SUTENT® (sunitinib malate) Capsules
`
`Mace L. Rothenberg, MD
`Senior VP, Clinical Development and Medical Affairs, Pfizer Inc
`Oncologic Drugs Advisory Committee Meeting
`
`12 April 2011
`FDA White Oak Campus
`Silver Spring, MD
`
`Proposed Indication
`
`(cid:132) SUTENT® is indicated for the treatment of unresectable
`pancreatic neuroendocrine tumors (pNET)
`
`2
`
`Ex. 1069-0001
`
`

`

`Topics for Today’s Discussion
`
`Mace Rothenberg, MD
`Head of Clinical Development & Medical Affairs
`Pfizer Oncology
`New York, NY
`
`Matthew Kulke, MD
`Director, Carcinoid & Neuroendocrine Tumor Program
`Dana-Farber/Brigham and Women’s Cancer Center
`Boston, MA
`
`(cid:132) Introduction and Background
`
`(cid:132) Clinical Aspects of Pancreatic NET
`
`(cid:132) Evaluation of SUTENT® in
`Pancreatic NET
`
`(cid:132) Perspectives on Treatment Options
`
`Additional Experts
`
`Eric Raymond, MD, PhD
`Chef de Service, Hôpital Beaujon, Clichy France
`(cid:132) Phase 3 Study Principal Investigator
`
`Robert Maki, MD, PhD, ,
`
`
`Senior Faculty in Medicine, Mount Sinai Medical Center, New York, NY
`(cid:132) Phase 3 Independent DMC Chair
`
`Gary Koch, PhD
`Professor of Biostatistics, University of North Carolina, Chapel Hill, NC
`(cid:132) Statistical Consultant
`
`3
`
`4
`
`Ex. 1069-0002
`
`

`

`History
`
`(cid:132) SUTENT® (sunitinib malate) was approved in 2006 for the
`treatment of:
`– Advanced renal cell carcinoma (RCC)
`
`Gastrointestinal stromal tumor (GIST) after disease progression on or– Gastrointestinal stromal tumor (GIST) after disease progression on or
`intolerance to imatinib mesylate
`
`(cid:132) Over 100,000 patients have been treated globally
`
`Development Timeline
`
`Phase 3 Trial
`(A6181111) Accrual
`
`Phase 2
`Activity in
`NET
`
`Study
`Start
`
`Study Closed
`for Efficacy
`
`sNDA
`Submission
`
`Sponsor
`Response
`Submitted
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`FDA Approval
`for RCC and
`GIST
`
`DMC 1
`
`DMC 2 DMC 3
`
`Pre-sNDA
`Meeting
`
`EU Approval
`for pNET
`
`FDA Meeting:
`Registrational
`Feasibility
`
`FDA Requests
`Additional
`Information
`
`5
`
`6
`
`Ex. 1069-0003
`
`

`

`Basis for sNDA
`
`(cid:132) Favorable Benefit/Risk profile
`
`(cid:132) ~6-month improvement in median PFS vs. placebo
`
`(cid:132) OS(cid:132) OS and ORR also favored sunitinibd ORR l f d iti ib
`
`
`
`
`
`
`
`
`
`
`
`
`
`(cid:132) No new or unexpected adverse events
`
`7
`
`Pancreatic Neuroendocrine Tumors
`
`Matthew Kulke, MD
`Director, Carcinoid and Neuroendocrine Tumor Program
`Dana-Farber/Brigham and Women’s Cancer Center
`Boston, MA
`
`Ex. 1069-0004
`
`

`

`Neuroendocrine Tumors:
`Incidence and Prevalence
`
`(cid:132) Early estimates of incidence
`1–2 per 100,000 population1
`
`Incidence per 100,000 for
`Neuroendocrine Tumors
`
`(cid:132) Diagnosed incidence increasing,
`
`likely due to improvedlikely due to improved
`awareness, classification, and
`diagnostic modalities2
`
`(cid:132) Prevalence estimated to be
`>100,000 in United States
`
`1. Modlin et al. Cancer 2003; 97: 934-59
`2. Yao JC et al. J Clin Oncol. 2008;26:3063-3072
`Cases selected from SEER database (1973 to 2004) using International Classification of Disease for Oncology histology codes 8150 to 8157, 8240 to 8246, and 8249
`
`Neuroendocrine Tumors:
`Histologic Classification
`
`Differentiation
`
`Well
`Differentiated *
`
`Grade
`Low
`(G1)
`Intermediate
`(G2)
`
`Mitotic Count
`< 2
`per 10 HPF
`2–20
`per 10 HPF
`
`Poorly
`Differentiated
`
`High
`(G3)
`
`>20
`per
`10 HPF
`
`KI-67 index
`
`(cid:148) 2%
`
`3–20%
`
`>20%
`
`ENETS, WHO
`Neuroendocrine Tumor,
`Grade 1
`Neuroendocrine Tumor,
`Grade 2
`Neuroendocrine Carcinoma,
`Grade 3,
`Small Cell
`Neuroendocrine Carcinoma
`Grade 3,
`Large Cell
`
`* This includes moderately differentiated
`
`HPF – high power field
`Kulke et al. J Clin Oncol 2011; 29: 934-43
`
`9
`
`10
`
`Ex. 1069-0005
`
`

`

`Neuroendocrine Tumors
`
`Carcinoid Tumors
`
`Pancreatic Neuroendocrine
`Tumors
`(Islet cell tumors)
`(cid:132) 6% of all NET (SEER)1
`
`(cid:132) 22–28% of all NET
`(Institutional Databases)2,3
`
`1. Yao JC et al. J Clin Oncol. 2008;26:3063-3072
`2. Pape UF et al. Endocrine-Related Cancer 2008; 15: 1083-97
`3. Ter-Minassian et al. Proc ASCO 2010
`
`Pancreatic NET:
`Classification by Hormone Secretion
`
`(cid:132) 30–40% associated with symptoms of hormone hypersecretion
`(cid:132) 60–70% “Non-functioning”
`Necrolytic Migratory Erythema
`
`AAssociated with Glucagonomai t d ith Gl
`
`
`
`
`Tumor SubtypesTumor Subtypes
`
`Strosberg et al. Pancreas 2009; 38: 255-258
`
`11
`
`12
`
`Ex. 1069-0006
`
`

