Exelixis Investor Update
ASCO GU Symposium
February 17, 2011
Forward-Looking Statements
This presentation contains certain statements that are forward-looking, including, without limitation, statements relating to Exelixis’
belief that cabozantinib is the primary value driver for the company, the continued development and clinical, therapeutic and
commercial potential of cabozantinib, Exelixis’ plan to continue enrollment in its non-randomized expansion cohort for metastatic
castration-resistant prostate cancer (CRPC), future development opportunities and priorities for cabozantinib, Exelixis’ belief that
there is significant commercial opportunity for cabozantinib in CRPC, Exelixis’ belief that medullary thyroid cancer (MTC) may be
the first regulatory filing for cabozantinib, the expected read-out for the ongoing phase 3 trial for MTC in the first half of 2011 and
plan to file a new drug application in MTC in the second half of 2011, Exelixis’ belief that data from the randomized discontinuation
trial for cabozantinib will drive the development of cabozantinib in other indications, Exelixis’ plan to prioritize development of
cabozantinib in CRPC, including advancing to phase 3, future cabozantinib data presentations, including at the 2011 ASCO Annual
Meeting, key cabozantinib milestones for the first half 2011 and Exelixis’ belief that such milestones will drive news flow, the
changing landscape of treatments for CRPC in 2011 and beyond, clinical development strategies and plans for cabozantinib in
CRPC, Exelixis’ phase 3 regulatory strategy, development plan and predictions for cabozantinib, future potential regulatory filings,
and the determination of the optimal dose selection for cabozantinib in CRPC and Exelixis’ belief that doses lower than the 100mg
starting dose may prove as active with improved tolerability. Words such as ―potential,‖ ―opportunity,‖ ―encouraging,‖ ―priorities,‖
―expect,‖ ―plan,‖ ―will,‖ ―driving,‖ ―appears,‖ ―aim,‖ ―predicts,‖ ―may,‖ ―anticipate,‖ likely,‖ ―strategy,‖ ―approach,‖ and similar
expressions are intended to identify forward-looking statements. These statements are only predictions and are based upon
Exelixis’ current plans, assumptions, beliefs and expectations, and are subject to risks and uncertainties. Exelixis’ actual results
and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks
and uncertainties, which include, without limitation, risks related to: the potential failure of cabozantinib to demonstrate safety and
efficacy in clinical testing; the ability to conduct clinical trials for cabozantinib sufficient to achieve a positive completion; the
uncertain timing and level of expenses associated with the development of cabozantinib; the sufficiency of Exelixis’ capital and
other resources; the availability of data at the referenced times; the uncertainty of the FDA approval process; market competition
and changes in economic and business conditions. These and other risk factors are discussed under ―Risk Factors‖ in Exelixis’
Quarterly Report for the quarter ended October 1, 2010 and Exelixis’ other reports filed with the Securities and Exchange
Commission. Exelixis expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any
forward-looking statements made in this discussion to reflect any change in Exelixis’ expectations with regard thereto or any
changes in events, conditions or circumstances on which any such statements are based.
