1

PFINOV 04340 Core DT4 04/21/23 16:22

Update on GIST Research

Michael Heinrich, M.D.

2

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

3

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)

4

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

5

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

6

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

7

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

8

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”

9

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

10

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

11

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

12

PDGFRA WT

IC 50 Crenolanib: 11 nM IC50 Imatinib: 9 nM

13

D842V

IC 50 Crenolanib: 7nM IC50 Imatinib: 720 nM

14

V561D + D842V

IC 50 Crenolanib: 18 nM IC50 Imatinib: >1000 nM

15

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)

16

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)

17

From All of Us

18

To All of You

19

Thanks!!!