`

`Management of Localized Disease:
`Surgical Resection
`
`(cid:132) Enucleation or distal pancreatectomy rather than Whipple
`resection may be possible depending on tumor size/location
`
`
`
`(cid:132) Prognosis good when complete resection performedg g p p
`
`
`
`
`
`
`
`13
`
`14
`
`Neuroendocrine Tumors:
`Survival by Stage
`
`Pape et al. Cancer 2008; 113: 256-65
`
`(cid:132) Survival shown from institutional
`series of pancreatic (n=131),
`duodenal (n=23) and gastric
`(n=48) NET
`
`(cid:132) Proportion alive at 10 years:
`– Stage I: 100%
`– Stage II: 89%
`– Stage III: 73%
`– Stage IV: 34%
`
`Ex. 1069-0007
`
`

`

`Metastatic Pancreatic NET:
`Overall Survival
`
`Median Survival in Single-institution
`Database (n=90): 5.8 Years
`
`Kaplan-Meier Curve of Overall Survival
`From Diagnosis of Metastases1
`1. Strosberg et al. Pancreas 2009; 38: 255-58
`2. Yao et al. J Clin Oncol 2008; 26: 3063-72
`
`Median Survival in SEER: 2 Years
`
`Site
`Appendix
`
`CecumCecum
`Colon
`Duodeum
`Gastric
`Liver
`Lung
`Pancreas
`Rectum
`Small bowel
`Thymus
`
`Median Survival (months)2
`Localized
`Regional
`>360
`>360
`
`135135
`
`107107
`261
`36
`107
`101
`154
`71
`50
`14
`227
`154
`136
`77
`290
`90
`111
`105
`110
`68
`
`Distant
`27
`
`4141
`5
`57
`13
`12
`16
`24
`22
`56
`40
`
`Metastatic and/or Unresectable Pancreatic NET:
`Current Treatment Options
`
`(cid:132) Somatostatin analogs
`
`(cid:132) Hepatic-directed therapies
`
`(cid:132) Cytotoxic chemotherapy
`
`15
`
`16
`
`Ex. 1069-0008
`
`

`

`Somatostatin Analogs in Pancreatic NET
`
`(cid:132) Effective in treating symptoms of hormone hypersecretion:
`– Indicated for treatment of VIPoma
`– Commonly used for symptoms of glucagonoma, gastrinoma
`
`h(cid:132) PROMID t d(cid:132) PROMID study showed improved TTP associated with d i d TTP i t d ith
`
`
`
`
`octreotide in midgut carcinoid tumors but did not include
`pancreatic NET1
`(cid:132) Antiproliferative effect of somatostatin analogs in pancreatic
`NET has not, to date, been demonstrated
`
`1. Rinke et al. J Clin Oncol 2009; 27: 4656-63
`
`Hepatic-directed Therapy
`
`(cid:132) Hepatic-directed approaches used in patients with liver
`metastases and limited extra-hepatic disease
`– Hepatic resection for patients with limited number of liver metastases
`
`– Embolization, chemoembolization, or radioembolization for unresectable , ,
`
`liver metastases
`– Transplant (rare)
`(cid:132) Little randomized data evaluating effect of hepatic-
`directed therapy on PFS or OS
`
`Moertel et al. Ann Int Med 1994; 120: 302-9
`
`17
`
`18
`
`Ex. 1069-0009
`
`

`

`Streptozocin-based Therapy for Pancreatic NET
`
`(cid:132) Approved by FDA for
`advanced pancreatic NET
`(1982)
`
`(cid:132) Streptozocin/Doxorubicin
`
`associated with responseassociated with response
`rate of 69% and survival
`benefit in randomized study
`(1992)1
`
`(cid:132) Many physicians are
`nevertheless reluctant to use
`streptozocin-based therapies
`
`1. Moertel et al. N Engl J Med 1992; 326: 519-23
`
`Median Survival 2.2 years (STZ/Dox)
`vs. 1.5 yrs (STZ/5FU)
`
`19
`
`Streptozocin-based Therapy: Challenges
`
`(cid:132) Response rates in pancreatic NET tumors not as high as initially reported:
`overall tumor response rate 6–39% in retrospective series1-3
`(cid:132) Cumbersome 5-day infusion schedule
`(cid:132) Toxicity: renal, hematologic, nausea/vomiting
`
`AE1
`Creatinine elevation3
`Chronic renal insuff.
`Leukopenia2
`Vomiting
`
`Streptozocin + 5-FU (%)
`Any
`Severe
`29
`7
`
`Streptozocin + Doxorubicin (%)
`Any
`Severe
`44
`2
`
`7
`
`25
`41
`
`56
`81
`
`4
`
`5
`20
`
`57
`80
`
`1. Cheng et al. Cancer 1999; 86: 944-8; 2. McCollum et al. Am J Clin Oncol 2004; 27: 485-8; 3. Kouvaraki et al. J Clin Oncol 2004; 22: 4762-71; 4. For vomiting and leukopenia the results
`are for the first course of therapy only. The values for creatinine elevation are for all courses. Only the patients who had toxic reactions are included; 5. Leukopenia: any = <4x109 cells/liter,
`severe = < 2x109 cells/liter; 6. Creatine elevation: any >0.03 mg/dl, severe >1.0 mg/dl. Adapted from Moertel 1992.
`
`20
`
`Ex. 1069-0010
`
`

