1. Fighting a Smarter War On Colon Cancer:
John L. Marshall, MD
Angiogenesis inhibition through all lines of therapy
Tel: (202)
Fax: (202) 1

2. Stakeholder Motivation
Stakeholders
FDA
CMS/Payers
NCI/CTEP
PhRMA
Community Onc
Academic Onc
Patients
Priority/Agenda
Safety and Efficacy
Cost Control/Value
Cure Cancer
Markets, ROI
Efficient/Quality Care
Clinical Trial Accrual
Cure/Benefit/Altruism

3. 2012 ESMO Guidelines: Sequence of Treatment by Line
Schmoll et al. Ann Oncol. 2012;23:

4. Pathway vs. Network signaling
In recent years the view of signaling had shifted from the canonical pathway signaling towards a concept of NETWORK SIGNALING. The latter takes into account a tremendous degree of overlap and cross-talk between the pathways. This network signaling concept came to existence as a result of studies based on Y2H and RNAi technologies.
Pathway
“Newtonian”
Network
“Chaotic”
A. Friedman and N. Perrimon, Cell 128, January 26, 2007

5. The Nature of the Disease

6. Multiple signaling pathways activated in CRC
Figure adapted from Siena S et al 20092
Multiple pathways implicated in CRC, including:1–3
EGF / EGFR
VEGF / VEGFR
PDGF / PDGFR
FGF / FGFR
Downstream pathways:
RAS–RAF–MEK–ERK
PI3K–PTEN–AKT–mTOR
Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI3
Provides rationale for using a multitargeted agent following progression
Macarulla T et al. Clin Colorectal Cancer 2006
Siena S et al. J Natl Cancer Inst 2009
Kopetz S et al. J Clin Oncol 2010

7. CORRECT study design Primary Endpoint: OS mCRC after standard therapy
RANDOM I ZAT I ON
Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off
Primary Endpoint: OS
90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025
mCRC after standard therapy
2 : 1
Placebo + BSC 3 weeks on, 1 week off
Multicenter, randomized, double-blind, placebo-controlled, phase III
2:1 randomization
Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region
Global trial: 16 countries, 114 active centers
1,052 patients screened, 760 patients randomized within 10 months
Secondary endpoints: PFS, ORR, DCR
Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers

8. CORRECT Primary Endpoint: Overall Survival
1.00
Median months months
95% CI
Hazard ratio: 0.77 (95% CI, )
1-sided P =
Placebo
Regorafenib
0.75
0.50
Survival Distribution Function
0.25
Placebo (n = 255)
Regorafenib (n = 505) 50
100
150
200
250
300
350
400
450
Days From Randomization
Primary endpoint met prespecified stopping criteria at interim analysis. (1-sided P< at approximately 74% of events required for final analysis).
Grothey A et al. Lancet. 2013;381: Reprinted with permission from Elsevier.

9. CORRECT Secondary Endpoint: Progression-Free Survival
1.00
0.50
0.25
0.75
200
100 50
150
300
250
350
Regorafenib Placebo
Median months months
95% CI
Hazard ratio: 0.49 (95% CI, )
1-sided P<
Survival Distribution Function
Placebo (n = 255)
Regorafenib (n = 505)
Days From Randomization
Grothey A et al. Lancet. 2013;381: Reprinted with permission from Elsevier.

10. CORRECT: Common Adverse Events
Treatment-related adverse events occurring in >10% of patients in either group from start of treatment to 30 days after end of treatment
Regorafanib (n=500)
Placebo (n=253)
Any Gr
Gr 3
Gr 4
Fatigue, n (%)
237 (47)
46 (9)
2 (<1)
71 (28)
12 (5)
1 (<1)
Hand-foot skin reaction, n (%)
233 (47)
83 (17)
19 (8)
Diarrhea, n (%)
169 (34)
35 (7)
21 (8)
2 (1)
Anorexia, n (%)
152 (30)
16 (3)
39 (15)
7 (3)
Voice changes, n (%)
147 (29)
14 (6)
Hypertension, n (%)
139 (28)
36 (7)
15 (6)
Oral mucositis, n (%)
136 (27)
15 (3)
9 (4)
Rash or desquamation, n (%)
130 (26)
29 (6)
10 (4)
Nausea, n (%)
72 (14)
28 (11)
Weight loss, n (%)
69 (14)
6 (2)
Thrombocytopenia, n (%)
63 (13)
13 (3)
5 (2)
This slide details the most common adverse drug reactions seen with STIVARGA.
Grothey A, et al. Lancet [epub].

