
28 / 35
80
3 years estimate (%)
37 / 49
70
P-value (logrank test)
0.15
60
50
40
30
20
10
0
0
1
2
3
4
5
(years)
KIT exon 9 mutants: 400 mg / 800 mg - Other patients: 400 mg / 800 mg
Postoperative Outcome in Primary GIST
Rationale for Adjuvant Therapy
Fraction Surviving
1.0
.8
.6
N=80
.4
5 yr survival 54%
.2
0.0
0
2
4
6
8
10
12
14
16
Years
DeMatteo, Ann Surg 2000; 231:51
Treatment of Localized Primary GIST
Resectable
Surgery
Unresectable
?
Imatinib
www.NCCN.org
Recurrence-Free Survival
Tumor size >10 cm
% Recurrence-Free and Alive
100
90
80
70
60
50
40
30
20
----- Imatinib
10
Placebo
(8 events)
p < 0.001
HR 0.19 (0.09-0.41)
(30 events)
0
0
1
3
4
Years
At risk:
Imatinib
Placebo
2
82
76
40
28
13
8
1
1
DeMatteo, 2009
RFS For Placebo Cases By Genotype
% Recurrence-Free and Alive
100
90
Exon 9 (n=22)
80
Exon 11 PM (n=55)
Wildtype (n=32)
Exon 11 Insertion (n=25) PDGFRA (n=28)
70
60
50
Exon 11 Deletion (n=93)
40
p=0.0240 vs WT
HR 3.45
30
20
(95% CI 1.177 -10.137)
10
0
0
6
12
18
24
30
36
42
48
54
Time in Months
Corless, 2011
60
RFS For PDGFRA D842V-Mutant Cases by Arm
% Recurrence-Free and Alive
100
Imatinib (n=15)
90
Placebo (n=13)
80
70
60
50
40
30
20
Treatment
10
0
0
6
12
18
24
30
36
42
48
Time in Months
Corless, 2011
54
RFS For Exon 11-Mutant Cases by Arm
100
% Recurrence-Free and Alive
90
80
Imatinib (n=173)
70
60
Placebo (n=173)
50
40
p<0.0001 at 24 months
30
HR 3.42 (95% CI 1.93 - 6.06)
20
Treatment
10
0
0
6
12
18
24
30
36
42
48
54
Time in Months
Corless, 2011
60
RFS For Wildtype Cases by Arm
% Recurrence-Free and Alive
100
90
80
Placebo (n=32)
70
60
Imatinib (n=32)
50
40
p=0.6126 at 24 months
30
20
10
Treatment
0
0
6
12
18
24
30
36
42
48
54
Time in Months
Corless, 2011
60
RFS For Exon 9-Mutant Cases by Arm
% Recurrence-Free and Alive
100
90
Placebo (n=22)
80
70
Imatinib (n=13)
60
50
p=0.8443 at 24 months
40
30
20
10
Treatment
0
0
6
12
18
24
30
36
42
48
54
Time in Months
Corless, 2009
60
Where are we Now?
• Two approved therapies for treatment of
metastatic disease: Imatinib and Sunitinib
• Evidence for improved disease control
following surgery with adjuvant imatinib
• Survival for patients with advanced GIST
has increased significantly
Where are we going?
• New Treatment Approaches for advanced
disease
• Mutation directed therapies
– IGF-1R inhibitors
– PDGFRA inhibitors
Regorafinib
• Novel kinase inhibitor
• Phase II trial completed
– Toxicities: hand foot syndrome
hypertension
liver function, electrolyte changes
• The majority of patients have had their
disease controlled for 4 months+
• To be presented at ASCO
Phase III trial of Regorafinib
• Study comparing regorafinib to placebo
• Very close follow-up in the first 3 months
• Patients whose tumors progress that were
receiving placebo will be candidates to
receive regorafinib
Hsp-90: Therapeutic Target
Xu and Neckers, Clin Cancer Res, 2007; 13(6):1625-9
Hsp-90: Target for cancer Therapy
• Normal cellular functions include
– Chaperone for proteins to maintain normal
homeostasis
– Chaperones oncogenes and stabilizes them
• Hsp-90 is different in oncogenic cells; mutated
receptors are more dependent on Hsp-90
• In vitro studies of Hsp-90 inhibitors suggest
preferential destruction of mutated receptors,
regardless of site of mutation(s)
HSP-90 targeted therapies
• A Non-Randomized, Open Label, MultiCenter Phase 2 Study Evaluating the
Efficacy and Safety of STA-9090 in
Patients with Metastatic and/or
Unresectable GIST Resistant or
Refractory to Prior Systemic Treatments
Including Imatinib and Sunitinib
HSP-90 targeted therapies
• An Open-Label, Randomised, MultiCentre, Phase II Study to Investigate the
Safety and Efficacy of AT13387, either as
Monotherapy or in Combination with
Imatinib, in Patients with Unresectable
and/or Metastatic Malignant GIST whose
Tumour has Progressed following
Treatment with a Maximum of Three
Tyrosine Kinase Inhibitors
IGF-1R is Highly Expressed in “WildType” GISTs
30-fold overexpressed
+
 >70%* of WT GISTs have
IGF-1R IHC score =3
 0% of mutant GISTs have
IGF-1R IHC score = 3
*(p= 0.001)
OSI-906
• Oral tyrosine kinase inhibitor with activity
against IGF-1R
• Phase II trial in WT GIST
• 150 mg BID
Correlative studies (FCCC, NIH, DFCI):
• KIT/PDGFRA/BRAF mutation testing (sequencing)
• IGF-1R, p-AKT quantification (IHC)
• Total serum IGF-1, free serum IGF, IGFBP3
quantification, (ELISA)
• IGF-I/IGF-II/IGF-1R/IGF-IIR/IR-A/-B quantitation (RTPCR)
• Full length IGF-1R sequencing (sequencing)
• Loss of imprinting of IGF-II locus (methylation)
• SDHB quantification (IHC)
• IGF-IR, AKT, pAKT, ERK, perk, mTOR, pmTOR
quantitation (Western Blot, when frozen tissue is
available)
CP-868,596 has an IC50 of 10-30nM
against PDGFRA exon 18 D842V
mutation
• CP-868,596 inhibited the phosphorylation of wild
type PDGFRA at an IC50 of 10 nM and PDGFRA
(D842V) with an IC50 between 10 to 30 nM.
• Imatinib was ineffective in blocking PDGFRA
(D842V) phosphorylation in these experiments
(IC50 > 1000 nM).
Heinrich, 2011
34
PDGFRA directed therapy
• Phase II Study of CP-868,596, A Selective
and Potent Inhibitor of PDGFR, for the
Treatment of Patients with Advanced
Gastrointestinal Stromal Tumors with the
D842V Mutation in the PDGFRA Gene
Conclusions
• We have come along way, but still have a
ways to go
• The laboratory is key to our clinical
development
• Future clinical studies I believe will be
combination therapies