Current Landscape of Immunotherapy in Prostate Cancer

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Current Landscape of Immunotherapy in Prostate Cancer

Current Landscape of Immunotherapy in

Prostate Cancer

Charles G. Drake MD, PhD

Associate Professor Oncology, Urology, and Immunology

Sidney Kimmel Comprehensive Cancer Center

Johns Hopkins University

Baltimore, Maryland


Disclosure of Financial

Relationships

• Consulting

Bristol-Myers Squibb Company, Dendreon

Corporation

• Other

Amplimmune, Bristol-Myers Squibb Company

2


Overview

• Mechanism of Action of Immunotherapy

• Sipuleucel-T

– Background

– Phase III Results

• Ipilimumab (Anti-CTLA4)

– How it Works

– Phase III Design

• PROSTVAC-VF

– Background

– Phase II Data

– Phase III Design

• Lessons from Current Approaches

3


Active Immunotherapy

(Vaccination)

CD4 + T cell

Cancer peptide

MHC class II

Cytokine

help

TCR

Prostate Tumor

Lysis

CD8 + T cell

MHC

class I

Activated

APC

Adapted from Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

4


A “Dendritic Cell” Vaccine:

Sipuleucel-T

Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

5


Sipuleucel-T: Randomized Phase III IMPACT Trial

(IMmunotherapy Prostate AdenoCarcinoma Treatment)

Asymptomatic or

Minimally

Symptomatic

Metastatic

Castration

Resistant

Prostate Cancer

(N = 512)

Median HPS 21 months

2:1

Sipuleucel-T

Q 2 weeks x 3

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

S

U

R

V

I

V

A

L

Primary endpoint:

Secondary endpoint:

Overall Survival

Time to Objective Disease Progression

Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422.

6


Sipuleucel-T:

Time to Objective Disease Progression

HR = 0.951 (95% CI: 0.77,1.17)

P = 0.628 (log rank)

Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422.

7


Percent Survival

100

Sipuleucel-T:

IMPACT

by FDA 4-29-10

75

P = 0.032 (Cox model)

HR = 0.775 [95% CI: 0.614, 0.979]

50

25

Placebo (n = 171)

Median Survival: 21.7 Months

Median Survival Benefit = 4.1 Months

Sipuleucel-T (n = 341)

Median Survival: 25.8 Months

0

0 6 12 18 24 30 36 42 48 54 60 66

Survival (Months)

Kantoff PW, et al. N Engl J Med. 2010;363(5):411-422.

8


In Cancer:

A Bit of a Problem

CD4 + T cell

Cancer peptide

MHC class II

Cytokine

help

TCR

Prostate Tumor

Lysis

CD8 + T cell

MHC

class I

Activated

APC

Adapted from Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

9


Immune

“Checkpoints”

Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

10


Blocking Immune

Checkpoints = Potent

(Ipilimumab, Tremelimumab)

• Single-Agent Activity

• Response Rate = 15-20%

• Regressions = Durable

• Regressions = Delayed

• Grade III-IV SAE = 30%

• Colitis

• Hypophysitis

• Phase III Trials:

Prostate Cancer

• Melanoma

Saenger YM, et al. Cancer Immunity. 2008;8:1.

11


Randomized, Double-Blind, Phase III Trial Comparing

Ipilimumab vs Placebo Following Radiotherapy in Subjects

With Castration Resistant Prostate Cancer that Have Received

Prior Treatment with Docetaxel

(NCT00861614, CA184-043)

SCREENING

INDUCTION

MAINTENANCE

CRPC

Prior

Docetaxel

IVRS

Radiotherapy (8 gy)

to bone metastases

Ipilimumab 10 mg/kg

weeks 1, 4, 7, 10

Ipilimumab 10 mg/kg

every 12 weeks

N = 800

day -2 or -1

Placebo

weeks 1, 4, 7, 10

Placebo

every 12 weeks

ICF, Baseline

Assessments

TA: weeks 12 and 24

PSA: weeks 7, 12, 18, 24

OA: weeks 7, 10, 12, 18, 24

TA: every 12 weeks

PSA: every 6 weeks

OA: every 12 weeks

Day -28 to Day -2 Day -2 to Week 24 Wk 24 to Wk 48+

TA = tumor assessment

PSA = prostate specific antigen

OA = outcome assessment

Available at: http://clinicaltrials.gov/ct2/show/NCT00861614. Accessed February 10, 2011.

