Updated Results of the IMPACT. Metastatic, Castration-Resistant Prostate Cancer (CRPC)

Size: px

Start display at page:

Download "Updated Results of the IMPACT. Metastatic, Castration-Resistant Prostate Cancer (CRPC)"

Arron Christian Sparks
5 years ago
Views:

1 Updated Results of the IMPACT Trial of Sipuleucel-T Tfor Metastatic, Castration-Resistant Prostate Cancer (CRPC) Philip Kantoff, MD Dana-Farber a abe Cancer Institute ue Professor of Medicine Harvard Medical School Sipuleucel-T is an investigational product that has not been approved by the FDA.

2 Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Active T-cell Fully activated, the APC is now sipuleucel-t Inactive INFUSE PATIENT T-cell T-cells proliferate and attack cancer cells sipuleucel-t activates T-cells in the body The precise mechanism of sipuleucel-t in prostate cancer has not been established. 2

3 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 Doctor s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4 3

4 Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or Sipuleucel-T Minimally Q 2 weeks x 3 Symptomatic Metastatic 2:1 Castration Resistant Prostate Cancer Placebo (N=512) Q 2 weeks x 3 P R O G R E S S I O N Treated at Physician i Discretion Treated at Physician Discretion and/or Salvage Protocol S U R V I V A L Pi Primary Endpoint: Overall llsurvival Secondary Endpoint: Objective Disease Progression 4

5 Statistical Analysis Plan Stratification Factors Bisphosphonate use Primary Gleason score Number of bone metastases HR and p-values Calculated from Cox model Adjusted for PSA and LDH 2 sided p-values Log rank as sensitivity analysis Analyses Interim: one Primary: p < required for statistical significance Primary analysis of 331 events (18 JAN 2009 cut-off date) Final analysis of 349 events (30 APR 2009 study closure date) 5

6 Patient Demographics and Baseline Characteristics Sipuleucel-T Placebo (N = 341) (N = 171) Age, median years (range) 72 (49 91) 70 (40 89) Race, caucasian (%) ECOG status, 0 (%) Gleason Score 7 (%) >10 Bone metastases (%) Bisphosphonate use Prior docetaxel (%) Serum PSA, ng/ml Alkaline phosphatase, g/dl LDH, U/L

7 Predicted Survival at Baseline Halabi Model Predicted Median Survival Placebo 21.2 months Sipuleucel-T 20.3 months Halabi Predicted Survival (Months) 7

8 IMPACT Overall Survival Primary Analysis (331 events) 34.1 mo median f/u HR = (95% CI: 0.614, 0.979) p = (Cox model) Median Survival Benefit = 4.1 months Sipuleucel-T (n = 341) Median Survival: 25.8 mo. 36 mo. survival: 31.7% Placebo (n = 171) Median Survival: 21.7 mo. 36 mo. survival: 23.0% No. at Risk Sipuleucel-T Placebo

9 IMPACT Overall Survival Final Analysis (349 events) 36.5 mo median f/u HR = (95% CI: 0.606, 0.951) p = (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 Placebo

10 Survival Effect Consistent Across Subpopulations (Primary Analysis) Favors sipuleucel-t Bisphosphonate Use: Yes No Primary Gleason Grade: 4 3 No. Bone Metastases: > 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 Hazard Ratio (95% Confidence Interval) 10

11 Did Differences in Post-ProgressionProgression Treatment Impact Outcomes? Sipuleucel-T Placebo (n = 341) (n =171) Any Intervention 81.8% 8% 85.4% Any Chemotherapy 65.4% 53.8% Docetaxel 57.2% 50.3% 11

12 Sipuleucel-T Survival Effect Persists after Censoring at Time of First Docetaxel Use Sipuleucel-T (n = 341) HR = (95% CI: 0.469, 0.898) Subjects receiving i docetaxel censored at time of first docetaxel dose (171 events) Placebo (n = 171) 12

13 Sipuleucel-T Survival Effect Persists in Model with Post-Randomization Docetaxel as Time Dependent Covariate Model HR (95% CI) p-value Treatment Only Treatment Group (Sipuleucel-T vs Placebo) (0.61, 0.98) Treatment + Docetaxel Treatment Group (Sipuleucel-T vs Placebo) (0.62, 0.98) Docetaxel (Yes vs No) (0.69, 1.12)

