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

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.

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

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

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):

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

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 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.

COLLABORATION

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

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

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

Patient disposition* Number of patients enrolled (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 (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

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 (% ) (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 (%) > 2 25 (55,6) 12 (26,7) 3 (6,7) 5 (11,1) *with centralized review)

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, ) Study achieved its primary endpoint

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

Efficacy: Progression-Free Survival Median PFS: 3.6 months (95% CI, ) 6-months PFS: 32.4% (95% CI, ) 1-year PFS: 22.5% (95% CI, )

Efficacy: Overall Survival Median OS: 12.4 months 6-months OS: 79.1% (95% CI, ) 1-year OS: 52.6 % (95% CI, )

Adverse events* (N=45 treated patients) Grade Grade 1,2 Grade 3,4 N%N% Clinical symptoms Dysgeusia Fatigue Nausea Myalgia Diarrhea Anorexia Weight loss Headache Alopecia Vomiting Gastroesophageal reflux disease 36.7 Abdominal pain Laboratory investigations Alanine aminotransferase increased Aspartate aminotransferase increased Dehydration Hypercalcemia Hyperkalemia Anemia *Related to the treatment)

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

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)

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

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