11. Summary of Survival From Pivotal Phase III Bevacizumab Studies
First Line
Second Line
Continued Beyond First Progression
Trial
AVF21071,2
(n=411 vs 402)
E32003
(n=285 vs 287)
ML181474
(n=410 vs 409)
Treatment
IFL vs IFL + Bev
FOLFOX4 vs FOLFOX4 + Bev
CT* vs CT* + Bev
OS, mos
P value HR
15.6 vs 20.3
<0.001
0.66
10.0 vs 12.9
0.001
0.75
9.8 vs 11.2
0.0057
Unstratified HR: 0.81
PFS, mos
6.2 vs 10.6
0.54
4.7 vs 7.3
<0.0001
0.61
4.4 vs 5.7
Unstratified HR: 0.68
*CT= Fluoropyrimidine + oxaliplatin-containing chemotherapy or Fluoropyrimidine + irinotecan-containing chemotherapy.
Data represent a summary of reported data and are not intended for cross-trial comparisons. 1. Hurwitz, et al. N Engl J Med. 2004;350: Hurwitz, et al. Oncologist. 2009;14: Giantonio, et al. J Clin Oncol. 2007;25: Bennouna J, et al. Lancet Oncol. 2012;pii: S (12) 11

12. ML18147: Randomized, Open-Label, Phase III Study of Bevacizumab + Chemotherapy Beyond Progression in Bevacizumab-Treated mCRC PD
Fluoropyrimidine-based chemotherapy until PD
Bevacizumab 5 mg/kg every
2 weeks or 7.5 mg/kg
every 3 weeks + Fluoropyrimidine-based chemotherapy until PD
mCRC treated with Bev + standard first-line chemotherapy (n=820)
Randomization – switch chemotherapy:
Oxaliplatinirinotecan
Irinotecanoxaliplatin
Chemotherapy options:
Fluoropyrimidine + oxaliplatin-containing chemotherapy
Fluoropyrimidine + Irinotecan-containing chemotherapy
Stratification:
First-line chemotherapy (oxaliplatin-based, irinotecan-based), first-line PFS (≤ or >9 months), time from last dose of bevacizumab (≤ or > 42 days), and ECOG PS (0, ≥1)
Primary endpoint: OS post progression
Secondary endpoints: PFS post progression, ORR post progression
ADDITIONAL INFORMATION
The ML18147 is a randomized, open label, phase III study
The ML18147 excluded patients who had progressed on first-line Avastin in <3 months and allowed patients to have up to a 3-month treatment break prior to randomization.
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)
Reference:
Bennouna J, et al. Lancet Oncol. 2012;pii:S (12) 12

13. ML18147: Demographic and Baseline Characteristics – Well Balanced
Fluoropyrimidine-based chemotherapy alone
(n=411)
Bev + Fluoropyrimidine-based chemotherapy
(n=409)
Sex, male, % 63 65
Age, median years
ECOG status, % 43 44 1 52 51 2 5
First-line PFS, %
≤9 months 56 54
>9 months 46
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)

14. ML18147: Demographic and Baseline Characteristics – Well Balanced (Cont.)
Fluoropyrimidine-based chemotherapy alone
(n=411)
Bev +
Fluoropyrimidine-based chemotherapy (n=409)
First-line chemo, %
Irinotecan based 58 59
Oxaliplatin based 42 41
Duration from last bevacizumab dose to randomization, %
≤42 days 77
>42 days 23
Liver metastasis only, % No 71 73
Yes 29 27
Number of organs with metastasis, % 1 39 36
>1 61 64
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)

15. ML18147: Second-line Chemotherapy During Study – Physician’s Choice
Second-line Chemotherapy Regimen, %
Fluoropyrimidine-based chemotherapy alone
(n=407)
Bevacizumab +
Fluoropyrimidine-based chemotherapy
sFOLFIRI 14 16
XELIRI 12
LV5FU2 + CPT11 7
FOLFOX4 9
sFOLFOX4
FOLFOX6 13
FUFOX 6
XELOX 11
Other regimens
Second-line Chemo During Study: Many Regimens—Physician’s Choice
sFOLFIRI=simplified fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 over 46 h, folinate 400 mg/m2 intravenously, and irinotecan 180 mg/m2 intravenously on day 1 every 2 weeks. LV5FU2 CPT11=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 (central venous line) over 22 h on days 1, 2, 15, and 16, folinate 200 mg/m2 intravenously on days 1, 2, 15, and 16, and irinotecan 180 mg/m2 intravenously on days 1 and 15 every 4 weeks. FOLFOX4=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 intravenously over 22 h on days 1 and 2, folinate 200 mg/m2 intravenously on days 1 and 2, and oxaliplatin 85 mg/m2 intravenously on day 1 every 2 weeks. sFOLFOX4=simplified folinate 400 mg/m2, fluorouracil 400 mg/m2 intravenous bolus, fluorouracil 2400 mg/m2 continuous infusion (over 46 h), and oxaliplatin 85 mg/m2 on day 1 every 2 weeks. FOLFOX6=fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 intravenously over 46 h on days 1 and 15, folinate 400 mg/m2 intravenously on days 1 and 15, and oxaliplatin 100 mg/m2 intravenously on days 1 and 15 every 4 weeks. FUFOX=fluorouracil 2000 mg/m2 over 22 h (central venous line) on days 1, 8, 15, and 22, folinate 500 mg/m2 intravenously on days 1, 8, 15, and 22, and oxaliplatin 50 mg/ m2 intravenously on days 1, 8, 15, and 22 every 5 weeks. XELIRI=capecitabine 800 mg/m2 orally twice daily on days 1–14 and 22–35, and irinotecan 200 mg/m2 intravenously on days 1 and 22 every 6 weeks. XELOX=capecitabine 1000 mg/m2 orally twice daily on days 1–14 and 22–35, and oxaliplatin 130 mg/m2 intravenously on days 1 and 22 every 6 weeks.
*Six of 409 patients in the bevacizumab and chemotherapy group and four of 411 in the chemotherapy group were not given any treatment; however, four patients in the Bevacizumab and chemotherapy group were misreported as having been given chemotherapy.
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)

