Post on 20-Jan-2016
transcript
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PFINOV 04340 Core DT4 04/21/23 16:22
Update on GIST Research
Michael Heinrich, M.D.
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Overview
• PDGFRA D842V mutant GIST– Clinical background– Lack of effective conventional therapy– Development of an active compound
• Pre-clinical studies• Newly opened phase 2 study
• Update on other OHSU GIST Clinical Studies
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KITKIT and and PDGFRAPDGFRA Mutations in >2000 GISTs Mutations in >2000 GISTs (Heinrich-Corless Lab)(Heinrich-Corless Lab)
Exon 11 (67%)Exon 11 (67%)
Exon 9 (9%)Exon 9 (9%)
Exon 13 (1%)Exon 13 (1%)
Exon 17 (1%)Exon 17 (1%)
KIT (78.5%)
Overall Mutation Frequency: 86%
Exon 14 (rare)Exon 14 (rare)
PDGFRA (7.5% total)
Exon 12 (2%)Exon 12 (2%)
Exon 18 (5.5%)Exon 18 (5.5%)
(35% of KIT-WT)
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PDGFRA exon 12 and 14 Mutations(2-3% of Adult GIST)
• PDGFRA exon 12 and 14 mutations are extremely sensitive to imatinib in vitro
• Sensitivity is similar to KIT exon 11 mutations
• Most commonly found in gastric tumors and may be associated with a reduced risk of recurrence
• Limited clinical data, but appears sensitive to imatinib
Heinrich et al. JCO 21:4342, 2003Debiec-Rychter et al. EJC 40:689. 2004Debiec-Rychter et al. EJC 42:1093, 2006Heinrich et al. JCO 26:5360, 2008Corless et al. JCO 23:5357 2005
Exon 12
Exon 12
Exon 14
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PDGFRA exon 18 D842V(~5% of Adult GISTs)
• PDGFRA D842V is the single most common PDGFRA mutation
• Vast majority are found in gastric GISTs
• May be associated with a lower overall risk of recurrence
• Resistant to imatinib in vitro
Heinrich et al. JCO 21:4342, 2003
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PDGFRA exon 18 D842V
• In vitro, PDGFRA D842V mutation is resistant to imatinib, sunitinib, nilotinib, and sorafenib
• ? Sensitive to high dose dasatinib in vitro
Biron et al. Abstract 10051, ASCO 2010Heinrich et al. JCO 26:5360, 2008Debiec-Rychter et al. Clin Cancer Res. 14:5749, 2008
Imatinib sensitive Imatinib resistant
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Imatinib Treatment of D842V-mutant GIST
• PDGFRA D842V-mutant GIST are under represented in the major imatinib clinical studies– These tumors may be less aggressive and have a lower incidence of
recurrence
– These tumors are often “KIT-negative” and were therefore not eligible for clinical studies
• Imatinib clinical studies– Phase 3 studies 0/8 patients responded– B2222 Phase 2 study 0/3 patients responded
• Sunitinib clinical studies– 0/3 responses for primary PDGFRA D842V mutant GIST– 0/1 responses for secondary PDGFRA D842V mutant GIST
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PDGFRA D842V Mutant GIST
• Survey of European GIST centers– 0/19 patients with PDGFRA D842V mutant GIST had a response
to imatinib– Progression free survival of 2.8 months– Median survival of 12.7 months
• To date, 0/33 patients in the literature with PDGFRA D842V mutation have responded to imatinib
• This particular subtype of GIST has not benefited from the “Gleevec revolution”
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Dosing Recommendations for KIT-mutant GIST
Exon 11(59.6%)Exon 11(59.6%)
Exon 9 (9.1%)Exon 9 (9.1%)
Exon 13 (1.9%)Exon 13 (1.9%)
Exon 17 (0.8%)Exon 17 (0.8%)
KIT
Imatinib 800 mgImatinib 400 mg
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Dosing Recommendations for PDGFRA-mutant GIST
PDGFRA
Exon 12 (2.5%)Exon 12 (2.5%)
Exon 18 (6.9%)Exon 18 (6.9%)
Exon 14 (0.5%)Exon 14 (0.5%)
Imatinib 800 mgImatinib 400 mg
D842VClinical study
Not D842VIM-sensitive
Not D842VIM-resistant Clinical study
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Pre-clinical development of a PDGFRA D842V mutant inhibitor
• Studies performed in partnership with AROG Pharmaceuticals (Dallas, Texas)
• First experiment Sepember 2010!
• Testing a novel PDGFRA inhibitor (crenolanib) against GIST-relevant mutations
• Crenolanib has already undergone phase I testing– Good bioavailability and pharmacokinetics– Well tolerated with a similar side effect profile to other similar
TKIs– Pfizer discontinued clinical development due to the large number
of TKIs that were being developed
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PDGFRA WT
IC 50 Crenolanib: 11 nM IC50 Imatinib: 9 nM
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D842V
IC 50 Crenolanib: 7nM IC50 Imatinib: 720 nM
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V561D + D842V
IC 50 Crenolanib: 18 nM IC50 Imatinib: >1000 nM
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Phase 2 Study of Crenolanib
• Primary or secondary PDGFRA D842V
• Open at Fox Chase Cancer Center (2 patients enrolled)
• Scheduled to open at OHSU by end of this month (3 patients awaiting study opening)
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Other OHSU GIST trials (opening soon)
• Phase 3 study of regorafenib as 3rd or 4th line therapy
• Phase 2 study of HSP90 inhibitor + imatinib
• Monoclonal antibody to PDGFRA
• Ongoing (but closed to enrollment)– Regorafenib phase 2 study– Persist-5 study (5 years of adjuvant imatinib for high-
risk resected GIST)
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From All of Us
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To All of You
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Thanks!!!