`

`Available Treatment Options
`
`(cid:132) Somatostatin analogs for symptoms of hormone hypersecretion; effect
`on tumor proliferation not demonstrated
`
`(cid:132) Hepatic-directed therapy may be helpful, but is limited to patients with
`
`hepatic-predominant diseasehepatic-predominant disease
`
`(cid:132) Cytotoxic chemotherapy used in selected patients due to side effect
`profile
`
`(cid:132) Clear need for new treatment options for patients with advanced
`pancreatic NET
`
`21
`
`22
`
`Novel Therapies: Targeting the RTK/PI3-K/AKT/mTOR
`Pathway in NET
`
`IGF-1
`PDGF
`VEGF
`IGF-1R
`
`VEGFRVEGFR
`PDGFR
`RET
`
`Growth Factors:
`
`Growth Factor Receptors:
`
`PI3-K
`
`AKT
`
`mTOR
`
`Cell Growth & Survival
`
`Targeted Agents
`
`Bevacizumab
`
`
`
`SunitinibSunitinib
`
`Pazopanib
`Sorafenib
`
`Everolimus
`Temsirolimus
`
`Ex. 1069-0011
`
`

`

`NCI Neuroendocrine Tumor Task Force
`Clinical Trials Planning Meeting Recommendations
`
`(cid:132) Biologically targeted therapies in NET associated with modest
`RECIST-defined response rates but high rates of disease
`stabilization
`
`O(cid:132) Overall survival may not be a practical primary endpoint for f
`
`
`advanced NET due to the variability of survival durations and
`likelihood of multiple post-study therapies
`
`(cid:132) Progression-free survival recommended as the primary endpoint
`for phase III studies in NET
`
`Kulke et al. J Clin Oncol 2011; 29: 934-43
`
`Conclusions
`
`(cid:132) Clear need for new therapeutic options for patients with
`advanced pancreatic NET
`
`(cid:132) For biologically targeted agents, PFS is an appropriate g y g g , pp p
`
`
`
`endpoint in trials for NET
`
`
`
`
`
`
`
`(cid:132) Targeted therapies attractive because:
`– Favorable safety profile, especially compared to current treatment
`– Availability of randomized data supporting their use
`
`23
`
`24
`
`Ex. 1069-0012
`
`

`

`SUTENT® (sunitinib malate) Capsules
`
`Mace L. Rothenberg, M.D.
`Senior VP, Clinical Development and Medical Affairs, Pfizer Inc
`
`Sunitinib Malate
`
`O
`
`CH3
`
`NH
`
`O
`
`NH
`
`F
`
`H
`(cid:132) Sunitinib is a receptor tyrosine kinase inhibitor of VEGFR2, VEGFR3,
`VEGFR1, PDGFR(cid:302), PDGFR(cid:533), KIT, FLT-3, CSF-1R, and RET1
`
`(cid:132) Anti-angiogenic and anti-tumor agent
`
`1. Mendel DB, et al. Clin Cancer Res 2003;9:327–37
`
`26
`
`C H3
`
`N C
`
`H3
`
`O H
`
`NH
`
`C H3
`
`HO2C
`
`CO2H
`
`Ex. 1069-0013
`
`

`

`Early Signals of Sunitinib Activity in NET
`(cid:132) Preclinical activity in RIP1-Tag2 transgenic model of pancreatic NET1
`
`(cid:132) Phase 1 clinical activity in patients with NET2
`– One PR confirmed in rectal NET
`– One minor response/stable disease was observed in NET of mediastinum
`
`Baseline
`
`12 Weeks
`
`1.
`2.
`
`Bergers et al. Science 1999; 284: 808-11
`Faivre S, et al. J Clin Oncol. 2006;24(1):25-35
`
`Phase 2 Experience with Sunitinib in NET
`
`Pancreatic NET Cohort
`Best objective response
`PR
`SD (cid:149)6 months
`Overall objective response rate (RECIST) %
`Median OS
`Median follow-up for OS
`
`N (%)
`
`N=66
`
`95% CI
`
`11 (16.7%)
`37 (56.1%)
`16.7%
`Not Reached
`12.5 months
`
`(8.6 – 27.9)
`
`(12.0, 15.5)
`
`27
`
`28
`
`Ex. 1069-0014
`
`

`

`Phase 3 Study Design
`
`Sunitinib
`37.5 mg/day
`
`Placebo
`
`Disease
`Progression
`
`Crossover to
`Sunitinib Treatment
`in Extension Studies
`
`ization1
`
`:1
`
`Random
`
`N = 340 patients
`(Planned)
`
`(cid:132) Unresectable
`pancreatic NET
`
`(cid:132) Well-differentiated
`
`(cid:132) Pre-study
`progression
`by RECIST
`
`Tumor Imaging at Week 5, 9,
`and
`Every 8 Weeks Thereafter
`
`29
`
`Major Entry Criteria
`
`(cid:132) Inclusion Criteria
`– Well-differentiated pancreatic islet cell tumor (histologically or cytologically proven)
`– Documented, RECIST-defined disease progression within the past 12 months
`– Not amenable to treatment with curative intent (surgery, radiation or combined modality)
`– ECOG performance status 0 or 1
`
`(cid:132) Exclusion Criteria
`– Current anticancer treatment, other than somatostatin analogs
`– Prior treatment with a tyrosine kinase inhibitor or an anti-VEGF angiogenesis inhibitor
`
`30
`
`Ex. 1069-0015
`
`

`

`Study Objectives
`
`(cid:132) Primary endpoint
`– Progression-Free Survival (PFS)
`
`(cid:132) Secondary endpoints
`– Overall survival (OS)
`– Objective response rate (ORR)
`(cid:138) Duration of response (DR)
`(cid:138) Time to tumor response (TTR)
`– Patient-reported outcomes (PROs)
`
`(cid:132) Safety and tolerability
`
`31
`
`32
`
`Statistical Design
`
`(cid:132) Sample size assumptions
`– Hypothesis to test (cid:149)50% improvement (HR(cid:100)0.67) in median PFS
`– 340 patients required to observe 260 PFS events with 90% power
`– Two-sided, unstratified log-rank test at a significance level of 0.049
`
`(cid:132) Analysis of primary endpoint (PFS) based on
`– Intent-to-treat (ITT) population
`– Investigator overall tumor assessment
`
`(cid:132) Planned analyses
`– Interim analysis at 130 events for safety, futility and efficacy (stop for p<0.0031)
`– Final analysis at 260 events
`
`Ex. 1069-0016
`
`

