Transcript Slide 1
Prostate Cancer Epidemiology:
Estimated 2010
Total Active Disease: 773,000
Stages I-III: 508,000
Metastatic (M+):
183,000
Castrate Sensitive*:
80,000
Castrate Resistant*:
103,000
US Census,
SEER 2007,
NODBIMPAC
Market
Research
Symptomatic
M+ CRPC
Asymptomatic
M+ CRPC
*Estimated based on physician reported percentages among 200
community oncologists and urologists.(2005).
Life After Traditional
Androgen Deprivation Failure
• Other Hormonal Therapy
• Chemo Therapy
• Immunotherapy
Rationale For Immunotherapy
• Cancer
• Cellular dysfunction
• Resistance to or escape from host defenses
• Active immunotherapy
• Suitable target antigen
• Effective presentation of antigen
• Mobilization of immune cascade
Antigen Presenting Cells
(APCs)
Dendritic cells (DCs) are antigen-presenting
cells that process and present MHC-peptide
complexes to activate a T-lymphocyte
response
T-cell
CD154
CD11/CD18
CD8
TCR CD4
CD28
Peptide
CD40
CD54
MHC class I
MHC class II
Dendritic cell
CD80
CD86
CTLA4
sipuleucel-T (Provenge®)
sipuleucel-T is an autologous active cellular
immunotherapy that activates the immune
system against prostate cancer
Sipuleucel-T: Patient-Specific Therapy
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is
manufactured
Dendreon
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
Percent without Progression
Primary Endpoint (Trial 9901)
Time to Disease Progression Study 1
100
sipuleucel-T (n=82)
placebo (n=45)
75
p = 0.052 (log rank)
HR = 1.45 [95% CI: 0.99, 2.11]
50
25
0
0
8
16 24 32 40 48 56 64 72 80
Weeks
Secondary Endpoint - Survival
Clinically Significant and Statistically
Persuasive Overall Survival Benefit
100
sipuleucel-T (n=82)
placebo (n=45)
75
p = 0.010 (log rank)
HR = 1.71 [95% CI: 1.13, 2.58]
50
Median benefit
4.5 months
34%
25
11%
0
0
6
12
18
24
30
36
Vote of FDA Expert Panel
17 – 0 for safety
13 – 4 for substantial evidence of efficacy
FDA Requires More Data
(<2% Event)
Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=512)
Primary endpoint:
Secondary endpoint:
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discretion
and/or Salvage
Protocol
Overall Survival
Time to Objective Disease Progression
S
U
R
V
I
V
A
L
Eligibility Criteria
Metastatic castrate resistant prostate cancer
Life expectancy of at least 6 months
Serum PSA ≥ 5.0 ng/mL
Castrate level of testosterone (< 50 ng/dL)
achieved via medical or surgical castration
Adequate hematologic, renal, and liver
function
Negative serology for HIV 1 & 2, HTLV-1, and
Hepatitis B & C
Patient Demographics and Baseline
Characteristics
Age, median yrs (range)
Race, white (%)
ECOG status, 0 (%)
Gleason Score ≤ 7 (%)
Sipuleucel-T
(N = 341)
72 (49 – 91)
89.4
82.1
75.4
Placebo
(N = 171)
70 (40 – 89)
91.2
81.3
75.4
Disease localization
Bone only (%)
Soft tissue only (%)
Bone & soft tissue (%)
>10 bone mets (%)
50.7
7.0
41.9
42.8
43.3
8.2
48.5
42.7
Bisphosphonate use
Prior docetaxel (%)
48.1
15.5
48.0
12.3
Baseline Median Laboratory Values
Sipuleucel-T
(N = 341)
Placebo
(N = 171)
Serum PSA, ng/mL
51.7
47.2
Serum PAP, U/L
2.7
3.2
Alk. Phosphatase, U/L
99.0
109.0
Hemoglobin, g/dL
12.9
12.7
LDH, U/L
194.0
193.0
6.2
6.0
WBC, 103/µL
IMPACT Overall Survival: Primary Endpoint
Intent-to-Treat Population
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
Percent Survival
100
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
75
50
25
Placebo (n = 171)
Median Survival: 21.7 Mos.
0
0
6
12
18
24
30
36
42
48
Survival (Months)
54
60
66
Overall Survival Summary
Survival Percentiles (months)