2
Michael Morrissey, PhD
President and CEO
Encouraging Cabozantinib CRPC Data at ASCO-GU
Clinical activity in both bone and soft tissue metastatic lesions in CRPC
• Overall disease control rate at week 12 is 74%
• Bone scan resolution (complete or partial) in 53 of 62 (85%) or stabilization in 8
of 62 patients (13%) associated Improvement in bone pain and reduction in
narcotic use
− Reduction in markers of bone resorption and formation
• PFS appears independent of prior docetaxel therapy
• Randomized discontinuation of cabozantinib resulted in early progression in the
placebo arm
− Median PFS for cabozantinib not yet mature; median PFS for placebo=40 days
Randomization was halted and patients unblinded due to observed activity
A non-randomized expansion cohort is currently accruing
Data of 100 CRPC patients reinforces early data reported in Nov 2010
4
Today’s Agenda
Welcome & Overview
Dr. Michael Morrissey
Cabozantinib Overview and Data Review
5
Experience at Dana Farber
Dr. Philip Kantoff
ASCO GU Data in mCRPC
Dr. Matthew Smith
Clinical Development Plan
Dr. Ron Weitzman
Dr. Howard Scher
Closing and Q&A
Dr. Michael Morrissey
Key Milestones for Cabozantinib in 1H 2011
ASCO GU – CRPC data
ASCO Annual Meeting
• CRPC
• Ovarian cancer
• Other RDT indications
• Renal cell carcinoma
Readout MTC top-line data
• Phase 3 readout expected in 1H 2011
• NDA filing planned for 2H 2011
IMPORTANT 1H 2011 MILESTONES DRIVING NEWS FLOW
6
The Changing Landscape of Prostate Cancer
Treatment: Cabozantinib (XL184)
Philip Kantoff MD
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
7
Prostate Cancer Landscape: February 2010
Hormone Sensitive
Newly diagnosed
Localized disease
Rising PSA,
No mets
Metastatic
Hormone-naïve
Surgery
Radiation
ADT or
observation
ADT
Castration Resistant
Non-metastatic
No standard
Second-line
hormones
Metastatic,
Chemotherapy-naïve
Metastatic,
Chemotherapy-naïve
Asymptomatic
Symptomatic
Second-line hormones
(Docetaxel)
Zoledronic acid for SREs
Docetaxel
Metastatic,
Post-docetaxel
No standard
Mitoxantrone
8
Prostate Cancer Landscape: February 2011
Hormone Sensitive
Newly diagnosed
Localized disease
Rising PSA,
No mets
Metastatic
Hormone-naïve
Surgery
Radiation
Active Surveillance
ADT or
observation
ADT
Castration Resistant
Non-metastatic
No standard
Second-line
hormones
Metastatic,
Chemotherapy-naïve
Metastatic,
Chemotherapy-naïve
Asymptomatic
Symptomatic
Provenge
Second-line hormones
(Docetaxel)
Zoledronic acid or
Denosumab for SREs
Docetaxel
Metastatic,
Post-docetaxel
Cabazitaxel
Mitoxantrone
9
Changing Landscape in 2011
• New agents in 2011
 Abiraterone-likely FDA approval in docetaxel treated CRPC
• Denosumab may delay development of bone metastases
10
Beyond 2011?
•
•
•
•
Abiraterone in docetaxel naïve CRPC
MDV3100 in post-docetaxel CRPC
MDV3100 in pre-docetaxel CRPC
Other CYP17 lyase inhibitors
 TAK700
 TOK001
• Other antiandrogens
 ARN-509
• Biologics combined with docetaxel
 Many
• Immunotherapeutics
 Anti-CTLA-4 and PD-1
 Prostvac-VF Tricom
11
Cabozantinib (XL184)
• Small molecule tyrosine kinase inhibitor
• Known spectrum of kinase activity (IC50 < 20nM)
• VEGFR2, MET, KIT, RET, AXL, Tie2, FLT3
12
Broad Anti-tumor Activity Across Multiple
Tumor Types
39 PRs in 269 pts with ≥ 1 post-baseline assessment
(N = 269)
Effects in bone
Courtesy of Exelixis
13
CRPC: Anti-Tumor Activity in Bone
and Soft Tissue
Baseline
Week 6
Yes
Prior Docetaxel
Maximum tumor
change, per
mRECIST
Improvement in
bone painb
–26%
Yes
tALP
PSA
3000
500
300
200
1000
Change in tALP
and PSA
PSA
tALP
400
2000
100
0
0
-2
BL
2
6
10
14
Weeks On Study
N/A, not available; NE, not evaluated due to no pain at baseline;
Bone scans at baseline and
during therapy with cabozantinib
PSA, prostate specific antigen; BL, Baseline
a
Independent radiologist review
b
14
Post-Hoc investigator survey of whether pain improved at week 6 and/or week 12
What is the Mechanism of this Major Bone
Activity?
Cabozantinib (XL184)
Bone metastases represent a major unmet medical need in oncology
• Bone metastases occur in ~300K cancer patients in the US annually
• Most common with prostate, breast & lung cancer & multiple myeloma
• Strong preclinical data supporting the bone activity of cabozantinib
Vehicle
cabozantinib
Cabozantinib
blocks
progression of
prostate tumor
xenografts
in bone in
preclinical models
16
Courtesy of Exelixis
Cabozantinib:Targets 3 Key Cell Types in
Metastatic Bone Lesions
Cabozantinib
Bone
Destruction
Bone
Formation
Tumor Cells
Osteoclasts
Osteoblasts
TUMOR CELLS, OSTEOBLASTS & OSTEOCLASTS EXPRESS ACTIVATED MET & VEGFR
17
Is MET Inhibition VEGFR2
Inhibition or Both Important?