`

`Third DMC Meeting – February 2009
`
`(cid:132) Data reviewed on 154 patients (73 PFS events)
`– 49 PFS events on placebo
`– 24 PFS events on sunitinib
`
`0 649)(cid:132) Observed HR for PFS was 0 397 (95% CI: 0 243(cid:132) Observed HR for PFS was 0.397 (95% CI: 0.243 – 0.649)
`
`
`– Conditional probability to stop with p<0.0031 after 130 events was 99.9% based on
`HR=0.397
`– Conditional probability to stop with p<0.0031 after 130 events was 91% based on
`HR=0.649
`
`(cid:132) 15 deaths on placebo and 5 deaths on sunitinib
`
`(cid:132) 28 SAEs on placebo and 20 SAEs on sunitinib
`
`Outcome: Study Closure
`
`(cid:132) DMC recommended that the study be closed based upon
`the differences in PFS, deaths and SAEs
`
`
`
`
`
`(cid:132) DMC recommendation accepted by Sponsor p y p
`
`(cid:132) Study was closed in April 2009
`
`33
`
`34
`
`Ex. 1069-0017
`
`

`

`Evolution of Data: Number of PFS Events Over Time
`
`PFS Events
`
`DMC1
`
`Sunitinib
`
`Placebo
`
`5
`
`15
`
`Evolution of Data: Number of PFS Events Over Time
`
`PFS Events
`
`DMC1
`
`DMC2
`
`Sunitinib
`
`Placebo
`
`5
`
`15
`
`16
`
`34
`
`35
`
`36
`
`Ex. 1069-0018
`
`

`

`Evolution of Data: Number of PFS Events Over Time
`
`PFS Events
`
`DMC1
`
`DMC2
`
`DMC3
`
`Sunitinib
`
`Placebo
`
`5
`
`15
`
`16
`
`34
`
`24
`
`49
`
`Evolution of Data: Number of PFS Events Over Time
`
`PFS Events
`
`DMC1
`
`DMC2
`
`DMC3
`
`Final
`
`Sunitinib
`
`Placebo
`
`5
`
`15
`
`16
`
`34
`
`24
`
`49
`
`30
`
`51
`
`Between the data cutoff for the DMC and study closure, 17 patients were randomized
`
`37
`
`38
`
`Ex. 1069-0019
`
`

`

`39
`
`40
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`120
`140
`160
`180
`200
`Number of PFS Events
`
`220
`
`240
`
`260
`
`280
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`0
`
`20
`
`40
`
`60
`
`80
`
`200
`180
`160
`140
`120
`100
`Number of PFS Events
`
`220
`
`240
`
`260
`
`280
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`Ex. 1069-0020
`
`

`

`41
`
`42
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`120
`140
`160
`180
`200
`Number of PFS Events
`
`220
`
`240
`
`260
`
`280
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`120
`140
`160
`180
`200
`Number of PFS Events
`
`220
`
`240
`
`260
`
`280
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`Ex. 1069-0021
`
`

`

`43
`
`44
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`120
`140
`160
`180
`200
`Number of PFS Events
`
`220
`
`240
`
`260
`
`280
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`Evolution of Data: Relationship to Early Stopping Boundary
`
`Lan-DeMets-O'Brien-Fleming Efficacy Boundary
`
`Interim Analysis
`
`Final Analysis
`
`56789
`
`01234
`
`cale
`
`Z Sc
`
`60
`
`80
`
`220
`
`240
`
`260
`
`280
`
`0
`
`20
`
`40
`
`100
`120
`140
`160
`180
`200
`Number of PFS Events
`Between the data cutoff for the DMC and study closure, 17 patients were randomized for a total of 171 patients
`
`Ex. 1069-0022
`
`

`

`Patient Enrollment and Allocation
`
`171 Randomized
`
`
`
`86 Allocated to Sunitinib86 ocated to Su t b
`
`
`
`85 Allocated to Placebo85 ocated to acebo
`
`
`
`
`
`
`
`83 Received
`Sunitinib
`
`3 Did Not
`Receive Sunitinib
`
`82 Received
`Placebo
`
`3 Did Not
`Receive Placebo
`
`45
`
`46
`
`Demographic and Baseline Characteristics
`
`N (%)
`
`Median (range) age, years
`(cid:149)65 years
`Sex
`Male
`
`FemaleFemale
`ECOG performance status
`0
`1
`2
`Race
`White
`Asian
`Other/unspecified*
`Prior systemic treatments
`
`*Per local regulations, ethnicity data were not routinely collected in France
`
`Sunitinib
`N=86
`56 (25–84)
`22 (25.6%)
`
`42 (48.8%)
`
`44 (51.2%)44 (51.2%)
`
`53 (61.6%)
`33 (38.4%)
`0
`
`48 (55.8%)
`13 (15.1%)
`25 (29.1%)
`57 (66.3%)
`
`Placebo
`N=85
`57 (26–78)
`23 (27.1%)
`
`40 (47.1%)
`
`45 (52.9%)45 (52.9%)
`
`41 (48.2%)
`43 (50.6%)
`1
`(1.2%)
`
`53 (62.4%)
`10 (11.8%)
`22 (25.9%)
`61 (71.8%)
`
`Ex. 1069-0023
`
`

