1. Sorafenib/Nexavar in Desmoid tumors Mrinal Gounder, M.D. Scientific Director, Desmoid Tumor Research Foundation Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, NY. DTRF 7 th Annual Patient Symposium Sept 28th, 2013

2. Sorafenib in desmoid tumor/deep fibromatosis (DT/DF) -- 26 patients with progressive disease -- Memorial Sloan-Kettering Cancer Center patients only, retrospective review

3. Index Case: 23 yr old woman with supraclavicular DT PARTIAL RESPONSE. On therapy 36+ months

4. 32 yo female with a large desmoid in her thoracic cavity displacing the mediastinum. At risk for cardiopulmonary collapse. Sx: +SOB, Orthopnea, swelling in LE SHRINKAGE. On therapy 27+ mo.

5. 35 yo male w/ axillary and neurovascular compromise. Heavily pre-treated. Forequarter amputation only surgical option. 10/28/08: Post Gadolinium (upper extremity) 1/12/10: Post Gadolinium SHRINKAGE. On Therapy: 25+ mo

6. 30 year old woman with chest wall mass 4/30/08: Post Gadolinium Chest Wall 3/10/09: Post Gadolinium Chest Wall STABLE DISEASE. On therapy: 35+ mo.

7. A multicenter, Phase III, double blind, randomized, placebo-controlled trial of sorafenib in desmoid tumors or aggressive fibromatosis. Study Chair/PI: Mrinal Gounder Co-PI: Gary Schwartz and Robert Maki ALLIANCE chair: Monica Bertagnolli

8. Desmoid tumor R 2:1 Sorafenib 400 mg dailyPlacebo CT or MRI scans every 2 months Decrease in size or stable Stay on sorafenib or placebo Increase in size If on placebo, then switch to sorafenib. If on sorafenib, then off study UNBLIND If progression UNBLIND Voluntary Biopsies

9. Why do this trial? This is the first Phase III trial in desmoid tumors. To avoid or delay surgeries, radiation or chemotherapies. If this is successful, it paves the way for evaluating new drugs in this and other rare tumors Largest trial and will be open in 100+ hospitals throughout the country. Why give placebo? To access whether sorafenib is truly more effective and if so, by how much better? Why do voluntary tumor biopsies? We know that not all patients benefit with sorafenib. Can we identify a blood or tumor test by which we can identify patients who will benefit and only treat those patients? Tumor biopsies will help us identify markers in the tumor which can give us valuable information on which patients stand to benefit. The funds for this study is already allocated by DTRF

10. Conclusions: -- PR: 25%. Stable Disease: 70%. POD: 5% -- Palliation of symptoms: 70% -- Durable clinical benefit : 36+ months -- T2 signal change seen 90% of patients with MRI as early as 3.5 months -- Mechanism of action of sorafenib is unknown.

11. A Phase 2 Study of Vismodegib, a hedgehog inhibitor in combination with RO4929097, a notch inhibitor in metastatic sarcomas NCT01154452 Mrinal Gounder, MD Melanoma and Sarcoma Service Memorial Sloan-Kettering Cancer Center, New York, NY

12. CROSS-TALK between Hedgehog and Notch pathway

13. Notch Pathway: Desmoid Tumors ND: No Drug JC34: GSI RO: R04929097 Nsi: Notch siRNA

14. GDC = Hh, RO = Notch

15. THANK YOU Our desmoid tumor patients at MSKCC for participation. Jeanne Whiting and Marlene Portnoy. Thank you all for supporting research on desmoid tumors. Questions