Transcript Diapositive 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
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
Study aim and endpoints
• 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 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)
45
Eligibility at baseline
• Eligible
45
Assessability for 6-month efficacy
• Eligible and assessable
- Eligible and assessable (two-stage Simon’s design)
• Not assessable at 6 months
40
37
5
Treatment n (% enrolled)
• Still under treatment
• Terminated
8 (17,8)
37 (82,2)
Reason for end of treatment (out of n=37) n,%
Adverse event
Death
Progressive disease
Physician’s choice
*A the time of analysis: October 17th, 2012
1 (2.7)
1 (2,7)
34 (91.9)
1 (2,7)
Baseline Characteristics
N=45 enrolled (%)
Sex, n (%)
Male
Female
Age
Median, years (range)
31 (68,9)
14 (31,1)
58,0 (27,0 – 85,0)
ECOG PS, n (% )
0
1
2
20 (44,4)
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)
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
%
29
22
64.4
48.9
15
22
12
10
7
5
18
4
3
3
33.3
48.9
26.7
22.2
15.6
11.1
40.0
1.6
6.7
6.7
1
.
2.2
.
.
.
1
2.2
4
1
.
5
5
8.9
2.2
.
11.1
11.1
2
2
1
1
.
4.4
4.4
2.2
2.2
.
6
13.3
1
2.2
Clinical symptoms
Dysgeusia
Fatigue
Nausea
Myalgia
Diarrhea
Anorexia
Weight loss
Headache
Alopecia
Vomiting
Gastroesophageal reflux disease
Abdominal pain
Laboratory investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Dehydration
Hypercalcemia
Hyperkalemia
Anemia
*Related to the treatment)
Exploratory analysis (N=40)
6-months RESPONSE
PD
Sex
Male
Female
Histological type
Conventional
Dedifferentiated
Clear cell subtype
Grade
.
1/2
3
ECOG
0/1
2
Number of metastatic
sites
0
≥1
Prior lines of
chemotherapy
0
≥1
SD
N
%
N
%
18
11
62.1
37.9
10
1
90.9
9.1
p-value
(Fisher’s exact test)
0.1244
1.0000
26
2
1
89.7
6.9
3.4
11
0
0
100.0
0.0
0.0
0.1595
1
21
3.4
72.4
0
11
0.0
100.0
7
24.1
0
0.0
0.5480
26
3
89.7
10.3
11
0
100.0
0.0
0.1278
7
22
24.1
75.9
6
5
54.5
45.5
1.0000
18
11
62.1
37.9
7
4
63.6
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)
Conclusion
• 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
Acknowledgements
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