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939P NEOADJUVANT SIPULEUCEL-T IN LOCALIZED PROSTATE
CANCER: EFFECTS ON IMMUNE CELLS WITHIN THE
PROSTATE TUMOR MICROENVIRONMENT
L. Fong1 , V. Weinberg1 , S. Chan1 , J. Corman2 , C. Amling3 , R.A. Stephenson4 ,
J. Simko1 , R.B. Sims5 , P. Carroll1 , E.J. Small1 1
Comprehensive Cancer Center, University of California, San Francisco,
San Francisco, CA, UNITED STATES OF AMERICA, 2 Surgery, Virginia Mason
Medical Center, Seattle, WA, UNITED STATES OF AMERICA, 3 Urology, Oregon
Health & Science University, Portland, OR, UNITED STATES OF AMERICA,
4
Urology, University of Utah, Salt Lake City, UT, UNITED STATES OF AMERICA,
5
Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF
AMERICA
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy
for patients with asymptomatic or minimally symptomatic metastatic castrate
resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with
mCRPC have studied immune response in peripheral blood. The immune effects of
sipuleucel-T in prostatic cancer tissue are unknown.
Methods: NeoACT (P07-1; NCT00715104) is an open-label, Phase 2 study of
patients with localized prostate cancer who received sipuleucel-T prior to radical
prostatectomy (RP) to examine the immunologic effects of treatment on prostate
tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals,
beginning 6-7 weeks prior to RP, and post-RP are being followed for immune
response. The primary endpoint was the change in the frequency of lymphocytes
between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed
by immunohistochemistry (IHC).
Results: Of the 42 enrolled patients (median age 61 years, all ECOG = 0, Gleason
Sum: ≤6 = 24%, 7 = 43%, ≥8 = 33%), 38 received all 3 pre-RP sipuleucel-T infusions
and were evaluable by IHC. Treatment-related AEs were manageable and transient.
Sipuleucel-T did not appear to affect operative complications, procedure time, or
estimated blood loss. Frequent events (>10% of patients) that occurred ≤1 day after
infusion were fatigue, headache, and myalgia. Significant increases (>3 fold) in
infiltrating CD3 + , CD3 + /CD4 + , and CD3 + /CD8+ T cell populations were
observed at the tumor rim (where benign and malignant glands interface), compared
with the pretreatment biopsy (all p = 0.0001). CD3 + /CD4 + /FoxP3+ cells were also
increased at the tumor rim (∼2-fold; P = 0.005), but represented a small proportion
of the observed T cells. This level of T cell infiltration was not seen in a cohort of 12
concurrent cases that did not receive neoadjuvant treatment.
Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased
frequency of T cells in the prostate at the interface of the benign and malignant
glands. These data demonstrate that sipuleucel-T can modulate the presence of
lymphocytes at prostate cancer tissue in vivo.
Disclosure: L. Fong: Research funding from Dendreon. R.B. Sims: Employee and
stockholder of Dendreon. P. Carroll: Honoraria from Takeda. Research funding from
Myriad and Abbot, E.J. Small: Honoraria from Dendreon. All other authors have
declared no conflicts of interest.
940P OVERALL SURVIVAL BENEFIT WITH SIPULEUCEL-T BY
BASELINE PROSTATE-SPECIFIC ANTIGEN (PSA): AN
EXPLORATORY ANALYSIS FROM THREE PHASE 3 TRIALS
P. Kantoff 1 , G. Chodak 2 , R.B. Sims 3 , J.B. Whitmore 4 , P. Schellhammer 5
1 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES
OF AMERICA, 2 Oncology, Weiss Memorial Hospital, Chicago, IL, UNITED
STATES OF AMERICA, 3 Clinical Affairs, Dendreon Corporation, Seattle, WA,
UNITED STATES OF AMERICA, 4 Biometrics, Dendreon, Seattle, WA, UNITED
STATES OF AMERICA, 5 Urology, Eastern Virginia Medical School / Urology of
Virginia, Virginia, VA, UNITED STATES OF AMERICA
Introduction and objective: Sipuleucel-T is an autologous cellular immunotherapy
approved for the treatment of asymptomatic or minimally symptomatic metastatic
castrate-resistant prostate cancer (mCRPC) based on improved overall survival (OS)
in the pivotal phase 3 IMPACT trial (NCT00065442). In a subgroup analysis of
pooled data from three Phase 3 trials of sipuleucel-T in mCRPC, baseline PSA was
found to be the most significant predictive factor for OS. To further investigate the
impact of baseline PSA levels on outcomes following sipuleucel-T, we conducted an
exploratory analysis of patients (pts) from three Phase 3 trials.
Methods: The analysis included all 737 randomized pts from three Phase 3 trials
(D9901, D9902A and IMPACT). Pts were categorized by baseline PSA quartile
(Table), as well as by ECOG PS, and median for other baseline prognostic variables
(i.e. lactate dehydrogenase [LDH], alkaline phosphatase [ALP], and hemoglobin
[Hgb]). Median OS and hazard ratio (HR) were estimated using Kaplan-Meier and
Cox models, respectively.