12


Virus-Based Cancer Vaccines

• Pox vectors

Vaccinia (rV-)

– Similar to smallpox vaccine

– Repetitive dosing = ineffective (host immunity)

Avipox (fowlpox rF-, ALVAC)

– CAN give repetitive dosing

• Can insert multiple transgenes

• Replication defective

• Efficiently infect antigen presenting cells including

dendritic cells

13


Improving Pox-Viral Vaccines:

Augment Co-Stimulation

APC

MHC + Peptide

Co-stimulatory

Molecule

B7-1

(CD80)

TCR

Ligand

CD28

T-Cell

Co-stimulatory

Mechanism

IL-2-R upregulation,

IL-2 secretion

ICAM-1

(CD54)

LFA-1

Tyrosine Kinase,

Phospholipase C

LFA-3

(CD58)

CD2

(Region 1)

Tyrosine Kinase,

Ca 2+ Mobilization

cAMP Production

14


T-cell Activation (CPM x 10 5 )

Co-Stimulators:

Vastly Improve Vaccine Response

None LFA-3 ICAM-1 B7-1 TRICOM

Co-stimulatory Molecule

15


PROSTVAC-VF in Patients

Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

16


Randomized Controlled

Double Blind Phase II Study

Asymptomatic or

Minimally

Symptomatic

Metastatic

Castration

Resistant

Prostate Cancer

(N = 125)

2:1

PSA-TRICOM +

GM-CSF

n = 84

Empty Vector +

placebo

n = 41

P

R

O

G

R

E

S

S

I

O

N

Treated at

physician

discretion

Treated at

physician

discretion

and/or Salvage

Protocol

S

U

R

V

I

V

A

L

Primary endpoint:

Secondary endpoint:

Progression-Free Survival

Overall Survival

Kantoff PW, et al. J Clin Oncol. 2010;28(7):1099-1105.

17


Overall survival (% patients)

PROSTVAC

Significantly Extended Overall Survival

100

80

N Deaths Median

Control 40 37 16.6

PROSTVAC 82 65 25.1

Δ 8.5

months

60

40

Hazard ratio:

0.56 (95% CI 0.37-0.85)

P = 0.0061

20

0

PROSTVAC

Control

0 12 24 36 48 60

Months

Kantoff PW, et al. J Clin Oncol. 2010;28(7):1099-1105.

18


Phase III

Patient Population: Metastatic CRPC (Asymptomatic or minimally

symptomatic)

R

A

N

D

O

M

I

Z

E

Arm A: PSA TRICOM with adjuvant GM-CSF (n = 400)

Arm B: PSA TRICOM with adjuvant placebo (n = 400)

Arm C: Empty Vector with adjuvant placebo (n = 400)

Primary endpoint: OS

No cross over

Critical HR 0.82

SPA Dec 2010

PI: Gulley

19


Multiple Prostate Cancer

Trials Support Clinical Benefit

IMPACT RCT Phase III (n = 512) Median Overall Survival

Placebo

21.7 months

Sipuleucel-T (P = 0.032) 25.8 months Δ 4.1 months

RCT Phase III (n = 127)

Placebo

21.4 months

Sipuleucel-T (P = 0.032) 25.9 months Δ 4.5 months

PSA TRICOM RCT Phase II (n = 125)

Vector control

16.6 months

PSA-TRICOM (P = 0.006) 25.1 months Δ 8.5 months

No improvement in progression-free survival

20


Tumor Burden

How Does Immunotherapy “WORK”?

† † †


Time

Stein WD, et al. Clinical Cancer Research. Published Online First November 24, 2010.