`

`Tumor and Disease Characteristics at Baseline
`
`N (%)
`
`Presence of distant metastases
`Non-functioning
`Functioning
`
`GastrinomaGastrinoma
`Glucagonoma
`Insulinoma
`VIPoma
`Somatostatinoma
`Other/multi-secretory/unknown
`Not specified
`Median (range) time since diagnosis, years
`
`Sunitinib
`N=86
`82 (95.3%)
`42 (48.8%)
`25 (29.1%)
`
`9 (10 5%)9 (10.5%)
`3
`(3.5%)
`2
`(2.3%)
`0
`(1.2%)
`1
`10 (11.6%)
`19 (22.1%)
`2.4 (0.1–25.6)
`
`Placebo
`N=85
`80 (94.1%)
`44 (51.8%)
`21 (24.7%)
`
`10 (11 8%)10 (11.8%)
`2
`(2.4%)
`2
`(2.4%)
`2
`(2.4%)
`0
`(5.9%)
`5
`20 (23.5%)
`3.2 (0.1–21.3)
`
`Analysis of PFS
`
`PFS Was Calculated Using 3 Different Methods to Determine Disease Progression
`Using RECIST and Identical Censoring Rules
`
`Analysis Method
`1. Investigator Overall
`Tumor Assessment
`
`2. Algorithmic Assessment
`
`3. Blinded, Independent
`Central Review
`
`Determination of
`Progression
`(cid:132) Investigators’ assessment of
`tumor measurements
`(cid:132) Sponsor’s analysis of
`investigators’ tumor
`measurements
`(cid:132) Central radiological review of
`CT/MRI scans
`
`Reason for
`Analysis
`
`Study specified
`
`FDA request
`
`FDA request
`
`47
`
`48
`
`Ex. 1069-0024
`
`

`

`49
`
`50
`
`Progression-Free Survival
`(Investigator Overall Tumor Assessment)
`
`N (%)
`
`Number with PFS event
`Type of event
`Disease progression
`Death without progression
`Kaplan-Meier estimate of median PFS
`(95% CI)
`Hazard ratio (95% CI)
`p-value
`Number censored
`
`Sunitinib
`N=86
`30 (34.9%)
`
`Placebo
`N=85
`51 (60.0%)
`
`48 (56.5%)
`27 (31.4%)
`3 (3.5%)
`3 (3.5%)
`5.5 months
`11.4 months
`(3.6, 7.4)
`(7.4, 19.8)
`0.418 (0.263, 0.662)
`0.000118
`
`56 (65.1%)
`
`34 (40.0%)
`
`Sunitinib (N=86)
` Median 11.4 months
`Placebo (N=85)
` Median 5.5 months
`
`Progression-Free Survival
`(IOTA)
`
`Hazard Ratio = 0.418
`95% CI (0.263 - 0.662)
`p = 0.000118
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`rvival Probability (%)
`
`Progression Free Surv
`
`0
`Number of subjects at risk
`86
`Sunitinib
`85
`Placebo
`
`3
`
`52
`42
`
`6
`
`34
`20
`
`12
`9
`Time (Month)
`20
`15
`9
`2
`
`15
`
`4
`2
`
`18
`
`2
`2
`
`21
`
`Ex. 1069-0025
`
`

`

`Progression-Free Survival
`(Algorithmic Assessment)
`
`N (%)
`
`Number with PFS event
`Type of event
`Disease progression
`Death without progression
`Kaplan-Meier estimate of median PFS
`(95% CI)
`Hazard ratio (95% CI)
`p-value
`Number censored
`
`Sunitinib
`N=86
`30 (34.9%)
`
`Placebo
`N=85
`49 (57.6%)
`
`46 (54.1%)
`27 (31.4%)
`3 (3.5%)
`3 (3.5%)
`5.4 months
`12.6 months
`(3.5, 6.0)
`(7.4, 16.9)
`0.401 (0.252, 0.640)
`0.000066
`
`56 (65.1%)
`
`36 (42.4%)
`
`Progression-Free Survival
`(Blinded Independent Central Review)
`
`N (%)
`
`Number with PFS event
`Type of event
`Disease progression
`Death without progression
`Kaplan-Meier estimate of median PFS
`(95% CI)
`Hazard ratio (95% CI)
`p-value
`Number censored
`
`Sunitinib
`N=86
`22 (25.6%)
`
`Placebo
`N=85
`39 (45.9%)
`
`34 (40.0%)
`19 (22.1%)
`5 (5.9%)
`3 (3.5%)
`5.8 months
`12.6 months
`(3.8, 7.2)
`(11.1, 20.6)
`0.315 (0.181, 0.546)
`0.000015
`
`64 (74.4%)
`
`46 (54.1%)
`
`51
`
`52
`
`Ex. 1069-0026
`
`

`

`53
`
`54
`
`Progression-Free Survival
`(Comparison of Estimates)
`
`Sunitinib (N=86)
`Investigator
`Algorithmic
`Independent
`
`Placebo (N=85)
`Investigator
`Algorithmic
`Independent
`
`0
`
`3
`
`6
`
`12
`9
`Time (Month)
`
`15
`
`18
`
`21
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`rvival Probability (%)
`
`Progression Free Surv
`
`Confidence Intervals for HR of PFS
`
`Hazard Ratio
`
`0.418 (IOTA)
`
`0.401 (Algorithmic)
`
`0.315 (BICR)
`
`Confidence Level
`95.0%
`99.7%
`95.0%
`99.7%
`95.0%
`99.7%
`
`LCL – lower confidence limit; UCL – upper confidence limit
`
`LCL, UCL
`0.263, 0.662
`0.208, 0.839,
`
`0.252, 0.640
`0.198, 0.813
`0.181, 0.546
`0.136, 0.722
`
`Ex. 1069-0027
`
`

