1. Pediatric GIST: KIT inhibitors & IGF1R-directed antibodies January 22, 2009 Katherine Janeway, MD

2. GIST TUMOR GIST CELLS

3. X X Genes Proteins Mutation

4. X Grow Divide ON OFF Gleevec (inhibitors) Receptor tyrosine kinase KIT PDGFRA IGF1R Antibody

5. Overview What are the differences between pediatric and adult GIST? Are gleevec and other KIT inhibitors useful in pediatric GIST? Are there any studies or new treatments for pediatric GIST?  Insulin like growth factor 1 receptor (IGF1R)

6. CharacteristicAdult GISTPediatric GIST AgePeak 60Median 12 Gender distributionEqual75% Female Receptor tyrosine kinase mutations Present in 85%Present in 15% KITPresent (except PDGFRA mutant) Present Pace of diseaseRapidSlow Research toolsCell lines, xenografts, transgenics None yet Features of Pediatric GIST

7. Many patients have multiple tumors in close proximity to each other at diagnosis  Multi-focal Slow pace of disease  In one study 10 of 11 patients with metastatic pediatric GIST were alive and the average length of time since diagnosis was 6 years  Half of people who ultimately have life threatening pediatric GIST survive for longer than 16 years

8. Are gleevec and other KIT inhibitors useful in pediatric GIST? KIT is not mutated (wildtype) in most pediatric GISTs BUT:  KIT is present in pediatric GIST  Some of the inhibitors work against wildtype KIT  Experience suggests KIT inhibitors may work in some pediatric GISTs  Studies show gleevec and sutent work in adult wildtype GIST

9. KIT is present in pediatric GIST

10. Some inhibitors work against wildtype KIT Generic name (Brand name)IC 50 Imatinib (Gleevec)3,132 Sorafenib (Nexavar)910 Dasatinib (Sprycel)316 Sunitinib (Sutent)245 Nilotinib (Tasigna)35 Activity against wildtype KIT (in model cells) Least active Most active

11. Imatinib (Gleevec) in the treatment of pediatric GIST Of 10 pediatric GISTs treated 1 got smaller and 3 were stable AgeGenderLocationResponse 13MLiverStable for 8 months (+) 15FPeritoneum, liverProgressive 10FPeritoneumProgressive 14FPeritoneumMixed for 6 months 10FPeritoneum, liverStable for 9 months (+) 18FPeritoneum, liverProgressive Agaram, Clin Cancer Research, 2008 Hayashi Y, et al. Pediatr Surg Int, 2005

12. Sunitinib (sutent) in the treatment of pediatric GIST Months of treatment before progression CaseResponse to Sutent ImatinibSunitinibSunitinib vs. imatinib 1Stable<17+6 2Smaller14>21+7 3Stable128-4 4Stable1618+2 5Stable<1>18+17 6Progression<1 - 7Stable1218+6

13. Imatinib and sunitinib work in some adult wildtype GISTs Imatinib (gleevec)  45% of adult patients with wildtype GIST will have tumor shrinkage or growth arrest with imatinib treatment The average time without tumor progression is 13 months Sunitinib (sutent)  56% of adult patients with wildtype GIST will have tumor shrinkage or growth arrest with treatment The average time without tumor progression is 19 months

14. Are gleevec and other KIT inhibitors useful in pediatric GIST? It depends  In some cases observation is recommended Review of pediatric GIST for physicians to be published next month  Includes evaluation and treatment recommendations The Children’s Oncology Group is developing guidelines for pediatric GIST evaluation and care

15. Are there any studies or new treatments for pediatric GIST? Insulin like growth factor 1 receptor (IGF1R)

16. What is Insulin like growth factor 1 receptor (IGF1R)? Receptor tyrosine kinase inhibitor Many cancers have IGF1R on the cell surface  But mutations are not present Is involved in normal growth It stimulates cells to grow and divide

17. IGF1R is present in Pediatric GIST but not adult GIST with KIT mutations IGF1R Pediatric KIT wildtype GIST KIT mutant GIST Actin Godwin, A, ASCO 2008

18. There are 8 antibody drugs and 2 small molecule drugs currently being tested in clinical studies  Most of these studies are restricted to certain tumor types Early results of clinical tests of IGF1R antibody drugs  Relatively few side effects High blood sugar in a few people – can be controlled  Some reports of responses to treatment in other sarcomas (Ewing sarcoma) Drugs attacking IGF1R

19. A phase II trial is in development with SARC  Several more months before finalized Who can be on the study?  Patients diagnosed with GIST without a KIT or PDGFRA mutation  Tumor(s) unable to be completely removed by surgery  Tumor(s) visible on CT scan  Those diagnosed at age 18 or older need to have received imatinib Pediatric GIST and IGF1R antibody

20. Pediatric GIST and IGF1R inhibitors Who can be on the study? (continued)  Need to have good organ function  No other anti-GIST medical therapy for 7 days prior or during the study  30 days since last study drug  Allowed to have paraganglioma / pulmonary chondroma  If diabetes, well controlled

21. THANKS!! Lee Helman and Su Young Kim Other physicians participating in the clinic George Demetri, Jonathan Fletcher and more  Mike Heinrich, Chris Corless, Antonio Perez-Atayde, Harry Kozakewich, Gina Z. D’Amato, Chris R. Garrett, Paolo Pedrazzoli, Salvatore Siena, Joel Picus, Dana C. Matthews, James E. Butrynski, Marcus Schlemmer SARC Patients and families Life Raft Group and GIST Support International

22. Carney-Stratakis syndrome and Carney Triad Carney Triad  GIST, paraganglioma and pulmonary chondroma  Not inherited Carney-Stratakis syndrome  GIST and paraganglioma  Inherited  Caused by mutations in succinate dehydrogenase genes (SDHB, SDHC, SDHD)