Immunotherapeutic Approaches in Castration Resistant Prostate Cancer (CRPC) Philip Kantoff, MD...

Immunotherapeutic Approaches in Castration Resistant Prostate Cancer (CRPC)

Philip Kantoff, MDChief, Division of Solid Tumor Oncology

Dana-Farber Cancer InstituteProfessor of Medicine

Harvard Medical School

Sipuleucel-T for Metastatic CRPC

Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein

Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

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Sipuleucel-T: Logistics of Therapy

Day 1Leukapheresis

Day 2-3sipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Central Processing Doctor’s Office

COMPLETE COURSE OF THERAPY:Weeks 0, 2, 4


Asymptomatic Metastatic

CRPC(N = 127) Sip-T

q2wks x 3(N = 82)

Placeboq2wks x 3

(N = 45)

PROGRESSION

Long-TermFollow-up

Sipuleucel-Tq2wks x 3

Randomized Phase III Trial of Sipuleucel-T in CRPC (D9901)

Small EJ et al. J Clin Oncol 2006;19(24):3089-94.

Originally published by the American Society of Clinical Oncology. [Small EJ et al: 24(19), 2006:3089-94].

Results: Time to Objective Disease Progression

Originally published by the American Society of Clinical Oncology. [Small EJ et al: 24(19), 2006:3089-94].

Results: Overall Survival

Results: Overall Survival Intent-To-Treat Population

21.4 5 (11%)4045Placebo

25.9 28 (34%)5482Sipuleucel-T

Median Survival (mos)

Alive at 36

Months*Deaths

Number of Subjects

Treatment

p-value — — .0046 .01


Results: Overall Survival Intent-to-Treat Population

21.4 5 (11%)4045Placebo

25.9 28 (34%)5482Sipuleucel-T

Alive at 36

Months*Deaths

Number of Subjects

Treatment

p-value — — .0046 .01



Results: Overall Survival Intent-to-Treat Population

21.4 5 (11%)4045Placebo

25.9 28 (34%)5482Sipuleucel-T


Alive at 36

Months*Deaths

Number of Subjects

Treatment

p-value — — .0046 .01


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Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment)

Asymptomatic or Minimally

Symptomatic mCRPC (N=512)


Symptomatic mCRPC (N=512)

Placebo Q 2 weeks

x 3

Placebo Q 2 weeks

x 3

Sipuleucel-T Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

2:1

Treated at Physician Discretion

and/or Salvage Protocol





Primary Endpoint: Overall SurvivalSecondary Endpoint: Objective Disease Progression

PROGRESSION

PROGRESSION

SURVIVAL

SURVIVAL


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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

>10 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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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

>10 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


Patient Demographics and Baseline Characteristics

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

Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8. 14

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Survival Effect Consistent Across Subpopulations (Primary Analysis)

0.0 0.5 1.0 1.5

Below MedianHemoglobin: Above Median

Below MedianAlkaline Phos: Above Median

Below MedianLDH: Above Median

Below MedianPSA: Above Median

Below MedianAge: Above Median

0ECOG Performance Status: 1

Bone + Soft TissueDisease Localization: Single

10≤No. Bone Metastases: > 10

3≤ 4≥Primary Gleason Grade:

NoBisphosphonate Use: Yes

Favors sipuleucel-T

Hazard Ratio (95% Confidence Interval)


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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)


Adverse Events More Commonly1 Reported in Sipuleucel-T Group

Preferred TermSipuleucel-T

N = 338%

PlaceboN = 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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Adverse Events More Commonly1 Reported in Sipuleucel-T Group

Preferred TermSipuleucel-T

N = 338%

PlaceboN = 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.


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 2009;115(16):3670-9; Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.


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


4.5 3.3 4.1


sipuleucel-T

placebo

34%

11%

32%

21%

32%

23%

Integrated

(N = 737)

0.735

p < 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


4.5 3.3 4.1


sipuleucel-T

placebo

34%

11%

32%

21%

32%

23%



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


4.5 3.3 4.1


sipuleucel-T

placebo

34%

11%

32%

21%

32%

23%

Integrated

(N = 737)

0.735

p < 0.001

3.9

33%

20%



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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


PROSTVAC® VF-Tricom™

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)

Schlom J et al. Exp Biol Med 2008;233(5):522-34. 25

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


Randomized Phase II Study

Primary endpoint: Progression Free SurvivalSecondary endpoint: Overall Survival


Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=125)


Symptomatic Metastatic Castrate Resistant

Prostate Cancer (N=125)

Empty Vector + placebo

Empty Vector + placebo

PROSTVAC-VF Tricom + GM

PROSTVAC-VF Tricom + GM

P R O

G R E S

S I O N

P R O

G R E S

S I O N

2:1

SURVIVAL

SURVIVAL

Treated at physician discretion







• 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

Randomized Phase II Trial


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)


Progression-Free Survival

P = 0.60 (stratified logrank)

Hazard Ratio = 0.88 (95% CI 0.57 to 1.38)

0

20

40

60

80

100

0 1 2 3 4 5 6Months

ControlPROSTVAC

N4082

Events3058

Median3.73.8


Overall Survival

P = 0.006 (stratified logrank)

Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)

0

20

40

60

80

100

0 12 24 36 48 60Months

ControlPROSTVAC

N4082

Deaths3765

Median16.625.1


Potential Effect Modifiers

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

favors PROSTVAC <HLA-A2 = NoHLA-A2 = YesPSA < 38.24PSA >= 38.24Alk Phos < 106.5Alk Phos >= 106.5LDH < 198.0LDH >= 198.0HGB < 12.90HGB >= 12.90ECOG PS > 0 = NoECOG PS > 0 = YesHalabi Median < 1.704Halabi Median >= 1.704

Vaccine Effect Hazard Ratios (& 95% CI)


Common Adverse Events


A Stepwise Approach to CRPC

Anti-androgen withdrawal

Secondary hormonal therapy

Chemotherapy

Vaccine (Sip-T) therapy

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?

Immunotherapeutic Approaches in Castration Resistant Prostate Cancer (CRPC) Philip Kantoff, MD...

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