`

`Subgroup Analysis
`
`All Patients
`
`Age <65 years
`Age (cid:149)65 years
`White
`Non-White
`Male
`Female
`ECOG PS 0
`ECOG PS 1/2
`
`(cid:148)2 disease sites(cid:148)2 disease sites
`(cid:149)3 disease sites
`Extrahepatic Distant disease
`Pancreas/Liver Only disease
`No somatostatin analogs used
`*Somatostatin analogs used
`0 or 1 prior systemic regimens
`(cid:149)2 prior systemic regimens
`Non-functioning tumor
`Functioning tumor
`Ki-67 (cid:148)5%
`Ki-67 >5%
`Time from diagnosis <3 years
`Time from diagnosis (cid:149)3 years
`
`N
`171
`
`126
`45
`101
`70
`82
`89
`94
`77
`
`112112
`59
`55
`114
`103
`68
`121
`50
`86
`46
`43
`29
`89
`82
`
`HR
`0.418
`
`0.474
`0.223
`0.487
`0.353
`0.374
`0.477
`0.404
`0.455
`
`0 4350.435
`0.428
`0.536
`0.414
`0.409
`0.428
`0.334
`0.607
`0.264
`0.747
`0.378
`0.634
`0.433
`0.292
`
`95% CI
`(0.263, 0.662)
`
`(0.284, 0.793)
`(0.071, 0.702)
`(0.257, 0.923)
`(0.179, 0.695)
`(0.200, 0.701)
`(0.242, 0.939)
`(0.222, 0.735)
`(0.219, 0.943)
`
`(0 245 0 772)(0.245, 0.772)
`(0.195, 0.941)
`(0.245, 1.170)
`(0.233, 0.736)
`(0.222, 0.752)
`(0.206, 0.887)
`(0.188, 0.594)
`(0.269, 1.370)
`(0.129, 0.539)
`(0.303, 1.841)
`(0.155, 0.922)
`(0.235, 1.711)
`(0.239, 0.786)
`(0.130, 0.657)
`
`* Includes all patients receiving somatostatin analogs at any time before and/or concomitant with study treatment.
`ECOG PS, Eastern Cooperative Oncology Group Performance Score
`
`Subgroup Analysis using IOTA
`
`55
`
`0.1
`
`Favors Sunitinib
`
`1
`
`Favors Placebo
`
`10
`
`Multivariate Analysis Adjusting for Selected
`Baseline Factors
`
`Factors Included in Model
`+ Time From Diagnosis ((cid:149)3 vs. <3 years)
`+ ECOG (0 vs.1/2)
`+ Number of Disease Sites (<3 vs. (cid:149)3)
`+ Liver-Directed Therapy (no vs. yes)
`+ Disease Extent (Pancreas/Liver Only vs. Extrahepatic Distant Mets)
`
`Multivariate Cox Model
`
`Hazard Ratio
`
`95% CI
`
`P value†
`
`Treatment Effect (sunitinib vs. placebo)
`
`0.400
`
`0.248, 0.647
`
`0.000185
`
`† Wald Chi-Square test
`
`All baseline factors, including age, race, gender, ECOG PS, no. of disease sites, distant metastases, SSA use, no. of prior systemic therapies,
`tumor function status and time from diagnosis were used in multivariate analyses
`
`Cox Analysis using IOTA
`
`56
`
`Ex. 1069-0028
`
`

`

`57
`
`58
`
`Overall Survival (April 2009)
`
`N (%)
`
`Number of deaths
`Patients censored
`Reason for censoring
`
`Alive and in follow up at data cutoffAlive and in follow-up at data cutoff
`Withdrew consent for additional follow-up
`Lost to follow-up
`Survival probability at 6 months
`(95% CI)
`Hazard ratio (95% CI)
`p-value
`
`Sunitinib
`N=86
`9 (10.5%)
`77 (89.5%)
`
`Placebo
`N=85
`21 (24.7%)
`64 (75.3%)
`
`61 (71 8%)61 (71.8%)
`
`75 (87 2%)75 (87.2%)
`
`1 (1.2%)
`2 (2.3%)
`2 (2.4%)
`0
`85.2%
`92.6%
`(77.1, 93.3)
`(86.3, 98.9)
`0.409 (0.187, 0.894)
`0.0204
`
`Overall Survival (April 2009)
`
`Hazard Ratio = 0.409
`95% CI (0.187 - 0.894)
`p = 0.0204
`
`Sunitinib (N=86, Death=9)
`Placebo (N=85, Death=21)
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Probability (%)
`
`Overall Survival
`
`3
`0
`Number of subjects at risk
`86
`72
`Sunitinib
`85
`66
`Placebo
`
`6
`
`57
`56
`
`9
`
`40
`41
`
`12
`Time (Month)
`34
`28
`
`15
`
`16
`12
`
`18
`
`7
`4
`
`21
`
`1
`
`24
`
`Ex. 1069-0029
`
`

`

`Sunitinib (N=86, Death=34)
` Median 30.5 months
`Placebo (N=85, Death=39)
` Median 24.4 months
`
`Overall Survival (June 2010)
`
`Patients in placebo armPatients in placebo arm
`
`who crossed over
`n = 59 (69%)
`
`Hazard Ratio = 0.737
`95% CI (0.465 - 1.168)
`p = 0.1926
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Probability (%)
`
`Overall Survival
`
`3
`0
`Number of subjects at risk
`86
`83
`Sunitinib
`85
`75
`Placebo
`
`6
`
`77
`68
`
`9
`
`73
`61
`
`12
`
`69
`55
`
`18
`15
`Time (Month)
`59
`49
`49
`39
`
`21
`
`41
`32
`
`24
`
`31
`24
`
`27
`
`18
`18
`
`30
`
`10
`10
`
`33
`
`5
`4
`
`36
`
`1
`
`59
`
`Objective Response Rate
`
`N (%)
`
`Best observed RECIST response
`Complete response
`Partial response
`
`S bl diStable disease/no response/
`
`Objective progression
`Not evaluable
`Objective response rate (95% CI)
`p-value
`Median time to response (range)
`Median response duration (range)
`
`NA, not applicable
`
`Sunitinib
`N=86
`
`2 (2.3%)
`6 (7.0%)
`
`54 (62 8%)54 (62.8%)
`12 (14.0%)
`12 (14.0%)
`9.3% (3.2, 15.4)
`
`3.1 months
`8.1+ months
`
`0.0066
`
`Placebo
`N=85
`
`0
`0
`
`51 (60 0%)51 (60.0%)
`23 (27.1%)
`11 (12.9%)
`0
`
`NA
`NA
`
`ORR using IOTA
`
`60
`
`Ex. 1069-0030
`
`

