The Clinical Approach to Wild Type GIST. Margaret von Mehren, MD Professor and Director of Sarcoma Oncology Fox Chase Cancer Center

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1 The Clinical Approach to Wild Type GIST Margaret von Mehren, MD Professor and Director of Sarcoma Oncology Fox Chase Cancer Center

2 Disclosure slide Scientific Advisor to Novartis, Pfizer, Merck Research funding from Merck

3 WT GIST Studies analyzing mutations in GIST have identified ~ 85% of GIST contain mutations in KIT or PDGFRA The other GIST have been called WT Mutations in alternate genes have been identified in some GIST

4 WT GIST SDH Deficient GIST Carney Triad: leiomyosarcoma /GIST Pulmonary chondroma Paraganglioma Carney Stratakis Syndrome GIST Paraganglioma Pediatric GIST Genomically unstable WT GIST NF-1 Associated GIST

5 IGF-1R and SDHB in WT GIST IGF1R SDHB Rink et al. Manuscript in preparation Belinsky et al, Genes, Chromosomes and Cancer, 2009 Janeway et al, Proceedings of the National Academy of Sciences, 2011

6 Pediatric GIST Defined in the literature as diagnosed prior to age 18 Female preponderance Anemia is a common presentation Gastric, multi-focal, lymph node involvement More indolent course, but recurrences common Genetically stable tumors

7 GIST, pulmonary chondromas, and paraganglioma that can be malignant Adrenal cortical adenomas Esophageal leiomyoma Carney Triad Young age, female predilection, multi-focal, + lymph nodes, slow growing, no family history Epithelioid predominance No identifiable mutation to date; recurrent losses of chromosome 1 Zhang et al. American Journal of Surgical Pathology, Images courtesy of M. von Mehren

8 Carney-Stratakis Diad Presents with 2 of 3 features in the triad Most commonly GIST and paraganglioma that can be malignant Often a family history Associated with mutations in SDHB, SDHC, and SDHD Mutations lead to loss of expression of the SDHB protein Hao H-X, et al. Science, 2009

9 NF-1 Associated GIST 200 fold increased risk of GIST Commonly located in the duodenum or small bowel Can be multi-focal 88% reported to have no activating mutation in KIT, PDGFRA Cells have activation of the MAPK pathway Mietinen and Lasota, Journal of Surgical Oncology, 2011 Maertens et al. Human Molecular Genetics, 2006

10 Non-Syndromic WT GIST In large series of GIST evaluating primarily adult patients, approximately 10% WT tumors Female predilection Course is variable Overlap with SDH deficient subtype Small population with distinct complex genetic changes

11 Unique issues for WT GIST Management Patients may require referral for genetic counseling: Patients with stigmata of neurofibromatosis Patients with paragangliomas Patients without evidence of the Carney triad Screen for paragangliomas utilizing MRI Evaluate for evidence of functional paraganglioma

12 Presence of mutations in WT GIST patients without Diad or Triad Janeway et al. Proceedings of the National Academy of Sciences, 2011

13 Age Related Penetrance of Tumors with SDHB and D mutations A: H&N parag, pheo B: Pheo C: H&N parag. D: Malig Pheo E: Renal tumors Ricketts et al. Human Mutation, 2010.

14 Surgical Approach Limited Resection Goal is to control symptomatic lesions, but retain as much normal gut as feasible Total gastrectomies are discouraged Pappo et al. Journal of Surgical Oncology, 2011

15 TKI-Therapeutic Approach Imatintib CR PR SD PD S % 33% 28.5% 18% EORTC 0% 23% 50% 19% NF Carney Triad Carney Stratakis Pediatric 1/5 4/5 Sunitinib CR PR SD PD Phase I/II 0% 0% 56% 44% NF-1 + Carney Triad Carney Stratakis Pediatric 1/7 5/7 1/7 + Heinrich et al. Journal of Clinical Oncology, 2006 Debiec-Rychter et al. European Journal of Cancer, 2006 Demetri et al. Clinical Cancer Research, 2009 Maertens et al. Human Molecular Genetics, 2006 Janeway et al. Pediatric Blood and Cancer, 2009

16 TKI-Therapeutic Approach CR PR SD PD side effects TOTAL Imatinib 0 (2) HD Imatinib Sunitinib Nilotinib Sorafenib Dasatinib TOTALS 1 ( 1%) 0 ( 0%) 27 (31%) 47 (54%) 12 (14%) 87 Data Courtesy of SY Kim, MD, PhD

17 Routine Management- What do I do? Adjuvant Therapy: ACOSOG Z9001, no difference in recurrence free survival. Advanced, measurable disease: Adults Consider TKI s Imatinib versus Sunitinib Advanced, measurable disease: Pediatrics Observation Consider TKI: Suntinib Role of surgery Advanced, measurable disease: Pediatrics

18 SARC022: A Phase 2 Study of OSI-906 in Pediatric & Adult Patients with Wild Type GIST Age 18 years Advanced, measurable disease Has documented wild-type KIT and PDGFRA genotyping from tumor Primary Objective: Response rate (CR and PR) as determined by RECIST 1.1. Secondary Objectives: Clinical benefit rate (SD 9 months, PR or CR)

19 Other Clinical Trials Pfizer Sponsored trial of Sunitinib in Pediatric GIST Investigator initiated trial of Vandatanib at the NCI in pediatric GIST

20 Conclusions Biologically different tumors High expression of IGF1-R and loss of SDHB expression, minimal genetic changes Low expression of IGF-1R without loss of SDHB, more complex genetics Require genetic counseling Surgical management need to consider the indolent course and probable recurrences Role of standard TKI s is limited Novel therapeutic strategies needed