14 Time to Objective Disease Progression (ODP) Secondary Endpoint Independent Radiologic Review Result Median time to ODP: 14.4 wks placebo, 14.6 weeks sipuleucel-t HR = (95% CI: 0.77, 1.17); 17) P = (log rank) 14

15 How Can We Reconcile Lack of Effect on Time to Objective Disease Progression in CRPC? Difficult endpoint to measure reliably (predominance of bony disease) Time to ODP doesn t always correlate with overall survival Studies where progression improvement but no survival benefit 1 Studies where survival benefit but no difference in progression 2 1 Sternberg, J Clin Onc Tannock, NEJM 2004; Kantoff, J Clin Oncol 2010; James, Eur Urol

16 Prostvac-VF Randomized Phase 2 Progression vs Overall Survival (N=122) Control PROSTVAC Months Time to Progression Months Overall Survival 16

17 Time to Objective Disease Progression How to Reconcile Lack of Effect? Anti-tumor effect from immunotherapy may be delayed and more prolonged Traditional parameters (RR, PFS) might be difficult to use New definitions of progression may be required for CRPC and immunotherapy trials 17

18 Adverse Events More Commonly 1 Reported in Sipuleucel-T Group Sipuleucel-T l Placebo Preferred Term N = 338 % N = 168 % Chills Pyrexia Headache Influenza-Like Illness Myalgia Hypertension Hyperhidrosis Groin Pain 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. 18

19 Serious Adverse Events ( 4 Patients) SAE Preferred Term Sipuleucel-T N = 338 % Placebo N = 168 % 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

20 Survival Results Across 3 Randomized Sipuleucel-T Studies D (N = 127) D9902A 1* (N = 98) IMPACT 2 (N = 512) Hazard Ratio p-value P = P = P = Median Survival Benefit (months) 36-Month Survival Sipuleucel-T 34% 32% 32% Placebo 11% 21% 23% 1 Unadjusted Cox model and log rank 2 Cox model adjusted for PSA and LDH * Enrollment in trial discontinued early, prior to survival results from D

21 Summary and Lessons Learned New treatment paradigm in oncology First active immunotherapy to demonstrate improvement in OS for metastatic CRPC Effect was upheld with longer follow-up The therapy was well-tolerated with short duration of administration RR and TTP may not be appropriate endpoints in therapeutic vaccine trials Use of immune therapy earlier in natural history of disease requires study 21

22 IMPACT Study Investigators t Acknowledgements We are indebted to the patients who volunteered for this trial. T. Ahmed N. Barth E. R. Berger G. Bernstein B. Bracken P. Burch J. Chin G. Chodak F. Chu J. Corman B. Curti N. Dawson R. Dreicer A. Ferrari M. Fishman R. Flanigan L. Garbo T. Gardner D. George T. Godfrey L. Gomella S. Hall J. Hanson C. Higano R. Israeli P. Kantoff V. Kassabian J. Katz L. Klotz R. Kratzke R. Lance J. Lech L. Leichman R. Lemon S.E. Martin D. McLeod D. McNeel B. Miles M. Murdock C. Nabhan J. Nemunaitis D. Notter A. Pantuck D. Penson P. Perrotte D. Pessis D. Petrylak J. Polikoff P. Pommerville M. Rarick C. Redfern R. Rifkin N. Rohatgi R. Rosenbluth R. Santucci P. Schellhammer I. Shapira D. Shepherd N. Shore E. Small S. Sridhar R. Stephenson C. Teigland J. Vacirca L. Villa N. Vogelzang g M. Wertheim J. Wolff R. Wurzel C. Yang J. Young Dendreon Personnel M. Frohlich R. Hershberg R. Laus D. Marcus M. Peshwa N. Provost I. Rios R. Sims E. Smith F. Stewart D. Urdal F. Valone S. Wilson J. Whitmore Y. Xu L. Yuh\ 22

David L. Urdal, Ph.D. Chief Scientific Officer Sipuleucel-T for the Active Cellular Immunotherapy of Prostate Cancer

David L. Urdal, Ph.D. Chief Scientific Officer Sipuleucel-T for the Active Cellular Immunotherapy of Prostate Cancer Hot Topic Symposium; isbtc Annual Meeting October 31, 2009 1 Presenter Disclosure Information