Immunotherapeutic%20Approaches%20in%20Castration%20Resistant%20Prostate%20Cancer%20(CRPC)

1
Immunotherapeutic Approaches in Castration
Resistant Prostate Cancer (CRPC)

• Philip Kantoff, MD
• Chief, Division of Solid Tumor Oncology
• Dana-Farber Cancer Institute
• Professor of Medicine
• Harvard Medical School

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Sipuleucel-T for Metastatic CRPC
3
Sipuleucel-T Autologous APCs Cultured with
Antigen Fusion Protein
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
4
Sipuleucel-T Logistics of Therapy
Day 1 Leukapheresis
Day 2-3 sipuleucel-T is manufactured
Day 3-4 Patient is infused
Apheresis Center
Central Processing
Doctors Office
COMPLETE COURSE OF THERAPY Weeks 0, 2, 4
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
5
Randomized Phase III Trial of Sipuleucel-T in
CRPC (D9901)
P R O G R E S S I O N
Sipuleucel-T q2wks x 3
Placebo q2wks x 3 (N 45)
Asymptomatic Metastatic CRPC (N 127)
Long-Term Follow-up
Sip-T q2wks x 3 (N 82)

Small EJ et al. J Clin Oncol 200619(24)3089-94.
6
Results Time to Objective Disease Progression
Originally published by the American Society of
Clinical Oncology. Small EJ et al 24(19),
20063089-94.
7
Results Overall Survival
Originally published by the American Society of
Clinical Oncology. Small EJ et al 24(19),
20063089-94.
8
Results Overall Survival Intent-To-Treat
Population
Alive at 36 Months
Deaths
Number of Subjects
Treatment
Median Survival (mos)
28 (34)
54
82
Sipuleucel-T
25.9
5 (11)
40
45
Placebo
21.4

p-value

.0046
.01
Small EJ et al. J Clin Oncol 200619(24)3089-94.
9
Results Overall Survival Intent-to-Treat
Population
Alive at 36 Months
Deaths
Number of Subjects
Treatment
Median Survival (mos)
28 (34)
54
82
Sipuleucel-T
25.9
5 (11)
40
45
Placebo
21.4

p-value

.0046
.01
Small EJ et al. J Clin Oncol 200619(24)3089-94.
10
Results Overall Survival Intent-to-Treat
Population
Alive at 36 Months
Deaths
Number of Subjects
Treatment
Median Survival (mos)
28 (34)
54
82
Sipuleucel-T
25.9
5 (11)
40
45
Placebo
21.4

p-value

.0046
.01
Small EJ et al. J Clin Oncol 200619(24)3089-94.
11
Randomized Phase 3 IMPACT Trial (IMmunotherapy
Prostate AdenoCarcinoma Treatment)
P R O G R E S S I O N
SURVIVAL
Sipuleucel-T Q 2 weeks x 3
Treated at Physician Discretion
Asymptomatic or Minimally Symptomatic mCRPC
(N512)
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Treated at Physician Discretion and/or Salvage
Protocol

