Every summer, the American Society for Clinical Oncology (ASCO) brings together internationally renowned cancer researchers, doctors and medical professionals to discover and discuss the latest in cancer research and patient care. This webinar, scheduled for June 19 2013 is presented by Dr. John Marshall, and will highlight the key colorectal cancer findings from the 2013 meeting and what these advances mean for you.

1. Save the date for our 10th National
Patient Conference
Learn more or register:
www.ccalliance.org or 1-877-422-2030

2. Presented by:

3. Fight Colorectal Cancer
Mission
Fight Colorectal Cancer demands a cure for colon and rectal
cancer. We educate and support patients, push for changes
in policy that will increase and improve research, and
empower survivors to raise their voices against the status quo.
Monthly Patient Webinar Series
3rd Wednesday every month
FightColorectalCancer.org
Fight CRC Toll-free Answer Line 1.877.427.2111
Join One Million Strong
CRCMillionStrong.org
Join us in March 2014 for Call on Congress

4. Fighting a Smarter War On Colon Cancer:
John L. Marshall, MD
The Biomarker Divide
Tel: (202) 444-0275
Fax: (202) 444-1229
http://lombardi.georgetown.edu/GI

5. 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

6. Gastrointestinal (GI) Cancers Facts
 GI cancers represent the most common and fatal cancers in the world
 2009: 275,720 new diagnosis of GI Cancers and 135,830 deaths in the
US alone
 Anal Cancer
 Colorectal Cancer
 Esophageal Cancer
 Gallbladder Cancer
 Liver Cancer
 Pancreatic Cancer
 Small Intestine Cancer
 Stomach/Gastric Cancer
No two cancers are alike and treatments must be selected based on an
individual’s tumor characteristics, by personalized medicine

7. Breast Cancer Nation

8. Why Not Brown?

9. Our Current Model of Colon Cancer

10. Antoni van Leeuwenhoek
(1632-1723)
Invented the microscope
around 1668
10

11. The view from 35,000 feet
Everything looks the same from up here

12. 12
Management of MCRC:
An Evolving Treatment Algorithm
Diagnosis of MCRC
Resectable Unresectable
Adjuvant therapy
Surgery
Neo-adjuvant/
Pre-operative
therapy
First-Line
Second-Line
Third-Line
Borderline/
Potentially
Resectable
Fourth-Line
Treatment
continuum

13. 13
Advances in the Treatment
of Colorectal Cancer
2000 2005 2008 2012
Capecitabine
Oxaliplatin
Cetuximab
Irinotecan
5-FU
Panitumumab
Targeted
therapies
Bevacizumab
KRAS
Aflibercept
Regorafanib

14. 2012 ESMO Guidelines:
Sequence of Treatment by Line
Schmoll et al. Ann Oncol. 2012;23:2479-2516.

15. 15
EGFR: One of Many Signaling Modules
in Cancer Cells
Hanahan, Weinberg, Cell 100:57, 2000

16. 16
Proliferation MetastasisAngiogenesisApoptosis
Resistance
Shc
PI3-K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
What is the Role of the Epidermal Growth Factor
Receptor (EGFR) in Cancer?
Cell Membrane
EGFR
Signaling
Proteins
Cell
Response
to Signaling

17. 17
A. Friedman and N. Perrimon, Cell 128, January 26, 2007
Pathway vs. Network signaling
Network
“Chaotic”
Pathway
“Newtonian”

18. The Nature of the Disease

19. 19
Shc
PI3-K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Proliferation MetastasisAngiogenesisApoptosis
Resistance
EGFR
Signaling
Proteins
Cell
Response
to Signaling

20. 20
Shc
PI3-K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Which Target?

21. 21
Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center
Sos-1
Ras
MEKK-1
MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK

22. 22
Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center
Sos-1
Ras
MEKK-1
MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
Where’s the target?
The EGF Receptor Interactome
638 Genes

23. 23
Colon Cancer Has Many Biologic
Subsets That Differ in Response to
EGFR-Targeted Agents
BRAF
KRAS
EREG or AREG
PI3K PTEN
EGFR
PIP1
PIP3
Signaling to the nucleus
Low expression of EGFR ligands
→ decreased response to EGFR
targeted agents
Mutant BRAF →
decreased response to
EGFR-targeted agents
PTEN loss of expression
→ decreased response
to EGFR-targeted agents
Mutant KRAS →
decreased response to
EGFR-targeted agents

24. 24
Q: Is More Always Better?