Up-regulation of MET as a Response to Treatment
VEGF Pathway
Inhibition
Androgen Receptor
Blockade
EGFR
Inhibition
Hypoxia, HIF1 stabilization
Up-regulation of MET
MET Expression
Selection for MET amplification
(NSCLC)
Relief of AR-mediated
repression (Prostate)
19
Is this Bone Effect Specific to CRPC?
Cabozantinib Activity in Bone Lesions
Extends Beyond CRPC
• Effects in Bone observed in
−
−
−
−
−
CRPC
Breast Cancer
Melanoma
Thyroid Cancer
Renal Cell Cancer
Resolution of Bone Scan Lesions often Accompanied by Pain Relief
21
Bone Scan Change in Subject with ER/PR+
Metastatic Breast Cancer
Prior Treatment
1.
Adjuvant AC
2.
Adjuvant Tam
3.
Arimidex
4.
Faslodex
5.
Ixabepilone
29% shrinkage in target
lesions
(improvement in pain)
Week 6
22
Bone Scan Changes in Renal Cell Carcinoma
Baseline
(9/23/10)
Anterior
7-Week Follow-up
(11/16/10)
Posterior
Anterior
Posterior
Prior therapies include: Sorafenib, an mTOR inhibitor, & Sunitinib
23
Radiographic Response in a Patient with RCC
Baseline
8-Week Follow-up
Prior therapies include: mTOR inhibitor, Sunitinib, &
24
Gemcitabine
Conclusions-Cabozantinib (XL 184)
• Known spectrum of kinase activity (IC50 < 20nM)
 VEGFR2, MET, KIT, RET, AXL, Tie2, FLT3
• Known spectrum of clinical activity
 Profound effect on bone-tumor compartment
 Regression of soft tissue disease
• Known single agent adverse event profile in CRPC




Most frequent – fatigue, diarrhea, epigastric distress, HFS
Needs management – hypertension
Rarely clinically significant HTN/cerebral effects
Minimal myelosuppression
25
Unanswered Questions and Future Directions
• What is mechanism of activity?
• What is optimal dose and schedule?
• Clinical development in CRPC
 Single agent approach
• Pain and bone scan resolution
• Overall survival
• Delay in development of bone metastases
 Combination with abiraterone
• Possible synergy with androgen inhibitors
– Both active agents, up-regulation of MET with
androgen blockade
• Abiraterone +/- Cabozantinib
 Other combination strategies to be discussed
26
Cabozantinib mCRPC Data Update
Matthew Smith, MD, PhD
Massachusetts General Hospital Cancer Center
Phase 2 Study of Cabozantinib (XL184) in a Cohort of Patients With
Castration-Resistant Prostate Cancer (CRPC) and Measurable Soft
Tissue Disease
David C. Smith1, Matthew R. Smith2, Eric J. Small3, Christopher J.
Sweeney4, Razelle Kurzrock5, Michael S. Gordon6, Nicholas J.