`

`61
`
`62
`
`Tumor Shrinkage in Patients Receiving Sunitinib
`
`50
`40
`30
`20
`10
`0
`
`-1010
`-20
`-30
`-40
`-50
`-60
`-70
`-80
`-90
`-100
`Confirmed Response
`Confirmed responses were those that persisted on repeat imaging (cid:149)4 weeks after initial documentation
`
`r sum of target lesions
`
`Best % change from baseline for
`
`Sunitinib
`
`Placebo
`
`Sunitinib Safety Profile in Pancreatic NET
`(cid:132) All Causality Adverse Events (AEs)
`
`(cid:132) Grade 3/4 all Causality AEs
`
`(cid:132) Serious Adverse Events (SAEs)
`
`(cid:132) Other SAEs of Interest
`
`(cid:132) Deaths
`
`(cid:132) Safety Conclusions
`
`Ex. 1069-0031
`
`

`

`All Causality Adverse Events (All Grades)
`
`All Grade Adverse Events ((cid:149)20% in Either Arm), N (%)
`Total
`Diarrhea
`Nausea
`Asthenia
`Vomiting
`Fatigue
`Hair color changes
`Neutropenia
`Abdominal pain
`Hypertension
`Hand–foot syndrome
`Anorexia
`Stomatitis
`Dysgeusia
`Epistaxis
`
`Sunitinib
`N=83
`82 (98.8%)
`49 (59.0%)
`37 (44.6%)
`28 (33.7%)
`28 (33.7%)
`27 (32.5%)
`24 (28.9%)
`24 (28.9%)
`23 (27.7%)
`22 (26.5%)
`19 (22.9%)
`18 (21.7%)
`18 (21.7%)
`17 (20.5%)
`17 (20.5%)
`
`Placebo
`N=82
`78 (95.1%)
`32 (39.0%)
`24 (29.3%)
`22 (26.8%)
`25 (30.5%)
`22 (26.8%)
`1
`(1.2%)
`3
`(3.7%)
`26 (31.7%)
`4
`(4.9%)
`2
`(2.4%)
`17 (20.7%)
`2
`(2.4%)
`4
`(4.9%)
`4
`(4.9%)
`
`All Causality Grade 3/4 Adverse Events
`
`N (%), of Patients ((cid:149)4 pts in Either Arm)
`Total
`Neutropenia
`Hypertension
`
`Hand–foot syndromeHand foot syndrome
`Leukopenia
`Diarrhea
`Asthenia
`Fatigue
`Abdominal pain
`Hypoglycemia
`Back pain
`
`Sunitinib
`N=83
`41 (49.4%)
`10 (12.0%)
`8 (9.6%)
`
`5 (6 0%)5 (6.0%)
`5 (6.0%)
`4 (4.8%)
`4 (4.8%)
`4 (4.8%)
`4 (4.8%)
`4 (4.8%)
`0
`
`Placebo
`N=82
`36 (43.9%)
`0
`1 (1.2%)
`
`00
`0
`2 (2.4%)
`3 (3.7%)
`7 (8.5%)
`8 (9.8%)
`1 (1.2%)
`4 (4.9%)
`
`63
`
`64
`
`Ex. 1069-0032
`
`

`

`All Causality Serious Adverse Events in 2 or More
`Patients in Either Arm
`
`N (%)
`Total
`Disease progression
`Cardiac failure
`Abdominal pain
`Abdominal pain upper
`
`NauseaNausea
`Vomiting
`Renal failure / Renal failure acute
`General physical health deterioration
`Hepatic pain
`Pyrexia
`Back pain
`Hematemesis
`Hepatic failure
`Hypoglycemia
`Hypotension
`Melena
`Pulmonary Embolism
`
`Sunitinib Placebo
`
`N=83
`N=82
`22 (26.5%)
`34 (41.5%)
`3 (3.6%)
`2 (2.4%)
`2 (2.4%)
`0
`2 (2.4%)
`4 (4.9%)
`2 (2.4%)
`0
`
`2 (2.4%)2 (2.4%)
`
`1 (1.2%)1 (1.2%)
`2 (2.4%)
`3 (3.7%)
`2 (2.4%)
`1 (1.2%)
`1 (1.2%)
`2 (2.4%)
`1 (1.2%)
`2 (2.4%)
`1 (1.2%)
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`0
`2 (2.4%)
`
`65
`
`Other Serious Adverse Events of Interest
`
`N (%)
`Hepatic encephalopathy
`Pancreatitis / Pancreatitis acute
`Cerebral hematoma
`
`Hepatic dysfunctionHepatic dysfunction
`Leukoencephalopathy
`Ventricular arrhythmia
`
`Sunitinib Placebo
`
`N=83
`N=82
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`0
`
`1 (1 2%)1 (1.2%)
`
`00
`1 (1.2%)
`0
`1 (1.2%)
`0
`
`66
`
`Ex. 1069-0033
`
`