25. 25
Correlation Between Survival and
Percentage of Patients Receiving Three
Drugs in Phase 3 Trials
3 drugs: 5-FU/LV, irinotecan, oxaliplatin.
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
12
13
14
15
16
17
18
19
20
21
22
0 10 20 30 40 50 60 70 80
Patients with three drugs (%)
MedianOS(months)

26. TRIBE Study Design
R
508 mCRC pts
1st line
unresectable
stratified by
 center
 PS 0/1-2
 adjuvant CT
FOLFIRI+bev
(up to 12 cycles)
FOLFOXIRI+bev
(up to 12 cycles)
5-FU/LV
+Bev
5-FU/LV
+Bev
PD
INDUCTION MAINTENANCE

27. Toxicity Profile – Safety population
G3/4 adverse events,
% patients
FOLFIRI + bev
N=254
FOLFOXIRI + bev
N=250
p
Nausea 3 3 1.000
Vomiting 3 4 0.492
Diarrhea 11 19 0.012
Stomatitis 4 9 0.048
Neutropenia 20 50 <0.001
Febrile neutropenia 6 9 0.315
Neurotoxicity 0 5 <0.001
Hypertension 2 5 0.157
Venous Thrombosis 6 7 0.593
Arterial Thrombosis 2 1 1.000
Bleeding 1 1 1.000

28. Secondary endpoint: Response rate (updated) - ITT population
Best Response, %
FOLFIRI + bev
N = 256
FOLFOXIRI + bev
N = 252
p
Complete Response 3% 5%
Partial Response 50% 60%
Response Rate 53% 65% 0.006
Stable Disease 32% 25%
Progressive Disease 11% 6%
Not Assessed 4% 4%

29. Median follow up: 32.3 mos
FOLFIRI + bev: N = 256 / Progressed = 226
FOLFOXIRI + bev: N = 252 / Progressed = 213
FOLFIRI + bev, median PFS : 9.7 mos
FOLFOXIRI + bev, median PFS : 12.1 mos
Unstratified HR: 0.77 [0.64-0.93]
p=0.006
Stratified HR: 0.75 [0.62-0.90]
p=0.003
Primary endpoint: PFS (updated) – ITT population
FOLFIRI/bev 256 203 94 46 26 14 7 3 0 0
FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1
Progression-freesurvivalprobability
F-up time (months)
FOLFIRI + bev
FOLFOXIRI + bev

30. Secondary endpoint: OS (preliminary) – ITT population
FOLFIRI/bev 256 233 216 172 109 69 36 15 5 0
FOLFOXIRI/bev 252 234 205 175 119 70 35 15 4 0
Overallsurvivalprobability
F-up time (months)
FOLFIRI + bev
FOLFOXIRI + bev
Median follow up: 32.3 mos
FOLFIRI + bev: N = 256 / Died = 155
FOLFOXIRI + bev: N = 252 / Died = 131
FOLFIRI + bev, median OS : 25.8 mos
FOLFOXIRI + bev, median OS : 31.0 mos
Unstratified HR: 0.83 [0.66-1.05]
p=0.125
Stratified HR: 0.79 [0.63-1.00]
p=0.054

31. Contrast of Appearance vs.
Expression Phenotyping
Microarray Low Risk High Risk
Microscope Low Grade High Grade
Treatment
Advice
31

32. We need to be careful with
our conclusions

33. pmTOR-immunostaining (Ventana)
Critical: Postsurgical ischemia

34. 34
Colon Cancer is more than one disease
kRAS Wild Type kRAS mutant
MSI-High MSS
+ EGFR Agents - EGFR Agents
? No 5FU
50-60% 40-50%
15-20% 80-85%
And of course it is very many more than the
4 sub-groups above

35. Clinical Research 2.0

36. 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
CML
0.8 76.40 0.17
Imatinib
GIST
0.4 55.90 1.22
Erlotinib vs
Chemo
Mut NSCL
0.75 52.80 0.71
Erlotinib
Pancreas
0.82 52.80 11.9
Bevacizumab 2nd
line CRC
0.74 22.90 0.8
Aflibercept
2nd line CRC
0.79 ????- 3.0
Value Metric

37. 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

39. 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

40. 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

42. Questions & Answers

43. Thank you!
Fight Colorectal Cancer
Answer Line 1-877-427-2111
FightColorectalCancer.org
Info@fightcrc.org
Colon Cancer Alliance
Helpline: 1-877-422-2030
www.CCAlliance.org
info@ccalliance.org