Vogelzang7, Christian Scheffold8, Marcus D. Ballinger8, and Maha
Hussain1
1University
of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 2Massachusetts General
Hospital Cancer Center, Boston, MA; 3University of California, San Francisco, San Francisco,
CA; 4Dana-Farber Cancer Institute, Boston, MA; 5MD Anderson Cancer Center, Houston, TX;
6Pinnacle Oncology Hematology, Scottsdale, AZ; 7Comprehensive Cancer Center of Nevada,
Las Vegas/US Oncology Research, NV; 8Exelixis Inc, South San Francisco, CA
28
Role for MET and VEGFR in Tumor-Bone Interactions in
CRPC
• Bone metastases are the major
cause of morbidity in CRPC and
are associated with high levels of
MET expression
• Osteoblasts and osteoclasts
express MET and VEGFRs, and
respond to HGF and VEGF
• HGF and VEGF may be important
factors directing crosstalk between
tumor cells, osteoblasts, and
osteoclasts
• Simultaneous inhibition of MET
and VEGFR may block the
progression of osteolytic and
osteoblastic bone lesions
29
METHODS
Study Design
• The CRPC cohort is investigated as part of a Phase 2 randomized discontinuation trial
• Patients received cabozantinib at 100 mg qd over a 12-week Lead-In Stage
• Treatment allocation after week 12 was based on response:
− patients with PR → open-label cabozantinib,
− patients with SD → were randomized to cabozantinib vs. placebo (1:1)
− patients with PD→ discontinued
• Accrual could be halted for either high rates of response or progression
Study End Points
• Efficacy end points:
– Objective response rate (ORR) per mRECIST 1.0 in the Lead-in Stage
– Progression-free survival (PFS) in the Randomized Stage
• Safety end points include adverse events and laboratory parameters
Key Study Eligibility Criteria
• Pathologically and radiologically confirmed CRPC
• Up to one prior line of chemotherapy with no restrictions on hormone therapies
• Progressive disease and measurable target lesion(s) per mRECIST
Assessments
• Tumor assessments by CT/MRI/bone scan at baseline and q6 weeks
30
RESULTS
This is an analysis of preliminary data from a fully enrolled study
Definition of Populations Analyzed
• Enrolled: patients enrolled as of January 27, 2011 (N = 168)
• Primary end point evaluable: patients with at least 12 weeks of follow-up (n = 100)
• Bone scan response evaluable: patients with known bone metastases and at least one
post-baseline bone scan (n = 62)
31
Baseline Characteristics (n = 100)
Age, years
Median (range)
≥ 65, n
68 (47–88)
69
ECOG performance status, %
0
54
1
46
PSA (ng/mL), median (range)
tALPa (U/L), median (range)
Hemoglobin (g/dL), median (range)
54 (2–1327)
108 (39-2283)
12.5 (9–15)
Prior lines of therapy, %
0
45
1
49
>1
6
Prior docetaxel, %
47
Measurable disease, %
100
Disease sites, %
Visceral
47
Lymph node
88
Bone
78
Bone Painb, %
Narcotics for Bone Painb
50
37
atALP=Serum
bPost-hoc
total alkaline phosphatase.
investigator survey on bone pain and narcotic use.
32
Patient Disposition
Summary of Treatment Status in the Lead-In Stage, n
100
Completed Lead-In Stagea,%
74
Treatment discontinuation ≤ week 12, (%)
26
Primary reason for discontinuation, %
Progressive disease
Adverse event
Otherb
Death
Lost to follow-up
aWeek
10
9
5
1
1
12 overall response of PR or SD
withdrawl of consent (n=3); subject request (n=2)
bIncludes
33
Frequently Reported Adverse Events During Lead-In
Stage Regardless of Causality (n = 100)
All Grades, %
Grade ≥ 3, %
Fatigueb
71
15
Decreased appetite
52
2
Diarrhea
46
1
Nausea
40
2
Constipation
34
—
Dysphonia
33
—
Vomiting
29
2
• No related Grade 5 events
Hypertensionb
25
8
Dysgeusia
24
—
PPE syndromeb,c
19
5
reported
• Patients experiencing ≥1 dose
reduction: 51%
Dyspnea
18
1
Weight decreased
18
—
Rashb
16
2
Mucosal inflammation
14
—
Hemorrhageb
12
2
Back pain
11
3
Cough
11
1
Abdominal pain
10
2
Adverse Eventa
aMedDRA
v. 12.1 Preferred Terms (converted to US spelling), CTCAE v.3.0 grading.
of Preferred Terms related to a particular medical condition.
cPalmar-Plantar Erythrodysesthesia syndrome.
bGroupings
34
Summary of Effects on Bone Scana
Bone scan evaluableb, n
62
Complete or partial resolution, n (%)
53 (85)
Stable, n (%)
8 (13)
Progressive disease, n (%)
1 (2)
aBest time
bBone
point evaluation of changes in areas of radiotracer uptake attributable to metastatic disease per independent radiologist review.
metastases at baseline and at least one post-baseline bone scan available.
