GDC-0449 in Patients With Advanced Chondrosarcomas:

a French Sarcoma Group/Frenchand 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):321-30.

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.

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. 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.

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 (02/2011-02/2012)

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

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 17th, 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 (% )0 1 2

20 (44,4)20 (44,4)5 (11,1)

Histological subtype (%)*Conventional chondrosarcomaDedifferentiated chondrosarcomaClear cell chondrosarcomaMesenchymal chondrosarcoma

39 (86,7)5(11,1)1 (2,2)0 (0,0)

Stage n (%)Locally advancedMetastatic

13 (28,9)32 (71,1)

Prior lines of chemotherapy n (%)012> 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,15.9- 47.0)

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, 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)

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)

Adverse events* (N=45 treated patients)

Grade

  Grade 1,2 Grade 3,4

N % N %

Clinical symptoms        Dysgeusia 29 64.4Fatigue 22 48.9Nausea 15 33.3Myalgia 22 48.9 1 2.2Diarrhea 12 26.7 . .Anorexia 10 22.2Weight loss 7 15.6Headache 5 11.1Alopecia 18 40.0Vomiting 4 1.6 . .Gastroesophageal reflux disease 3 6.7Abdominal pain 3 6.7 1 2.2

Laboratory investigations        Alanine aminotransferase increased 4 8.9 2 4.4Aspartate aminotransferase increased 1 2.2 2 4.4Dehydration . . 1 2.2Hypercalcemia 5 11.1 1 2.2Hyperkalemia 5 11.1 . .Anemia 6 13.3 1 2.2

*Related to the treatment)

Exploratory analysis (N=40)

6-months RESPONSE p-value

(Fisher’s exact test) PD SD

N % N %

Sex 0.1244 Male 18 62.1 10 90.9 Female 11 37.9 1 9.1 Histological type 1.0000 Conventional 26 89.7 11 100.0 Dedifferentiated 2 6.9 0 0.0 Clear cell subtype 1 3.4 0 0.0 Grade 0.1595 . 1 3.4 0 0.0 1/2 21 72.4 11 100.0

3 7 24.1 0 0.0

ECOG 0.5480 0/1 26 89.7 11 100.0 2 3 10.3 0 0.0 Number of metastatic sites

0.1278

0 7 24.1 6 54.5 ≥1 22 75.9 5 45.5 Prior lines of chemotherapy

1.0000

0 18 62.1 7 63.6 ≥1 11 37.9 4 36.4

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