N
75%
50%
25%
Sipuleucel-T
341
15.1
25.8
41.3
Placebo
171
11.0
21.7
35.6
4.1 mos
Sipuleucel-T
Placebo
% Survival (K-M estimates
24 Mos.
36 Mos.
48 Mos.
52.1
31.7
20.5
41.2
23.0
8.7%
16.0
Survival Consistency Between Population
Subsets
Favors sipuleucel-T
Bisphosphonate Use: Yes
No
Primary Gleason Grade: 4
3
No. Bone Metastases: > 10
10
Disease Localization: Single
Bone + Soft Tissue
ECOG Performance Status: 1
0
Age: Above Median
Below Median
PSA: Above Median
Below Median
LDH: Above Median
Below Median
Alkaline Phos: Above Median
Below Median
Hemoglobin: Above Median
Below Median
0.0
0.5
1.0
1.5
Hazard Ratio (95% Confidence Interval)
Survival Results Confirmed by Multiple
Sensitivity Analyses
Favors sipuleucel-T
0.775
P = 0.032
0.766
P = 0.023
0.763
P = 0.036
0.772
P = 0.036
Primary Model (Adj. for PSA, LDH)
Unadjusted/Log Rank
Adjusted for Docetaxel Use
PCa-Specific Survival
0.0
0.5
1.0
Hazard Ratio (95% Confidence Interval)
1.5
Most Common Adverse Events (≥ 5%)
Higher Rate in Sipuleucel-T (p ≤ 0.05)
Sipuleucel-T
N = 338
%
54.1
Placebo
N = 168
%
12.5
Pyrexia
29.3
13.7
Headache
16.0
4.8
Influenza-like illness
9.8
3.6
Hypertension
7.4
3.0
Hyperhidrosis
5.3
0.6
Preferred Term
Chills
Serious Adverse Events*
Safety Population
SAE Preferred Term
Any SAE
Pyrexia
Cerebrovascular accident
Pulmonary embolism
Spinal cord compression
Nausea
Atrial fibrillation
Dehydration
Cardiac failure congestive
Pneumonia
Hematuria
Deep vein thrombosis
Renal failure acute
*Occurring in ≥ 4 patients.
Sipuleucel-T
N=338
%
24.0
1.8
1.8
1.2
1.2
0.9
0.9
0.9
0.6
0.6
0.6
0.3
0.3
Placebo
N=168
%
23.8
0.6
1.8
0.0
1.2
1.2
0.6
0.6
1.2
1.2
1.2
1.8
2.4
Consistency Across Phase 3 Studies
D9901*
D9902A*
IMPACT **
Integrated**
(N = 127)
(N = 98)
(N = 512)
0.586
0.786
0.775
(N=737)
0.735
p = 0.010
p = 0.331
p = 0.032
p < 0.001
4.5
3.3
4.1
3.9
sipuleucel-T
34%
32%
32%
33%
placebo
11%
21%
23%
20%
Hazard Ratio
p-value
Median Survival Benefit
(months)
36-Month survival (%)
*Unadjusted Cox model & log rank
**Cox model adjusted for PSA and LDH
Summary
First active immunotherapy to demonstrate
improvement in overall survival for cancer
Highly favorable benefit to risk profile
Short duration of therapy
Potential to create new paradigm in treatment
of metastatic, castrate resistant prostate
cancer
Time to Objective Disease Progression
Secondary endpoint
Result
– Independent radiologic review
– HR=0.951 (95% CI: 0.77,1.17); P=0.628 (log rank)
Consistent with other trials in advanced
prostate cancer
Difficult endpoint to measure reliably and
doesn’t correlate with overall survival
PSA-TRICom Randomized Phase II Study
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=125)
PROSTVAC-VF
Tricom + GM
2:1
Empty Vector +
placebo
P
R
O
G
R
E
S
S
I
O
N
Treated at
physician
discretion
Treated at
physician
discretion
and/or Salvage
Protocol
Primary endpoint:
Progression Free Survival
Secondary endpoint:
Overall Survival
S
U
R
V
I
V
A
L
PSA-TRICom Progression-Free Survival
Hazard Ratio = 0.88 (95% CI 0.57 to 1.38)
P = 0.60 (stratified logrank)
100
80
60
40
20
N
Control
40
PROSTVAC 82
0
0
1
Events Median
30
3.7
58
3.8
2
3
Months
4
5
6
25
PSA-TRICom Overall Survival
Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)
P = 0.006 (stratified logrank)
100
N
Control
40
PROSTVAC 82
Deaths Median
37
16.6
65
25.1
80
60
40
20
0
0
12
24
36
Months
48
60
26
Background-The Development of
PROSTVAC-VF-Tricom
Vaccinia
– Potent immunological priming agent
– Derived from wild-type Wyeth strain (used in millions of
immunizations)
Fowlpox
– Minimally/non-cross-reactive with vaccinia
Enables boosting
Slightly altered PSA transgene
Tricom
– Lymphocyte function-associated antigen LFA-3 (CD58)
– Intercellular adhesion molecule ICAM-1 (CD54)
– Costimulatory molecule for the T-cell receptor B7.1
(CD80)
27
PROSTVAC-PSA-Tricom
Vaccinia-PSA-Tricom
Fowlpox-PSA-Tricom
Prime
Boosts
28
Conclusions
Poxviral-based immunotherapy is feasible and safe
Primary endpoint of prolonged PFS was not met
Secondary endpoint of prolonged median OS
– 8.5 month difference in OS, HR 0.56 (95% CI 0.37-0.85) with
p=0.0061
Baseline characteristics of patients in both arms
similar
Need to validate these findings in large Phase III study
with survival endpoint