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GIST Research at Fox Chase Cancer Center

GIST Research at Fox Chase Cancer Center. Margaret von Mehren, MD. 1.0. 0.9. 0.8. 0.7. 0.6. 0.5. 0.4. 0.3. 0.2. 0.1. 0. 10. 20. 30. Survival Following Recurrence or Metastases in GIST. Survival Probability. DFCI Data, 1995-2000. Time from Recurrence to Death (Months). TOTAL.

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GIST Research at Fox Chase Cancer Center

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

  2. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 10 20 30 Survival Following Recurrenceor Metastases in GIST Survival Probability DFCI Data, 1995-2000 Time from Recurrence to Death (Months) TOTAL DEAD ALIVE MEDIAN 23.0 39 33 72

  3. 1.0 0.8 0.6 0.4 0.2 0.0 Time to Progression with Chemotherapy in GIST Probability 0 2 4 6 8 10 Time to Progression (Months) Demetri, G

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

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

  6. Randomized Phase II Trial of STI571 in Metastatic GIST 400 mg/day R E G I S T E R Treat Daily x 24 months S C R E E N Progression 600 mg/day Serial Correlative Studies Imaging and Biopsies

  7. Response

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

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

  10. Histology Pre-treatment 7 Days Post-treatment

  11. Progression free survival 100 90 80 70 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 6 400 mg 800 mg Estimated hazard ratio:0.89 in both studies

  12. Overall survival 100 90 80 70 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 6 400 mg 800 mg

  13. 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 (years) 0 1 2 3 4 5 0 1 2 3 4 5 Mutation status KIT exon 11 mutants – KIT exon 9 mutants – Wild types - Other

  14. Overall survival KIT exon 9 mutants 100 90 80 70 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 KIT exon 9 mutants: 400 mg / 800 mg - Other patients: 400 mg / 800 mg

  15. 1.0 .8 .6 Fraction Surviving N=80 .4 5 yr survival 54% .2 0.0 0 2 4 6 8 10 12 14 16 Years Postoperative Outcome in Primary GIST Rationale for Adjuvant Therapy DeMatteo, Ann Surg 2000; 231:51

  16. ? Treatment of Localized Primary GIST Resectable Unresectable Surgery Imatinib www.NCCN.org

  17. 100 90 80 70 ----- Imatinib(8 events) Placebo (30 events) 60 50 40 30 20 10 0 Recurrence-Free SurvivalTumor size >10 cm % Recurrence-Free andAlive p < 0.001 HR 0.19 (0.09-0.41) 0 1 2 3 4 Years At risk: Imatinib 82 40 13 1 Placebo 76 28 8 1 DeMatteo, 2009

  18. RFS For Placebo Cases By Genotype 100 90 Exon 9 (n=22) 80 Exon 11 PM (n=55) PDGFRA (n=28) Exon 11 Insertion (n=25) 70 Wildtype (n=32) 60 % Recurrence-Free and Alive 50 Exon 11 Deletion (n=93) 40 p=0.0240 vs WT HR 3.45 (95% CI 1.177 -10.137) 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Time in Months Corless, 2011

  19. RFS For PDGFRA D842V-Mutant Cases by Arm 100 Imatinib (n=15) 90 Placebo (n=13) 80 70 60 % Recurrence-Free and Alive 50 40 30 20 Treatment 10 0 0 6 12 18 24 30 36 42 48 54 Time in Months Corless, 2011

  20. RFS For Exon 11-Mutant Cases by Arm 100 90 80 Imatinib (n=173) 70 60 Placebo (n=173) % Recurrence-Free and Alive 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 60 Time in Months Corless, 2011

  21. RFS For Wildtype Cases by Arm 100 90 80 Placebo (n=32) 70 60 Imatinib (n=32) % Recurrence-Free and Alive 50 p=0.6126 at 24 months 40 30 20 10 Treatment 0 0 6 12 18 24 30 36 42 48 54 60 Time in Months Corless, 2011

  22. RFS For Exon 9-Mutant Cases by Arm 100 90 Placebo (n=22) 80 70 Imatinib (n=13) 60 % Recurrence-Free and Alive 50 p=0.8443 at 24 months 40 30 20 10 Treatment 0 0 6 12 18 24 30 36 42 48 54 60 Time in 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 CancerRes, 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. >70%* of WT GISTs have IGF-1R IHC score =3 • 0% of mutant GISTs have IGF-1R IHC score = 3 • *(p= 0.001) IGF-1R is Highly Expressed in “Wild-Type” GISTs 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 IC50 of 10-30nM against PDGFRA exon 18 D842V mutation Heinrich, 2011 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). 34

  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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