35
Summary of Effects on Bone Pain per Investigatora
Bone metastases and bone pain at baselineb, n
Pain improvement at week 6 or 12, n (%)
Narcotic medication for bone pain at baselinec, n
43
26 (60)
33
Pain improvement at week 6 or 12, n (%)
21 (64)
Decrease or discontinuation of narcoticsd, n (%)
13 (46)
aPost-hoc
survey of whether pain improved at week 6 and/or week 12, and whether narcotics taken for bone pain were decreased or discontinued.
to patients with ≥1 post-baseline assessment of pain improvement (43 of 50 patients with bone pain at baseline).
cLimited to patients with ≥1 post-baseline assessment of pain improvement (33 of 37 patients taking narcotics for bone pain at baseline).
dLimited to patients with ≥1 post-baseline assessments of both pain improvement and changes in narcotics (28 of 33 patients).
bLimited
36
Examples of Patients with Complete or Partial Bone Scan Resolutiona
Baseline
Week 6
Baseline
Week 6
Baseline
Week 6
Baseline
Week 6
Baseline
Week 6
Bone scans
at baseline
and during
therapy with
cabozantinib
Prior
Docetaxel
yes
yes
yes
No
No
Maximum
tumor
change, per
mRECIST
-14
-26%
-17%
-28%
-12%
Improvement
in bone painb
NE
yes
No
NE
yes
500
0
0
-2
BL
2
6
10
14
Weeks On Study
0
-2
BL
2
6
Weeks On Study
a
0
10
tALP
tALP
tALP
500
200
300
500
200
250
100
0
0
-2
BL
2
6
10
14
Weeks On Study
80
1000
800
60
800
600
40
400
20
200
0
0
-2
BL
2
6
10
14
Weeks On Study
120
600
80
400
PSA
1000
750
tALP
PSA
1000
PSA
20
1000
PSA
400
1500
400
PSA
40
600
1000
tALP
1500
800
PSA
Change in
tALP
and PSA
2000
tALP
PSA
tALP
PSA
tALP
PSA
60
tALP
tALP
PSA
1000
40
200
0
0
-2
BL
2
6
Weeks On Study
Independent radiologist review b Post-Hoc investigator survey of whether pain improved at week 6 and/or week 12
NE, not evaluated due to no pain at baseline; BL, Baseline
37
Single Patient with Bone Scan Progression as a Best Responsea
Baseline
Week 6
No
Prior Docetaxel
Maximum tumor
change, per
mRECIST
Improvement in bone
painb
-5%
Yes
tALP
PSA
2000
1500
1000
1000
PSA
Change in tALP
and PSA
tALP
1500
500
500
0
-2
BL
2
6
Weeks On Study
0
10
Bone scans at baseline and
during therapy with cabozantinib
N/A, not available; NE, not evaluated due to no pain at baseline; PSA, prostate specific antigen; BL, Baseline
Independent radiologist review
b Post-Hoc investigator survey of whether pain improved at week 6 and/or week 12
a
38
20
0
-20
-40
-60
B. Maximum CTx Change in
Patients With Known Bone
Metastases (n = 48)
40
C. Median Changes in tALP and
Plasma CTx Levels Over Time in
Patients With Known Bone
Metastases
Bisphosphonate treated
Bisphosphonate naïve
tALP
40
20
0
-20
-40
-60
Median % Change
from Baseline
A. Maximum tALP in Patients
With Elevated Levels at
Baseline and Known Bone
Metastases (n = 16)
+65%
Bisphosphonate treated
Bisphosphonate naïve
40
% Change From Baseline
% Change From Baseline
Effects on Markers of Osteoblast (tALP) and Osteoclast
(CTx) Activity
CTx
20
0
-20
-40
-60
-80
BL0
-80
-80
6
12
18
Weeks On Study
24
-100
-100
39
Changes in Hemoglobin Levels Over Time in Patients
with Anemia (Hb <11 g/dL)
4
Change in Hb from
Baseline (g/dL)
3
2
1
0
-1
-2
-3
2
4
6
8
10 12
15
21
27
Study Week
• The median maximum rise in Hb was 2.2 g/dL (range, 0.6-3.5)
40
Summary of mRECIST Response in the Lead-In Stage
RECIST response evaluablea, n
100
Best objective response rate, %
Confirmed responseb
6
Stable diseasec
82
Progressive disease
4
12 week DCRd, n (%)
74
Enrolled ≥ 12 weeks prior to data cutoff ; post-baseline overall assessments not performed for 8 patients.
