Pediatric Gastrointestinal Stromal Tumors

1. �Pediatric� Gastrointestinal Stromal Tumors June 18, 2008

2. Overview Differences between GIST in children and GIST in adults Carney-Stratakis syndrome, Carney Triad KIT in pediatric GIST KIT inhibitors in the treatment of pediatric GIST imatinib, sunitinib, nilotinib, sorafenib and others Insulin like growth factor (IGF1R) IGF1R antibodies and inhibitors The Carney-Stratakis syndrome and succinate dehydrogenase mutations

3. Miettinen AFIP: 11 patients metastatic disease, 5 AWD, deaths 5 to 35 years Antonescu, 1st paper: 5 patients all with metastatic disease. 1 death 12 yrs post dx; AWD 2-12 years after dx St. Judes experience: 7 patients; 2 DOD 1.2-2.2 years after dxMiettinen AFIP: 11 patients metastatic disease, 5 AWD, deaths 5 to 35 years Antonescu, 1st paper: 5 patients all with metastatic disease. 1 death 12 yrs post dx; AWD 2-12 years after dx St. Judes experience: 7 patients; 2 DOD 1.2-2.2 years after dx

4. Carney-Stratakis syndrome and Carney Triad Carney Triad GIST, paraganglioma and pulmonary chondroma Not inherited Carney-Stratakis syndrome GIST and paraganglioma Inherited

5. Receptor tyrosine kinase mutations in pediatric GIST Most pediatric GISTs have no mutations in KIT or PDGFRA (called wildtype) 27 cases plus 31 previously published genotyped cases: 15% of pediatric GISTs harbor KIT or PDGFRA mutations Pediatric Adult KIT exon 11 5% 66% KIT exon 9 9% 10% PDGFRA 3% 7% Mutation testing

6. No PDGFRA expressionNo PDGFRA expression

7. KIT inhibitors and pediatric GIST Studied in model cells, different from GIST BAF3 WT KIT transfected cellsBAF3 WT KIT transfected cells

8. Imatinib (Gleevec) treatment of pediatric GIST

9. Sunitinib (sutent) treatment of pediatric GIST IM: 3 pts PD, 3 pts SD, 1 patient adjuvant TTP in patients with SD 12-16 mos mean 13 mos. One patient had a PR, five patients had SD and one patient had PD Duration of SD/PR ranged from 7 to 21 months with a mean of 15 months Two patients continue to take sunitinib for greater than 18 and 21 months for sustained SD/PR. Mean increase 7 months In five of six patients with SD/PR, sunitinib resulted in a longer time to tumor progression than that achieved during prior imatinib therapy. IM: 3 pts PD, 3 pts SD, 1 patient adjuvant TTP in patients with SD 12-16 mos mean 13 mos. One patient had a PR, five patients had SD and one patient had PD Duration of SD/PR ranged from 7 to 21 months with a mean of 15 months Two patients continue to take sunitinib for greater than 18 and 21 months for sustained SD/PR. Mean increase 7 months In five of six patients with SD/PR, sunitinib resulted in a longer time to tumor progression than that achieved during prior imatinib therapy.

10. Sunitinib related side effects Since end of data collection one other pt has developed hypothyroidism Cardiac toxicity seen in COG studySince end of data collection one other pt has developed hypothyroidism Cardiac toxicity seen in COG study

11. Nilotinib (Tasigna) treatment of pediatric GIST Review of pediatric GIST patients getting nilotinib as part of the compassionate use trial is planned.

13. Insulin-like growth factor 1

14. A number of pediatric tumors have IGF1R on the cell surface In most cases, when IGF1R is active cells multiply and are resistant to death A number of drugs that attack IGF1R are being developed In early studies these drugs seem to have relatively few side effects Some reports of responses to treatment in other sarcomas Insulin-like growth factor 1 and cancer

15. A phase II trial in development with SARC Pediatric GIST and Insulin Like Growth Factor 1 Receptor (IGF1R)

16. Succinate Dehydrogenase Mutations in Carney-Stratakis Syndrome 9 families, 11 patients Age 9 to 37 In 7 families, germline mutations (or deletion) of SDHB, SDHC or SDHD Of note, 2 patients had no significant family history

17. Succinate dehydrogenase Part of the electron transport chain The energy factory 4 components (A, B, C and D) Mutations in B, C, D in paraganglioma, pheochromocytoma that runs in families Tumors of nerve cells

18. Succinate Dehydrogenase in Carney Triad and pediatric GIST Carney Triad No mutations but loss of SDHC Pediatric GIST

19. On the horizon Drug levels and response Adjuvant imatinib New drugs and mechanisms HSP90 inhibitors Combinations of inhibitors New Inhibitors PI3 Kinase mTOR Mutation testing: Recommended for all patients especially young patients Imatinib drug levels are related to response to treatment in preliminary studies. These studies are ongoing as is a study of sutent drug levels and response Adjuvant imatinib: Also only preliminary results. Hard to study well. May delay relapse in older patients but doesn�t seem to prolong life. B/c so many pd cases are KIT WT / IM unresponsive, not recommended Mutation testing: Recommended for all patients especially young patients Imatinib drug levels are related to response to treatment in preliminary studies. These studies are ongoing as is a study of sutent drug levels and response Adjuvant imatinib: Also only preliminary results. Hard to study well. May delay relapse in older patients but doesn�t seem to prolong life. B/c so many pd cases are KIT WT / IM unresponsive, not recommended

20. THANKS!! Lee Helman, Alberto Pappo, Norman Scherzer Su Young Kim George Demetri, Jonathan Fletcher and many many 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 Patients and families