`

`Other Serious Adverse Events of Interest
`
`N (%)
`Hepatic encephalopathy
`Pancreatitis / Pancreatitis acute
`Cerebral hematoma
`
`Hepatic dysfunctionHepatic dysfunction
`Leukoencephalopathy
`Ventricular arrhythmia
`Acidosis
`Cerebrovascular Accident
`Cholangitis
`Duodenal Ulcer Perforation
`Deep vein thrombosis
`Multi-Organ Failure
`
`Sunitinib Placebo
`
`N=83
`N=82
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`1 (1.2%)
`0
`
`1 (1 2%)1 (1.2%)
`
`00
`1 (1.2%)
`0
`1 (1.2%)
`0
`0
`1 (1.2%)
`0
`1 (1.2%)
`0
`1 (1.2%)
`0
`1 (1.2%)
`0
`1 (1.2%)
`0
`1 (1.2%)
`
`67
`
`Summary of Deaths
`
`N (%) of Patients
`Deaths
`Patients who Died While On Studya
`Disease under study
`
`Cardiac FailureCardiac Failure
`Dehydration
`Hepatic Failure
`Patients who Died During Follow-upb
`Disease under study
`Cardiac Failure
`
`Sunitinib
`N=83
`9 (10.8%)
`5 (6.0%)
`4 (4.8%)
`
`1 (1 2%)1 (1.2%)
`0
`0
`4 (4.8%)
`3 (3.6%)
`1 (1.2%)
`
`Placebo
`N=82
`21 (25.6%)
`9 (11.0%)
`7 (8.5%)
`
`00
`1 (1.2%)
`1 (1.2%)
`12 (14.6%)
`12 (14.6%)
`0
`
`Deaths of patients in extension studies are included
`N = number of patients
`a On study deaths are those that occurred after the first dose of study drug and within 28 days of last dose of study medication
`b Follow-up deaths are those that occurred more than 28 days after last dose of study medication
`Based on April 2009 analysis
`
`68
`
`Ex. 1069-0034
`
`

`

`Safety Conclusions
`(cid:132) The most common sunitinib-related AEs were generally consistent
`with the known safety profiles of sunitinib and pancreatic NET
`
`(cid:132) AEs were manageable through the use of dose modifications and/or
`standard medical therapy
`
`(cid:132) No new or unexpected AEs
`
`(cid:132) Safety profile is well characterized in >10,000 patients in clinical trials
`across multiple tumor types
`
`69
`
`70
`
`Patient-reported Outcomes Assessment
`
`(cid:132) PROs were measured using the validated, self-administered EORTC
`QLQ-C30*1, 2 which includes:
`– Global HRQoL
`– Functional scales
`
`(cid:138) Cognitive emotional physical role and social functioning(cid:138) Cognitive, emotional, physical, role and social functioning
`– Symptom items/scales
`(cid:138) Appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting, pain
`
`(cid:132) Patients completed questionnaire at baseline (Cycle 1, Day 1), Day 1
`of every cycle thereafter (treatment cycle = 28 days), and at end of
`treatment or withdrawal
`
`* European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (version 3.0)
`1. Fayers PM, et al. EORTC QLQ-C30 Scoring Manual, 2001
`2. Aaronson NJ, et al. J Natl Cancer Inst 1993;85:365–76
`
`Ex. 1069-0035
`
`

`

`71
`
`72
`
`EORTC QLQ-C30: Global HRQoL
`Change from Baseline Over Time
`No Statistically or Clinically Significant Difference or Change Was Observed Within
`as Well as Between Treatment Arms in Global HRQoL
`
`e Score
`obal QoL
`
`Change
`Mean glo
`
`29
`21
`
`31
`18
`
`25
`14
`
`28 Day Treatment Cycles
`45
`38
`33
`37
`27
`25
`
`61
`61
`
`54
`52
`
`50
`39
`
`N S
`
`unitinib
`Placebo
`
`* Between-treatment differences in mean change from baseline were neither clinically ((cid:149)10 points) nor statistically (95% CI) significant at all time points through 10 cycles
`
`Summary
`(cid:132) Sunitinib provides a clinically meaningful, ~6 month improvement in PFS while
`maintaining Global HRQoL in patients with pancreatic NET
`
`(cid:132) The improvement in PFS is consistent across all analyses, confirming the robust
`treatment effect of sunitinib
`
`
`
`
`
`(cid:132) Sunitinib favorably impacts overall survival (HR = 0 409)(cid:132) Sunitinib favorably impacts overall survival (HR 0.409)
`
`(cid:132) Sunitinib results in objective tumor shrinkage (RR = 9.3% in sunitinib vs. 0% in placebo)
`
`(cid:132) Adverse events are consistent with the known safety profile of sunitinib and/or the signs
`and symptoms of pancreatic NET
`
`These data demonstrate a favorable benefit/risk profile for sunitinib
`in patients with unresectable pancreatic NET
`
`Ex. 1069-0036
`
`

`

`Clinical Perspective
`
`Matthew Kulke, MD
`Director, Carcinoid and Neuroendocrine Tumor Program
`Dana-Farber/Brigham and Women’s Cancer Center
`Boston, MA
`
`OS Analyses Adjusting for Crossover
`
`Approach
`ITT Analysis (June 2010)
`
`Censor at Crossover Analysis
`Time Dependent Treatment Analysis
`RPSFT * Analysis
`
`*Rank Preserving Structural Failure Time
`
`HR (95% CI)
`0.737 (0.465, 1.168)
`
`0.416 (0.230, 0.752)
`0.468 (0.268, 0.818)
`0.499 (0.351, 0.947)
`
`OS 3
`
`Ex. 1069-0037
`
`

`

`Sunitinib (N=86)
`April 2009
`December 2009
`June 2010
`
`Placebo (N=85)
`April 2009
`December 2009
`June 2010
`
`Overall Survival
`All Three Analyses – Phase 3
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`robability (%)
`
`Overall Survival Pr
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`30
`
`33
`
`36
`
`Time (months)
`
`OS 9
`
`Overall Survival (June 2010)
`Placebo Re-baseline at Crossover – Phase 3
`
`Sunitinib (N=86, Death=34) Median 30.5 months
`Placebo (N=85, Death=39) Median 24.4 months
`Placebo with crossover re-baselined at crossover
`(N=59, Death=19) Median Not Reached
`
`100
`90
`80
`70
`
`6060
`50
`40
`30
`20
`10
`0
`
`obability (%)
`
`Overall Survival Pro
`
`0
`
`3
`
`6
`
`9
`
`