Confirmed responders time on study: 36, 30+, 29, 19+, 18, and 17+ weeks.
c Two uPRs await confirmation; time on study: 18+ and 12+ weeks.
d Disease control rate defined as PR + SD at week 12.
a
b
• Median follow-up for all 100 patients was 117 days, (range 21-462 days)
41
Kaplan-Meier Plots of Investigator-Assessed
Progression-Free Survival (PFS)
PFS from Day 1
PFS from Week 12 Randomization
1.00
0.75
Docetaxel Naive (n=46)
Docetaxel Pretreated (n=37)
0.50
0.25
Proportion
Progression-Free
Proportion
Progression-Free
1.00
0.75
Cabozantinib (n=14)
Placebo (n=17)
0.50
0.25
0.00
0
100
200
300
PFS per mRECIST (days)
400
-84
12-w eek 0
Lead-in Period
100
200
300
PFS per mRECIST, Post Randomization (days)
• Median PFS not yet reached for
• Median PFS for cabozantinib arm not yet
either group
• Censoring rates: docetaxel-naïve
85%; docetaxel pretreated 78%
reached
• Median PFS for placebo is 40 days (95%
CI: 37,82 days)
• Censoring rates: cabozantinib 79%;
placebo 29%
42
Best Time Point Response in Target Lesions for Patients
With ≥SLD
1 Post-Baseline
Assessment
(n = 91)
% Change inTumor
Prostate
Cancer Subjects
% ChangeFrom Baseline
% Change from Baseline
40
20
0
-20
-40
*********
Docetaxel-naïve
Prior docetaxel
* 0% change from baseline
-60
-80
43
Target Lesion Size
(% change from baseline)
Effects of Cabozantinib Treatment on PSA and Tumor
Measurements at Week 6 (n = 88)
60
30
0
-30
-60
-100
0
100
200
300
850 950
PSA (% change from baseline)
Changes in PSA independent of:
• Reduction or stability of tumor target lesions
• Resolution of bone lesions on bone scans
• Changes in bone pain
44
SUMMARY
Cabozantinib (Cabo) shows encouraging clinical activity in both bone and soft
tissue metastatic lesions in CRPC patients
• Overall disease control rate at week 12 of 74%
• Bone scan resolution (complete or partial) in 53 of 62 (85%) or stabilization in 8 of 62
patients (13%) associated with:
– Improvement in bone pain and reduction in narcotic use
– Reduction in markers of bone resorption and formation
• PFS appears independent of prior docetaxel therapy
• Randomized discontinuation of cabo resulted in rapid progression in the placebo arm
– Median PFS for cabo arm not yet mature; median PFS for placebo arm=40 days
PSA changes were independent of changes in other parameters, including target
lesions, bone scan and bone pain
Tolerability profile consistent with other tyrosine kinase inhibitors
Simultaneous targeting of MET and VEGFR with cabo results in unique effects in
patients with CRPC
• Randomization was halted and patients unblinded due to observed activity
• A non-randomized expansion cohort is currently accruing
45
Cabozantinib Development Plan
Ron Weitzman, MD
Vice President, Clinical Development
Howard Scher, MD
Memorial Sloan-Kettering Cancer Center
Phase 3 Regulatory Strategy & Development Plan:
Outline of General Approach
Phase 3 to leverage the unique attributes of cabozantinib
• Dual effect on both metastatic soft tissue and bone lesions
• Resolution of symptomatic bone pain reported by patients/PI’s
Address key CRPC populations underserved with available therapies
• Relieve/control symptomatic bone pain
• Prolong overall survival in mCRPC
• Prevention of bone metastases
Go head-to-head against active comparator when appropriate
• Pursue lowest effective dose where feasible
Multiple potential filings targeting CRPC patients with bone disease
47
Phase 3 Trials Aim to Follow Signals in Phase 2
Phase 3
Phase 2 Signal
Pain Relief
Study Population
Primary Endpoints
Painful Bone Mets
Study 1:
Composite Endpoint
Pain & Bone Scan
mCRPC patients with
bone mets
Resolution of lesions
on bone scan
Pre-metastatic CRPC
Study 2:
Overall Survival
Study 3:
Metastasis-Free Survival
Effects on bone biomarkers in phase 2 strongly predict for reduced risk of
developing SREs in Studies 1 and 2 as a secondary endpoint
48
Optimal Dose Selection in CRPC