Results: HR values suggest consistent treatment effect in all subsets, although there is
inadequate power to show statistical significance within each quartile. There was a
trend toward an increased magnitude of treatment benefit in pts with a lower
baseline PSA (Table). Results for other baseline prognostic variables also suggest a
trend toward greater benefit with better prognostic features. However, results for
baseline Hgb indicated an opposite trend
Conclusions: Although not powered for statistical significance, this analysis supports
a consistent OS benefit with sipuleucel-T across PSA quartiles in patients enrolled in
Phase 3 trials. The greater benefit with lower baseline PSA suggests that pts with less
advanced disease may benefit more from sipuleucel-T.
Baseline PSA (ng/mL)
≤22.3 >22.3– ≤ 49.9 >49.9– ≤ 137.8 >137.8
n
Median OS, mos
184 184 184 183
Sipuleucel-T 41.2 25.9 20.6 15.1
Control 26.7 22.0 14.8 13.5
Difference 14.5 3.9 5.8 1.6
HR; 95% CI 0.48;
0.32–0.73
0.76;
0.53–1.11
Annals of Oncology
0.67;
0.47–0.95
0.88;
0.62–1.25
Disclosure: P. Kantoff: Advisory boards for Dendreon Corporation G. Chodak: Stock
ownership in Amgen; Advisory boards for Dendreon Corporation and Janssen;
Honoraria for Dendreon Corporation and Amgen. R.B. Sims: Stock ownership and
employee of Dendreon Corporation. J.B. Whitmore: Employee of Dendreon
Corporation; Stock ownership in Dendreon Corporation and Amgen, P.
Schellhammer: Honoraria for Dendreon Corporation
941P IMPACT OF SALVAGE THERAPY WITH APC8015F ON THE
OVERALL SURVIVAL (OS) BENEFIT ACHIEVED WITH
SIPULEUCEL-T IN THREE PHASE 3 STUDIES OF
METASTATIC CASTRATE-RESISTANT PROSTATE CANCER
(MCRPC)
D.J. George 1 , L.G. Gomella 2 , T. Devries 3 , J.B. Whitmore 3 , M.W. Frohlich 4 ,
C. Nabhan 5
1 Medicine, Duke University, Durham, NC, UNITED STATES OF AMERICA,
2 Urology, Thomas Jefferson University, Philadelphia, PA, UNITED STATES OF
AMERICA, 3 Biometrics, Dendreon, Seattle, WA, UNITED STATES OF AMERICA,
4 Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF
AMERICA, 5 Hematology and Medical Oncolgoy, Advocate Lutheran General
Hospital, Park Ridge, IL, UNITED STATES OF AMERICA
Background: Sipuleucel-T is an autologous cellular immunotherapy approved for
asymptomatic or minimally symptomatic mCRPC. Three Phase 3 sipuleucel-T trials
(D9901, D9902A, IMPACT) allowed control patients (pts) to receive salvage
treatment with an autologous product derived from previously frozen cells
(APC8015F). We previously reported that APC8015F demonstrated no deleterious
effect. Control pts who received APC8015F had more favorable baseline prognostic
features; however, after adjusting for these imbalances, APC8015F appears to have
prolonged OS in control pts, potentially reducing the observed sipuleucel-T
treatment effect. This exploratory integrated analysis estimates the OS benefit
conferred by sipuleucel-T, adjusting for APC8015F in control pts.
Methods: A rank-preserving structural failure time (RPSFT) model was used to
estimate control arm OS if treatment with APC8015F had not occurred. This allows
estimation of the treatment effect of sipuleucel-T, adjusting for salvage effect.
Results: Median OS from randomization in the three pooled trials was 25.4 months
with sipuleucel-T (n = 488) and 21.5 months with control (n = 249). Of the control
arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from
randomization in the control population was 23.6 months for pts receiving
APC8015F and 12.7 months for those who did not. Using the RPSFT model, and
assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for
control pts was 17.3 months, representing an 8.1 month median increase in OS with
sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is
assumed to have less treatment effect than sipuleucel-T, will be presented.
Conclusions: These analyses estimate a median OS benefit for sipuleucel-T between
3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable
efficacy to sipuleucel-T, respectively. These results suggest a possible greater
treatment effect of sipuleucel-T than was reported in the three Phase 3 studies.
Future studies should account for potential crossover treatment bias as this may
diminish estimates of OS benefit.
Disclosure: D.J. George: Consultant, Investigator, or Lecturer for the following
companies: Astellas, Bayer, BMS, Dendreon, Exelixis, Genentech/Roche, GSK, Ipsen,
Jansen, Medivation, Novartis, Pfizer, Sanofi, Viamet, L.G. Gomella: Consultant/
Advisor and Clinical Trials for Dendreon, T. Devries: Employee and Stockholder of
Dendreon. J.B. Whitmore: Employee and Stockholder of Dendreon. M.W. Frohlich:
Employee and Stockholder of Dendreon. C. Nabhan: I am on the speakers bureau of
Dendreon and have received honoraria for speaking engagements.
ix310 | Abstracts Volume 23 | Supplement 9 | September 2012