21


PROSTVAC-VF

Anecdotal Patient Data

PSA

Radical prostatectomy

Vaccine treatment

Second vaccine treatment

External beam radiation

Age

Gleason grade: 4 + 3 = 7

Age at which

Doubling time PSA would equal 1000

Trend before radical prostatectomy ( ) 5.8 months 65 years

Trend after radical prostatectomy. External beam radiation ( ) 9.6 months 75 years

Trend after first vaccine trial ( ) 28.6 months 93 years

Trend after second vaccine trial ( )

27 years

22


Size Matters

Hypothesis:

– The subset of patients with less

aggressive disease / lower tumor

burdens are more likely to benefit

from vaccine therapy

23


Prognostic Model for Predicting

Survival in Men With Hormone-

Refractory Metastatic Prostate Cancer

Conclusion:

Can predict

survival

probabilities

Volume of disease

Aggressiveness of disease

Halabi S, et al. J Clin Oncol. 2003;21(7):1232-1237.

24


Halabi Predicted Survival vs Actual Survival

All Patients

Patients with Halabi

Predicted Survival

< 18 Months

Patients with Halabi

Predicted Survival

≥ 18 Months

Vaccine: PROSTVAC (n = 32)

Halabi Predicted survival

(months)

17.4

12.3

20.9

Actual median overall

survival (months)

26.6

14.6

Not reached (8 of 15 pts

alive at 37.3 months)*

Difference (months)

9.2

2.3

≥ 16.4

Patients survival longer

than predicted by

Halabi nomogram

22 of 32 (69%)

10 of 17 (59%)

12 of 15 (80%)

P = 0.035

*There is a plateau in the OS curve at 51% after 38 months with 8 of 14

patients alive at a median potential follow-up of 44 months.

Gulley J, et al. Cancer Immunology, Immunotherapy. 2010;59(5):663-674.

25


Immune Response Matters

• Metastatic castrate-resistant prostate

cancer (CRPC) n = 32

• Chemotherapy naïve

• Primary endpoint: immune response by

ELISPOT

• Secondary / exploratory endpoints:

Response, Survival

Gulley J, et al. Cancer Immunology, Immunotherapy. 2010;59(5):663-674.

26


Fold increase in PSA specific T-cells

PSA Specific

Immune Response (ELISPOT)

Patients

13 / 29 patients had a ≥ 2 X increase

5 / 29 patients had a ≥ 6 X increase

Gulley J, et al. Cancer Immunology, Immunotherapy. 2010;59(5):663-674.

27


Survival Based PSA-Specific

T-Cell Response

ELISPOT > 6 Fold Increase

P = 0.055

ELISPOT< 6 Fold Increase

Gulley J, et al. Cancer Immunology, Immunotherapy. 2010;59(5):663-674.

28


Percent Survival

100

PSA-TRICOM (PROSTVAC)

75 Sipuleucel-T (n = 82)

50

25

0

Placebo (n = 45)

0 6 12 18 24 30 36

Months

100

75

50

Sipuleucel-T (n = 341)

Time

25

Placebo (n = 171)

Matters …

0

0 6 12 18 24 30 36 42 48 54 60 66

Survival (Months)

29


Therapies Shown to Improve

Overall Survival in CRPC

Stop

Treatment

2º AE

Improvement

in

Median OS

Hazard

Ratio

Reduction

in

Death Rate

Approved

Docetaxel 11% 2.4 months 0.76 24% 2004

Cabazitaxel 18% 2.4 months 0.70 30% 2010

Sipuleucel-T 1.5% 4.1 months 0.78 22% 2010

Abiraterone -- 3.9 months 0.66 34% ? 2011

Phase II data

PROSTVAC ~ 2% 8.5 months 0.56 44% ---

30


Current Conclusions

• Sipuleucel-T Approved 2010

– Vaccines “work”

• Multiple Phase III and II Trials

– Vaccines = well tolerated

• Immune Checkpoint Blockade

– In Phase III for Prostate Cancer

• Lessons Learned

– Overall Survival without TTP (Affect growth kinetics?)

– Bigger is NOT Better

– Patience is a Virtue

31


Thanks !

32

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