Placebo Q 2 weeks x 3
Primary Endpoint Overall Survival Secondary
Endpoint Objective Disease Progression
11
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
12
Patient Demographics and Baseline Characteristics
Sipuleucel-T (N 341) Placebo (N 171)
Age, median years (range) 72 (49 91) 70 (40 89)
Race, Caucasian () 89.4 91.2
ECOG status, 0 () 82.1 81.3
Gleason score 7 () 75.4 75.4
gt10 Bone metastases () 42.8 42.7
Bisphosphonate use 48.1 48.0
Prior docetaxel () 15.5 12.3
Serum PSA, ng/mL 51.7 47.2
Alkaline phosphatase, g/dL 99.0 109.0
LDH, U/L 194.0 193.0
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
13
Patient Demographics and Baseline Characteristics
Sipuleucel-T (N 341) Placebo (N 171)
Age, median years (range) 72 (49 91) 70 (40 89)
Race, Caucasian () 89.4 91.2
ECOG status, 0 () 82.1 81.3
Gleason score 7 () 75.4 75.4
gt10 Bone metastases () 42.8 42.7
Bisphosphonate use 48.1 48.0
Prior docetaxel () 15.5 12.3
Serum PSA, ng/mL 51.7 47.2
Alkaline phosphatase, g/dL 99.0 109.0
LDH, U/L 194.0 193.0
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
14
IMPACT Overall Survival Final Analysis (349
events)
36.5 mo median f/u HR 0.759 (95 CI 0.606,
0.951) p 0.017 (Cox model) Median Survival
Benefit 4.1 months
Sipuleucel-T (n 341) Median Survival 25.8
mo. 36 mo. survival 32.1
Placebo (n 171) Median Survival 21.7 mo. 36
mo. survival 23.0
No. at Risk
Sipuleucel-T 341 274 142 56 18 3
Placebo 171 123 59 22 5 2
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
15
Survival Effect Consistent Across Subpopulations
(Primary Analysis)
15
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
16
No difference in time to objective disease
progression

• Result
• Median TTP 14.4 wks placebo, 14.6 weeks
  sipuleucel-T
• HR 0.951 (95 CI 0.77, 1.17) P 0.628 (log
  rank)

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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
17
Adverse Events More Commonly1 Reported in
Sipuleucel-T Group
Preferred Term Sipuleucel-T N 338 Placebo N 168
Chills 54.1 12.5
Pyrexia 29.3 13.7
Headache 16.0 4.8
Influenza-like illness 9.8 3.6
Myalgia 9.8 4.8
Hypertension 7.4 3.0
Hyperhidrosis 5.3 0.6
Groin pain 5.0 2.4
1 Reported by 5 of sipuleucel-T patients and
having a 2-fold difference from placebo. The
majority of the most common AEs were mild or
moderate in severity.
Safety results obtained from primary analysis did
not substantively change with additional data
obtained after study closure.
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
18
Adverse Events More Commonly1 Reported in
Sipuleucel-T Group
Preferred Term Sipuleucel-T N 338 Placebo N 168
Chills 54.1 12.5
Pyrexia 29.3 13.7
Headache 16.0 4.8
Influenza-like illness 9.8 3.6
Myalgia 9.8 4.8
Hypertension 7.4 3.0
Hyperhidrosis 5.3 0.6
Groin pain 5.0 2.4
1 Reported by 5 of sipuleucel-T patients and
having a 2-fold difference from placebo. The
majority of the most common AEs were mild or
moderate in severity.
Safety results obtained from primary analysis did
not substantively change with additional data
obtained after study closure.
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
19
Consistency Across Phase III Studies
D9901 (N 127) D9902A (N 98) IMPACT (N 512)
Hazard ratio for OS benefit p-value 0.586 p 0.010 0.786 p 0.331 0.775 p 0.032
Median survival benefit (months) 4.5 3.3 4.1
36-month survival () sipuleucel-T placebo 34 11 32 21 32 23
Higano CS et al. Cancer 2009115(16)3670-9
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
20
Consistency Across Phase III Studies
Integrated (N 737)
0.735 p lt 0.001
3.9
33 20
D9901 (N 127) D9902A (N 98) IMPACT (N 512)
Hazard ratio p-value 0.586 p 0.010 0.786 p 0.331 0.775 p 0.032
Median survival benefit (months) 4.5 3.3 4.1
36-month survival () sipuleucel-T placebo 34 11 32 21 32 23
Higano CS et al. Cancer 2009115(16)3670-9
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
21
Consistency Across Phase III Studies
D9901 (N 127) D9902A (N 98) IMPACT (N 512)
Hazard ratio p-value 0.586 p 0.010 0.786 p 0.331 0.775 p 0.032
Median survival benefit (months) 4.5 3.3 4.1
36-month survival () sipuleucel-T placebo 34 11 32 21 32 23
Higano CS et al. Cancer 2009115(16)3670-9
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
22
Consistency Across Phase III Studies
Integrated (N 737)
0.735 p lt 0.001
3.9
33 20
D9901 (N 127) D9902A (N 98) IMPACT (N 512)
Hazard ratio p-value 0.586 p 0.010 0.786 p 0.331 0.775 p 0.032
Median survival benefit (months) 4.5 3.3 4.1
36-month survival () sipuleucel-T placebo 34 11 32 21 32 23
Higano CS et al. Cancer 2009115(16)3670-9
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
23
Summary and Lessons Learned

