Save the date for our 10th National Patient Conference

Learn more or register:www.ccalliance.org or 1-877-422-2030

Presented by:

Fight Colorectal CancerMissionFight 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 Series3rd Wednesday every monthFightColorectalCancer.org Fight CRC Toll-free Answer Line 1.877.427.2111

Join One Million StrongCRCMillionStrong.org

Join us in March 2014 for Call on Congress

Fighting a Smarter War On Colon Cancer:

John L. Marshall, MD

The Biomarker Divide

Tel: (202) 444-0275Fax: (202) 444-1229

http://lombardi.georgetown.edu/GI

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

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

Breast Cancer Nation

Why Not Brown?

Our Current Model of Colon Cancer

Antoni van Leeuwenhoek (1632-1723)

Invented the microscope around

166810

The view from 35,000 feet

Everything looks the same from up here

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/PotentiallyResectable

Fourth-Line

Treatment continuum

13

Advances in the Treatment of Colorectal Cancer

2000 2005 2008 2012

Capecitabine

Oxaliplatin

Cetuximab

Irinotecan

5-FU

Panitumumab

Targeted therapies

Bevacizumab

KRASAfliberceptRegorafanib

2012 ESMO Guidelines: Sequence of Treatment by Line

Schmoll et al. Ann Oncol. 2012;23:2479-2516.

15

EGFR: One of Many Signaling Modules in Cancer Cells

Hanahan, Weinberg, Cell 100:57, 2000

16Proliferation MetastasisAngiogenesisApoptosis

Resistance

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNKERK

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

17A. Friedman and N. Perrimon, Cell 128, January 26, 2007

Pathway vs. Network signaling

Network

“Chaotic”

Pathway

“Newtonian”

The Nature of the Disease

19

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

Proliferation MetastasisAngiogenesisApoptosis Resistance

EGFR

Signaling Proteins

Cell Response

to Signaling

20

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

Which Target?

21

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

Sos-1

Ras

MEKK-1MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK

22

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center

Sos-1

Ras

MEKK-1MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK

Where’s the target?

The EGF Receptor Interactome

638 Genes

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

Q: Is More Always Better?

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 (%)

Me

dia

n O

S (

mo

nth

s)

TRIBE Study Design

R

508 mCRC pts1st lineunresectablestratified 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

Toxicity Profile – Safety population

G3/4 adverse events, % patients

FOLFIRI + bevN=254

FOLFOXIRI + bevN=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

Secondary endpoint: Response rate (updated) - ITT population

Best Response, %

FOLFIRI + bevN = 256

FOLFOXIRI + bevN = 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%

Median follow up: 32.3 mos

FOLFIRI + bev: N = 256 / Progressed = 226FOLFOXIRI + bev: N = 252 / Progressed = 213

FOLFIRI + bev, median PFS : 9.7 mosFOLFOXIRI + 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

Pro

gre

ssio

n-f

ree

surv

ival

pro

bab

ility

F-up time (months)

FOLFIRI + bev

FOLFOXIRI + bev

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

Ove

rall

su

rviv

al p

rob

abili

ty

F-up time (months)

FOLFIRI + bev

FOLFOXIRI + bev

Median follow up: 32.3 mos

FOLFIRI + bev: N = 256 / Died = 155FOLFOXIRI + bev: N = 252 / Died = 131

FOLFIRI + bev, median OS : 25.8 mosFOLFOXIRI + 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

Contrast of Appearance vs.Expression Phenotyping

Microarray Low Risk High Risk

Microscope Low Grade High GradeTreatment

Advice

31

We need to be careful with our conclusions

pmTOR-immunostaining (Ventana)

Critical: Postsurgical ischemia

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

Clinical Research 2.0

Agent HR $ Cost/Month(÷100)

Toxicity(G1+2) * (G3+4) # Patients

QOL/Utility ScorePass/Fail

Imatinib vs IFNCML 0.17 55.90 0.67

Nilotinib vs ImatCML 0.8 76.40 0.17

ImatinibGIST 0.4 55.90 1.22

Erlotinib vs ChemoMut NSCL

0.75 52.80 0.71

ErlotinibPancreas 0.82 52.80 11.9

Bevacizumab 2nd line CRC 0.74 22.90 0.8

Aflibercept2nd line CRC 0.79 ????- 3.0

Value Metric

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

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

Fundamental Shifts In Cancer CareYesterday• 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

Questions & Answers

Thank you!

Fight Colorectal CancerAnswer Line 1-877-427-2111FightColorectalCancer.org

Info@fightcrc.org

Colon Cancer AllianceHelpline: 1-877-422-2030

www.CCAlliance.org info@ccalliance.org