1. GDC-0449 in Patients With Advanced Chondrosarcomas: a French Sarcoma Group / French and US NCI phase II collaborative study Antoine Italiano, Axel Le Cesne, Jean-Yves Blay, Sophie Piperno-Neumann, Florence Duffaud, Nicolas Penel, Philippe Cassier, Julien Domont, Naoko Takebe, Carine Bellera, Binh Bui

2. Chondrosarcoma Chondrosarcoma is the most common primary malignancy of bone in adults. Localized disease: surgery ++ Locally unresectable/metastatic disease: conventional cytotoxic agents and radiotherapy are generally considered as not effective.

3. Hedgehog pathway Four mechanims of activation -mutation driven: basel cell carcinoma, medulloblastoma -autonomous tumor cell activation -Stroma supporting -Cancer stem cell

4. Hedgehog pathway is overexpressed in chondrosarcomas Tiet TD et al. Am J Pathol 2006;168(1):321-30.

5. Hedgehog: a crucial pathway in chondrosarcomas Inhibition of the hedgehog pathway in chondrosarcoma xenografts results in reduced cell proliferation and decreased tumor size Tiet TD et al. Am J Pathol 2006;168(1):321-30.

6. SMO inhibitors have preclinical activity in chondrosarcomas Campbell et al. AACR 2011 abstract number LB-380

7. GDC-0449 (Vismodegib) background GDC-0449 is a selective Hh pathway inhibitor that blocks Hh signaling by binding to SMO and inhibiting activation of downstream Hh target genes Preclinical activity in several tumor models: medulloblastoma, colorectal cancer, pancreatic carcinoma… FDA approved on Jan. 30 2012 for the treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

8. COLLABORATION

9. Aim: To assess the efficacy and safety of GDC-0449 in patients with locally advanced (unresctable) and/or metastatic chondrosarcomas First endpoint: 6-months clinical benefit rate (CR, PR and SD as per RECIST criteria, based on centralized review) Secondary endpoints: Objective response rate (RECIST) Best overall response (RECIST) 1-year and 2-year progression-free survival 1-year and 2-year overall survival Safety Biomarkers:PTCH and SMO sequencing PTCH, SMO, GLI1 expression (qRT-PCR) Study aim and endpoints

10. Study design Single-arm phase 2 clinical trial based on two-stage Simon’s design. Study population: Adult patients with unresectable locally advanced or metastatic chondrosarcoma (with confirmation of histology based on centralized review) GDC-0449: 150 mg, take with or without food at the same time every day (day 1-day 28) Radiological tumor assessment performed at baseline and every eight weeks Centralized histological and radiological review

11. Statistical hypothesis No chemotherapy historical series to build a statistical hypothesis Based on the following hypotheses: H0: 20% 6-month non-progression rate H1: 40% 6-month non-progression rate 10% type I error rate + 90% power  37 eligible and assessable patients required. Stage 1: 17 patients (4/17 non-prog required to continue) Stage 2 : 20 patients (11/37 non-prog required to claim efficacy) 45 patients recruited to account for not assessable patients

12. Patient disposition* Number of patients enrolled (02/2011-02/2012) Eligibility at baseline Eligible Assessability for 6-month efficacy Eligible and assessable - Eligible and assessable (two-stage Simon’s design) Not assessable at 6 months Treatment n (% enrolled) Still under treatment Terminated 45 40 37 5 8 (17,8) 37 (82,2) Reason for end of treatment (out of n=37) n,% Adverse event Death Progressive disease Physician’s choice 1 (2.7) 1 (2,7) 34 (91.9) 1 (2,7) *A the time of analysis: October 17 th, 2012

13. Baseline Characteristics Sex, n (%) Male Female N=45 enrolled (%) 31 (68,9) 14 (31,1) Age Median, years (range)58,0 (27,0 – 85,0) ECOG PS, n (% ) 0 1 2 20 (44,4) 5 (11,1) Histological subtype (%)* Conventional chondrosarcoma Dedifferentiated chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma 39 (86,7) 5(11,1) 1 (2,2) 0 (0,0) Stage n (%) Locally advanced Metastatic 13 (28,9) 32 (71,1) Prior lines of chemotherapy n (%) 0 1 2 > 2 25 (55,6) 12 (26,7) 3 (6,7) 5 (11,1) *with centralized review)

14. Efficacy: First endpoint 11 patients out of 37 achieved stable disease at 6-months after central radiological review Clinical benefit rate: 29.7% (95% CI,15.9- 47.0) Study achieved its primary endpoint

15. Male 80 years GDC-0449 start: 11/2011 Still under treatment (11/2012) RECIST: SD (0%) DCE-MRI: partial response

16. Efficacy: Progression-Free Survival Median PFS: 3.6 months (95% CI, 1.9-5.5) 6-months PFS: 32.4% (95% CI,18.2-47.5) 1-year PFS: 22.5% (95% CI, 10.1-37.9)

17. Efficacy: Overall Survival Median OS: 12.4 months 6-months OS: 79.1% (95% CI, 62.4-88.9) 1-year OS: 52.6 % (95% CI, 33.8-68.3)

18. Adverse events* (N=45 treated patients) Grade Grade 1,2 Grade 3,4 N%N% Clinical symptoms Dysgeusia 2964.4 Fatigue 2248.9 Nausea 1533.3 Myalgia 2248.912.2 Diarrhea 1226.7.. Anorexia 1022.2 Weight loss 715.6 Headache 511.1 Alopecia 1840.0 Vomiting 41.6.. Gastroesophageal reflux disease 36.7 Abdominal pain 36.712.2 Laboratory investigations Alanine aminotransferase increased 48.924.4 Aspartate aminotransferase increased 12.224.4 Dehydration..12.2 Hypercalcemia 511.112.2 Hyperkalemia 511.1.. Anemia 613.312.2 *Related to the treatment)

19. Exploratory analysis (N=40) All patients with 6-months clinical benefit have grade 1 or 2 conventional chondrosarcoma

20. Translational study No mutation of PTCH and SMO Overexpression of HH ligand in 65% of cases No significant correlation between HH, GLI1, GLI2 gene expression and outcome (Wilcoxon two-sample test)

21. International academic collaboration is feasible in the context of rare cancer GDC-0449 is well tolerated with limited dysguesia, alopecia and myalgia being the most frequent adverse events GDC-0449 is associated with long-term stable disease in a subset of patients with advanced chondrosarcoma Conclusion

22. The authors would like to thank: the patients and their families the investigators and staff at the participating centers Study funded by the French National Cancer Institute Acknowledgements