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GIST Research at GIST Research at Fox Chase Cancer CenterFox Chase Cancer Center
Margaret von Mehren, MDMargaret von Mehren, MD
MEDIANMEDIANALIVEALIVEDEADDEADTOTALTOTAL
7272 3333 3939 23.023.0
Time from Recurrence to Death (Months)Time from Recurrence to Death (Months)
DFCI Data,DFCI Data,1995-20001995-2000
Survival Following Recurrenceor Metastases in GIST
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
00 1010 2020 3030
Su
rviv
al P
rob
abil
ity
Su
rviv
al P
rob
abil
ity
Time to Progression (Months)Time to Progression (Months)
Pro
ba
bili
tyP
rob
ab
ility
00 22 44 66 88 1010
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
Time to Progression with Chemotherapy in GIST
Demetri, G
SLFSLF
P
P
P
P
PP
Ligand-dependent Activation of Wild-type c-kit
P
P
P
P
PP
Ligand-independent Activation of Mutant KIT (Exon 11)
In frame mutation of exon 11
Randomized Phase II Trial of STI571 in Metastatic GIST
SCREEN
REGISTER
400 mg/day
600 mg/day
Treat Dailyx 24
months
Serial Correlative StudiesImaging and Biopsies
Progression
Response
Best response 400 mg 600 mg All pts (95% CI)
Partial response (%) 50 68 59 (47-69)
Stable disease (%) 27 24 26 (12-39)
Progression (%) 21 5 13 (7-23)
Pre- and Post-STI571
8/16/00
2/6/01
PET Before and after STI57112/7/00 1/9/01
7 Days Post-treatment Pre-treatment
Histology
Hazard ratio 0.89
P-value 0.04
Median PFS (months) 19 / 23
3 years estimate (%) 30 / 34
(years)
0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
400 mg 800 mg
Progression free survival
Median PFS (months) 19 / 23
3 years estimate (%) 30 / 34
Hazard ratio 0.89
P-value (logrank test) 0.04
Estimated hazard ratio:0.89 in both studies
(years)
0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
400 mg 800 mg
Overall survival
Median OS (months) 49 / 49
3 years estimate (%) 60 / 61
Hazard ratio 1.00
P-value (logrank test) 0.97
Mutation status
Median PFS (months) 26 / 13 / 16 / 11
3 years estimate (%) 38 / 11 / 27 / 9
Median OS (months) 60 / 31 / 43 / 17
3 years estimate (%) 69 / 44 / 57 / 34
(years)0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Progression free survival
(years)0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Overall survival
KIT exon 11 mutants – KIT exon 9 mutants – Wild types - Other
(years)0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Overall survival
Median OS (months) 28 / 35
3 years estimate (%) 37 / 49
P-value (logrank test) 0.15
KIT exon 9 mutants
KIT exon 9 mutants: 400 mg / 800 mg - Other patients: 400 mg / 800 mg
DeMatteo, Ann Surg 2000; 231:51
Postoperative Outcome in Primary GISTRationale for Adjuvant Therapy
Years
1614121086420
Fra
ctio
n S
urvi
ving
1.0
.8
.6
.4
.2
0.0
5 yr survival 54%
N=80
Treatment of Localized Primary GIST
Resectable
www.NCCN.org
ImatinibSurgery
Unresectable
?
Recurrence-Free SurvivalTumor size >10 cm
p < 0.001HR 0.19 (0.09-0.41)
0 1 2 3 4
Years
0
10
20
30
40
50
60
70
80
90
100
% R
ecu
rren
ce-F
ree
and
Ali
ve
76 28 8 1Placebo82 40 13 1 Imatinib
At risk:
----- Imatinib (8 events)
Placebo (30 events)
DeMatteo, 2009
PDGFRA (n=28)Wildtype (n=32)
Exon 9 (n=22)
RFS For Placebo Cases By Genotype
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
an
d A
liv
e
Exon 11 Deletion (n=93)
Exon 11 PM (n=55)Exon 11 Insertion (n=25)
p=0.0240 vs WTHR 3.45
(95% CI 1.177 -10.137)
Corless, 2011
RFS For PDGFRA D842V-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54
Time in Months
% R
ec
urr
en
ce
-Fre
e a
nd
Ali
ve
Imatinib (n=15)
Placebo (n=13)
Treatment
Corless, 2011
RFS For Exon 11-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ec
urr
en
ce
-Fre
e a
nd
Ali
ve
Imatinib (n=173)
Placebo (n=173)
Treatment
p<0.0001 at 24 months
HR 3.42 (95% CI 1.93 - 6.06)
Corless, 2011
RFS For Wildtype Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=32)
Placebo (n=32)
Treatment
p=0.6126 at 24 months
Corless, 2011
RFS For Exon 9-Mutant Cases by Arm
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60
Time in Months
% R
ecu
rren
ce-F
ree
and
Aliv
e
Imatinib (n=13)
Placebo (n=22)
Treatment
p=0.8443 at 24 months
Corless, 2009
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, Multi-Center 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, Multi-Centre, 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 “Wild-IGF-1R is Highly Expressed in “Wild-Type” GISTsType” GISTs
>70%* of WT GISTs have >70%* of WT GISTs have IGF-1R IHC score =3 IGF-1R IHC score =3
0% of mutant GISTs have 0% of mutant GISTs have IGF-1R IHC score = 3IGF-1R IHC score = 3
*(p= 0.001)*(p= 0.001)
+
30-fold overexpressed30-fold overexpressed
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 (RT-
PCR)• 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
34
• 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
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
