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GIST Research at Fox Chase Cancer Center Margaret von Mehren, MD.

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Presentation on theme: "GIST Research at Fox Chase Cancer Center Margaret von Mehren, MD."— Presentation transcript:

1 GIST Research at Fox Chase Cancer Center Margaret von Mehren, MD

2 MEDIANALIVEDEADTOTAL Time from Recurrence to Death (Months) DFCI Data, Survival Following Recurrence or Metastases in GIST Survival Probability

3 Time to Progression (Months) Probability Time to Progression with Chemotherapy in GIST Demetri, G

4 SLF P P P PPP Ligand-dependent Activation of Wild-type c-kit

5 P P P PPP Ligand-independent Activation of Mutant KIT (Exon 11) In frame mutation of exon 11

6 Randomized Phase II Trial of STI571 in Metastatic GIST SCREENSCREEN REGISTERREGISTER 400 mg/day 600 mg/day Treat Daily x 24 months Serial Correlative Studies Imaging and Biopsies Progression

7 Response

8 Pre- and Post-STI571 8/16/00 2/6/01

9 PET Before and after STI571 12/7/00 1/9/01

10 7 Days Post-treatment Pre-treatment Histology

11 Hazard ratio0.89 P-value0.04 Median PFS (months)19 / 23 3 years estimate (%)30 / 34 (years) mg800 mg Progression free survival Median PFS (months)19 / 23 3 years estimate (%)30 / 34 Hazard ratio0.89 P-value (logrank test)0.04 Estimated hazard ratio: 0.89 in both studies

12 (years) mg800 mg Overall survival Median OS (months)49 / 49 3 years estimate (%)60 / 61 Hazard ratio1.00 P-value (logrank test)0.97

13 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) Progression free survival (years) Overall survival KIT exon 11 mutants – KIT exon 9 mutants – Wild types - Other

14 (years) 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

15 DeMatteo, Ann Surg 2000; 231:51 Postoperative Outcome in Primary GIST Rationale for Adjuvant Therapy Years Fraction Surviving yr survival 54% N=80

16 Treatment of Localized Primary GIST Resectable ImatinibSurgery Unresectable ?

17 Recurrence-Free Survival Tumor size >10 cm p < HR 0.19 ( ) Years % Recurrence-Free and Alive Placebo Imatinib At risk: Imatinib (8 events) Placebo (30 events) DeMatteo, 2009

18 PDGFRA (n=28) Wildtype (n=32) Exon 9 (n=22) RFS For Placebo Cases By Genotype Time in Months % Recurrence-Free and Alive Exon 11 Deletion (n=93) Exon 11 PM (n=55) Exon 11 Insertion (n=25) p= vs WT HR 3.45 (95% CI ) Corless, 2011

19 RFS For PDGFRA D842V-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=15) Placebo (n=13) Treatment Corless, 2011

20 RFS For Exon 11-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=173) Placebo (n=173) Treatment p< at 24 months HR 3.42 (95% CI ) Corless, 2011

21 RFS For Wildtype Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=32) Placebo (n=32) Treatment p= at 24 months Corless, 2011

22 RFS For Exon 9-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=13) Placebo (n=22) Treatment p= at 24 months Corless, 2009

23 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

24 Where are we going? New Treatment Approaches for advanced disease Mutation directed therapies –IGF-1R inhibitors –PDGFRA inhibitors

25 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

26 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

27 Hsp-90: Therapeutic Target Xu and Neckers, Clin Cancer Res, 2007; 13(6):1625-9

28 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)

29 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

30 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

31 IGF-1R is Highly Expressed in “Wild- Type” GISTs  >70%* of WT GISTs have IGF-1R IHC score =3  0% of mutant GISTs have IGF-1R IHC score = 3 *(p= 0.001) + 30-fold overexpressed

32 OSI-906 Oral tyrosine kinase inhibitor with activity against IGF-1R Phase II trial in WT GIST 150 mg BID

33 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)

34 CP-868,596 has an IC 50 of 10-30nM against PDGFRA exon 18 D842V mutation 34 CP-868,596 inhibited the phosphorylation of wild type PDGFRA at an IC 50 of 10 nM and PDGFRA (D842V) with an IC 50 between 10 to 30 nM. Imatinib was ineffective in blocking PDGFRA (D842V) phosphorylation in these experiments (IC 50 > 1000 nM). Heinrich, 2011

35 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

36 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


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