RDT starting dose 100 mg (free base) across 9 different tumor types
 100 mg dose represents the upper bound of a range of active doses
 Lower doses are clearly active:
Bone responses, disease/pain control maintained on lower doses
Lower doses result in benefit post cross-over from placebo
Lower doses effective at disease control for 3+ years in MTC
 Both fatigue and hand-foot syndrome appear to be dose dependent
Dose optimization approach to rely on:
 Matthew Smith IST probing the lowest active dose in mCRPC
 Phase 3 composite endpoint study to include a lower dose in a 3rd arm
Cabozantinib at 100 mg qd is an acceptable starting dose
Lower doses may prove as active with improved tolerability
49
Ongoing and Planned Trials of Cabozantinib in CRPC
2010
mCRPC
chemo
treated
2011
RDT
2012 & beyond
ASCO-GU
ASCO Annual Meeting
Non-Randomized Extension
Potential Subpart H Filing
Inform Composite Endpoint
Phase 3
Composite Endpoint
mCRPC
Lifecycle management
Phase 3 Survival
Combination Studies
premCRPC
Dose Range Finding
Phase 3 Met-Free Survival
50
The Response to an FDA Challenge To Develop New
Prostate Cancer Trial Metrics: ODAC 3/5/2005
1. Traditional measures of ―response‖ of limited value
2. Objectives: Response: Control, relieve, eliminate: PAIN
Time to event: Survival
3. Less reliance on PSA; traditional response measures of limited value
4. Align phase 3 endpoints to phase 2 trial results
51
Survival vs Pain Endpoint in mCRPC Phase 3 Studies
Approval based on overall survival endpoint
 Generally offers a much broader label
 Survival studies are large, and require longer follow-up
 Outcome prone to effects of active post-study salvage therapies
 No agent with OS label has a pain label
Approval based on pain endpoint
 More narrow label due to uniqueness of population
 Pain studies are smaller, require shorter follow-up
 Outcome prone to effects of missing data, bias and unintentional unblinding
due to differential toxicity profiles between treatment arms
 No agent with pain label in mCRPC extends survival
FDA previously granted full approval on the basis of either endpoint
52
History of Relevant Regulatory Approvals in mCRPC
Agent
1º Endpoint
Sample Size Pain Label?
Approval
Docetaxel
vs
Mitoxantrone/P
Survival
1006
No
Full
Survival
755
No
Full
Pain
Response
161
Yes
Full
Week-4 Pain
Response
Study A:118
Study B:152
Yes
Full
Cabazitaxel
vs
Mitoxantrone/P
Mitoxantrone
vs
Prednisone
Samarium
vs
Placebo
OGX-011 SPA with FDA confirms acceptability of pain endpoint for full approval
53
Survival vs Pain Endpoint in mCRPC P3 Studies
Primary composite endpoint: pain palliation + bone scan response
 Definition of ―pure‖ pain response is widely accepted/validated
 A novel definition of bone scan response has been developed
Composite endpoint strengthens the design of the study
 Reduces concerns that reported pain improvement reflects bias due to
unmasking of treatment assignment
 Bone scans provide evidence that patient reported pain improvement are due
to bone effects and not to non-specific analgesia
Additional secondary objective endpoints will be supportive
 Effects on hemoglobin and bone markers
 CTC
 PFS, SRE
 ORR
54
Overview of Phase 3 Study 306 (Composite Endpoint)
Composite of pain and bone scan response with additional endpoints
 Duration of pain and bone scan responses
 SREs, PFS, OS
 Effects on Hgb and bone markers
Validated method of pain assessment and collection
 Brief Pain Inventory, 11 point numerical rating score (0-10), validated instrument
Population
 Baseline pain
 Prior docetaxel therapy required, may have also failed other agents
Anticipate sample size of ~ 300 patients
Likely evaluate three treatment arms
• Cabozantinib full dose (100 mg) and low dose (TBD) vs. Mitoxantrone/prednisone
Final components of trial design to be determined as part of SPA
55
Lessons Learned From (Failed) Satraplatin Submission
56
Wrap Up and Q&A
Exelixis Investor Update
ASCO GU Symposium
February 17, 2011