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Immunotherapeutic Approaches in Castration Resistant Prostate Cancer (CRPC) Philip Kantoff, MD Chief, Division of Solid Tumor Oncology Dana-Farber Cancer.

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Presentation on theme: "Immunotherapeutic Approaches in Castration Resistant Prostate Cancer (CRPC) Philip Kantoff, MD Chief, Division of Solid Tumor Oncology Dana-Farber Cancer."— Presentation transcript:

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

2 Sipuleucel-T for Metastatic CRPC

3 Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

4 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 ProcessingDoctor’s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

5 Asymptomatic Metastatic CRPC (N = 127) Sip-T q2wks x 3 (N = 82) Placebo q2wks x 3 (N = 45) PROGRESSIONPROGRESSION Long-Term Follow-up Sipuleucel-T q2wks x 3 Randomized Phase III Trial of Sipuleucel-T in CRPC (D9901) Small EJ et al. J Clin Oncol 2006;19(24):3089-94.

6 Originally published by the American Society of Clinical Oncology. [Small EJ et al: 24(19), 2006:3089-94]. Results: Time to Objective Disease Progression

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

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

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

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

11 11 Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or Minimally Symptomatic mCRPC (N=512) Placebo Q 2 weeks x 3 Sipuleucel-T Q 2 weeks x 3 2:1 Treated at Physician Discretion and/or Salvage Protocol Treated at Physician Discretion Primary Endpoint: Overall Survival Secondary Endpoint: Objective Disease Progression PROGRESSIONPROGRESSION PROGRESSIONPROGRESSION SURVIVALSURVIVAL SURVIVALSURVIVAL Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

12 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 (%) 89.491.2 ECOG status, 0 (%) 82.181.3 Gleason score ≤ 7 (%)75.4 >10 Bone metastases (%)42.842.7 Bisphosphonate use 48.148.0 Prior docetaxel (%) 15.512.3 Serum PSA, ng/mL 51.747.2 Alkaline phosphatase, g/dL 99.0109.0 LDH, U/L 194.0193.0 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

13 13 Sipuleucel-T (N = 341) Placebo (N = 171) Age, median years (range) 72 (49 – 91)70 (40 – 89) Race, Caucasian (%) 89.491.2 ECOG status, 0 (%) 82.181.3 Gleason score ≤ 7 (%)75.4 >10 Bone metastases (%)42.842.7 Bisphosphonate use 48.148.0 Prior docetaxel (%) 15.512.3 Serum PSA, ng/mL 51.747.2 Alkaline phosphatase, g/dL 99.0109.0 LDH, U/L 194.0193.0 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8. Patient Demographics and Baseline Characteristics

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-T341274142 56 183 Placebo171123 59 22 52 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8. 14

15 15 Survival Effect Consistent Across Subpopulations (Primary Analysis) Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

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

17 Adverse Events More Commonly 1 Reported in Sipuleucel-T Group Preferred Term Sipuleucel-T N = 338 % Placebo N = 168 % Chills54.112.5 Pyrexia29.313.7 Headache16.04.8 Influenza-like illness9.83.6 Myalgia9.84.8 Hypertension7.43.0 Hyperhidrosis5.30.6 Groin pain5.02.4 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. Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8. 17

18 18 Adverse Events More Commonly 1 Reported in Sipuleucel-T Group Preferred Term Sipuleucel-T N = 338 % Placebo N = 168 % Chills54.112.5 Pyrexia29.313.7 Headache16.04.8 Influenza-like illness9.83.6 Myalgia9.84.8 Hypertension7.43.0 Hyperhidrosis5.30.6 Groin pain5.02.4 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. Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 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) 4.53.34.1 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.

20 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) 4.53.34.1 36-month survival (%) sipuleucel-T placebo 34% 11% 32% 21% 32% 23% Integrated (N = 737) 0.735 p < 0.001 3.9 33% 20% Higano CS et al. Cancer 2009;115(16):3670-9; Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8.

21 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) 4.53.34.1 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. Consistency Across Phase III Studies

22 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) 4.53.34.1 36-month survival (%) sipuleucel-T placebo 34% 11% 32% 21% 32% 23% Integrated (N = 737) 0.735 p < 0.001 3.9 33% 20% Higano CS et al. Cancer 2009;115(16):3670-9; Kantoff PW et al. Proc Genitourinary Cancers Symposium 2010;Abstract 8. Consistency Across Phase III Studies

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

24 PROSTVAC ® VF-Tricom™

25 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

26 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 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 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 27

28 Randomized Phase II Study Primary endpoint: Progression Free Survival Secondary endpoint: Overall Survival Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=125) Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=125) Empty Vector + placebo PROSTVAC-VF Tricom + GM PROGRESSIONPROGRESSION PROGRESSIONPROGRESSION 2:1 SURVIVALSURVIVAL SURVIVALSURVIVAL Treated at physician discretion and/or Salvage Protocol Treated at physician discretion Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013.

29 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 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 29

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) Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 30

31 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 0123456 Months Control PROSTVAC N 40 82 Events 30 58 Median 3.7 3.8 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 31

32 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 1224364860 Months Control PROSTVAC N 40 82 Deaths 37 65 Median 16.6 25.1 Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 32

33 Potential Effect Modifiers 0.20.40.60.811.21.41.6 favors PROSTVAC < HLA-A2 = No HLA-A2 = Yes PSA < 38.24 PSA >= 38.24 Alk Phos < 106.5 Alk Phos >= 106.5 LDH < 198.0 LDH >= 198.0 HGB < 12.90 HGB >= 12.90 ECOG PS > 0 = No ECOG PS > 0 = Yes Halabi Median < 1.704 Halabi Median >= 1.704 Vaccine Effect Hazard Ratios (& 95% CI) Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 33

34 Common Adverse Events Kantoff PW et al. Proc Genitourinary Cancers Symposium 2009;Abstract 5013. 34

35 A Stepwise Approach to CRPC Anti-androgen withdrawal Secondary hormonal therapy Chemotherapy Vaccine (Sip-T) therapy

36 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?

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