• New treatment paradigm in oncology
• Represents first step
• First active immunotherapy to demonstrate
  improvement in OS for mCRPC
• RR and TTP may not be appropriate endpoints in
  therapeutic cancer vaccine trials

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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2010Abstract 8.
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PROSTVAC VF-Tricom
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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
• Modified HLA-A2 epitope. Increased HLA-A2
  binding and immunogenicity.
• Tricom
• Lymphocyte function-associated antigen LFA-3
  (CD58)
• Intercellular adhesion molecule ICAM-1 (CD54)
• Costimulatory molecule for the T-cell receptor
  B7.1 (CD80)

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Schlom J et al. Exp Biol Med 2008233(5)522-34.
26
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
27
PROSTVAC-VF-Tricom-Clinical Development

• Clinical studies have been conducted with over
  500 patients with PROSTVAC and derivatives and
  later constructs
• Good safety profile
• Documented immunogenicity

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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
28
Randomized Phase II Study
P R O G R E S S I O N
S U R V I V A L
Treated at physician discretion
PROSTVAC-VF Tricom GM
Asymptomatic or Minimally Symptomatic Metastatic
Castrate Resistant Prostate Cancer (N125)
21
Treated at physician discretion and/or Salvage
Protocol
Empty Vector placebo

Primary endpoint Progression Free
Survival Secondary endpoint Overall Survival
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.

29
Randomized Phase II Trial

• Accrual November 2003-July 2005
• Multi-center randomized double blind phase II
  trial
• 125 patients enrolled
• 43 sites
• 84 PROSTVAC-VF-Tricom GM-CSF
• 41 Empty Vectors (VF) placebo

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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
30
Treatments/Assessments

• Planned 7 vaccinations over 5 months
• Days 0, 14, 28, 56, 84, 112, 140
• Progression assessed at 2, 4, and 6 months
• Cross-Over Controls eligible for PROSTVAC-VF
  Tricom treatment on progression (21/41)

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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
31
Progression-Free Survival
Hazard Ratio 0.88 (95 CI 0.57 to 1.38)
100
P 0.60 (stratified logrank)
80
60
40
20
N
Events
Median
Control
40
30
3.7
PROSTVAC
82
58
3.8
0
0
1
2
3
4
5
6
Months
31
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
32
Overall Survival
Hazard Ratio 0.56 (95 CI 0.37 to 0.85)
100
P 0.006 (stratified logrank)
80
N
Deaths
Median
Control
40
37
16.6
60
PROSTVAC
82
65
25.1
40
20
0
0
12
24
36
48
60
Months
32
Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
33
Potential Effect Modifiers
Vaccine Effect Hazard Ratios ( 95 CI)
favors PROSTVAC lt
HLA-A2 No
HLA-A2 Yes
PSA lt 38.24
PSA gt 38.24
Alk Phos lt 106.5
Alk Phos gt 106.5
LDH lt 198.0
LDH gt 198.0
HGB lt 12.90
HGB gt 12.90
ECOG PS gt 0 No
ECOG PS gt 0 Yes
Halabi Median lt 1.704
Halabi Median gt 1.704
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
34
Common Adverse Events
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Kantoff PW et al. Proc Genitourinary Cancers
Symposium 2009Abstract 5013.
35
A Stepwise Approach to CRPC
Anti-androgen withdrawal
Secondary hormonal therapy
Vaccine (Sip-T) therapy
Chemotherapy
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Remaining Questions

• How do these immunotherapies actually work?
• Can we develop biomarkers that predict response?
• Can we develop biomarkers of response?
• Can we build upon these first steps?