16. ML18147: Overall Survival (OS)a – ITT Population
1.0
0.8
0.6
0.4
0.2
Fluoropyrimidine-based chemotherapy alone (n=410)
Bev + Fluoropyrimidine-based chemotherapy (n=409)
Unstratifiedb HR: 0.81 (95% CI: )
P= (log-rank test)
OS Estimate
9.8
11.2
Time, Months
Number at risk
Fluoropyrimidine-based Chemotherapy alone
Bev+Fluoropyrimidine-based Chemotherapy
410
409
293
328
162
189 51 64 24 29 7 13 3 4 2 1
aFrom randomization.
bPrimary analysis method.
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)

17. ML18147: Secondary Endpoints
PFSa – ITT Population
1.0
0.8
0.6
0.4
0.2
Fluoropyrimidine-based chemotherapy alone (n=410)
Bev + Fluoropyrimidine-based chemotherapy (n=409)
Unstratifiedb HR: 0.68 (95% CI: ) P< (log-rank test)
PFS Estimate
4.1
5.7
Time, Months
Number at risk
Fluoropyrimidine-based Chemotherapy alone
Bev+Fluoropyrimidine-based Chemotherapy
410
409
119
169 20 45 6 12 4 5 2
There was no significant difference in response rate.
aFrom randomization.
bPrimary analysis method.
Bennouna J, et al. Lancet Oncol. 2012;pii: S (12)

18. What about VEGF + EGFR?
Bond-2 vs CAIRO 2 and PACCE

19. “Bond-2” PR TTP OS 11% 23% 0.05 38% 0.03 1.5 mo 5.6 mo >0.01 4.1 mo
C225 Alone
C Bev P
Value
C CPT-11
C CPT Bev
P Value PR
11%
23%
0.05
38%
0.03
TTP
1.5 mo
5.6 mo
>0.01
4.1 mo
7.9 mo OS
6.9 mo NR -
8.6 mo

20. Kaplan-Meier estimates of time to tumor progression: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).
Kaplan-Meier estimates of time to tumor progression: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).
Saltz L B et al. JCO 2007;25:
©2007 by American Society of Clinical Oncology

21. Kaplan-Meier estimates of survival: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).
Kaplan-Meier estimates of survival: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab).
Saltz L B et al. JCO 2007;25:
©2007 by American Society of Clinical Oncology

22. Colon Cancer is more than one disease
50-60%
40-50%
kRAS Wild Type
kRAS mutant
+ EGFR Agents
15-20%
- EGFR Agents
80-85%
MSI-High
MSS
? No 5FU
And of course it is very many more than the 4 sub-groups above

23. Clinical Research 2.0

24. Value Metric Agent HR $ Cost/Month (÷100) Toxicity (G1+2) * (G3+4)
# Patients
QOL/Utility
Score
Pass/Fail
Imatinib vs IFN
CML
0.17
55.90
0.67
Nilotinib vs Imat
0.8
76.40
Imatinib
GIST
0.4
1.22
Erlotinib vs Chemo
Mut NSCL
0.75
52.80
0.71
Erlotinib
Pancreas
0.82
11.9
Bevacizumab 2nd line CRC
0.74
22.90
Aflibercept
2nd line CRC
0.79
????-
3.0

25. Finding Value Come together Listen to each other Respect what we hear
Find the common threads
Weave a new fabric - provide global healthcare with value

27. Engaging the 97% Better education/information
Incentives for patients and providers
No added incentives for delivering SOC
Honor our “soldiers” in the war on cancer
Recognized the shared investment in research
Docs, hospitals, NCI, Industry, Payers, Patients
Target “substantial therapeutic benefit”
“Breakthrough Designation”
Reduce concept to approval time line
Embrace the emerging markets

28. Fundamental Shifts In Cancer Care
Yesterday
Consumption
Individual Practices
Rich Countries
Microscope
Safety and Efficacy
Large trials
1.4 months
QOL
Patient as a “Subject”
Chaotic Data Collection
Institutional IRBs
National Approvals
Tomorrow
Outcomes
Healthcare Systems
All Countries
Gene Profile
Value
Small trials
“Substantial Improvement”
Patient Reported Outcomes
Patient as a “Partner”
Standard Data Collection
Central/National IRBs
Global Approvals