Dr. Gail Eckhardt Professor and Head of the Division of Medical Oncology at the University of Colorado Denver and Health Sciences Center. Join us for an exciting webinar about pathways and targets. Dr. Eckhardt will discuss the basic of pathways within a cancer cell, and how (and why) they can affect treatment options for patients. She'll explain how we learn about how new pathways are discovered, and how this information tell us what drugs may work in certain patients and why some drugs don’t. Dr. Eckhardt will discuss the idea of targeted therapies, and the difference between them and regular chemotherapy. She'll talk about the relationship between pathways and targeted drugs, and how this may impact drug development in the future.

1. Welcome!
Pathways and Targets:
How do these affect my treatment
options?
Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series
Our webinar will begin shortly
www.FightColorectalCancer.org
877-427-2111

2. Fight Colorectal Cancer
1. Tonight’s speaker: Dr. Gail Eckhardt, MD
2. Archived webinars: Link.FightCRC.org/Webinars
3. Follow up survey to come via email. Get a free Blue Star of
Hope pin when you tell us how we did tonight.
4. Ask a question in the panel on the right side of your screen and
look for hyperlinks during throughout the presentation.
5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111
www.FightColorectalCancer.org
877-427-2111

3. Fight Colorectal Cancer
Disclaimer
The information and services provided by Fight Colorectal
Cancer are for general informational purposes only.
The information and services are not intended to be substitutes
for professional medical advice, diagnosis, or treatment.
If you are ill, or suspect that you are ill, see a doctor
immediately. In an emergency, call 911 or go to the nearest
emergency room.
Fight Colorectal Cancer never recommends or endorses any
specific physicians, products or treatments for any condition.
www.FightColorectalCancer.org
877-427-2111

4. Fight Colorectal Cancer
Up coming webinars
Peripheral Neuropathy: Will it ever go away?
Problems, Causes, Solutions
October 16, 2013
8 - 9:30pm EDT
Advances in Surgical Treatments for Colon and
Rectal Cancer Patients
November 20, 2013
8 - 9:30pm EDT

5. Fight Colorectal Cancer
www.FightColorectalCancer.org
877-427-2111
Dr. Gail Eckhardt, MD
Professor and Division Head
University of Colorado Division of Medical Oncology

6. Pathways and Targets: How do
these affect my treatment
options?
S. Gail Eckhardt, M.D.
University of Colorado Cancer Center

7. CRC: What Have We Learned?
• Patient selective trials are needed earlier in order to
avoid thousands of patients being treated with
ineffective agents (EGFR Ab/KRAS)
• Indiscriminant addition of biological agents to
adjuvant therapy is not warranted
(bevacizumab/cetuximab)
• Dual biological combinations in unselected patients
may lead to more toxicity with little benefit
(bevacizumab + cetuximab)

8. Treatment for colorectal cancer has
improved, but . . .
Courtesy of Wells Messersmith, MD

9. • Solid tumors cannot grow beyond 1-2 mm3 without an increase in blood
supply via new vessel formation
• Angiogenesis is thus required for tumor growth and metastasis
• Inhibition of tumor angiogenesis leads to tumor cell growth arrest, death
of tumor cells, and in some cases, tumor regression
Tumor angiogenesis is
stimulated…
New vessels then facilitate
tumor growth
Slide Courtesy of Novartis Oncology
Targeting Angiogenesis in CRC

10. VEGF: A Central Mediator of
Angiogenesis
Binding and activation
of VEGF receptor
Environmental factors
(hypoxia, pH)
Growth factors,
hormones
(EGF, bFGF, PDGF,
IGF-1, IL-1 , IL-6, estrogen)
Genes involved in
tumorigenesis
(p53, p73, src, ras, vHL,
bcr-abl)
P
P
P
P
ANGIOGENESIS
ProliferationSurvival Migration
Endothelial cell
activation
VEGF
1. Dvorak. J Clin Oncol. 2002;20:4368.
2. Ferrara et al. Nat Med. 2003;9:669.
3. Ebos et al. Mol Cancer Res. 2002;1:89.

11. VEGF
Small-molecule TKIs
Antibodies
VEGFR-2
(KDR/flk-1)
VEGFR-1
(flt-1)
VEGFR-1/2
heterodimer
P
P
P
P
P
P
P
P
P
P
P
P
Soluble, truncated
receptors
Targeting VEGF and its receptors
Several Approaches
Courtesy of Herb Hurwitz

12. Pivotal Randomized Phase III Trial of 813 Advanced CRC
Patients Comparing IFL Regimen +/- Bevacizumab
Primary Endpoint: Survival
Previously untreated
pts with metastatic
colorectal cancer
Arm A: IFL + Bevacizumab
Arm B: IFL + Placebo
IFL = Irinotecan / 5-FU / Leucovorin
Hurwitz et al, N Engl J Med.
2004 Jun 3;350(23):2335-42.

13. p<.001
Results: Bevacizumab added to IFL significantly
improved overall survival by > 4 months
Hurwitz et al, N Engl J Med. 2004 Jun 3;350(23):2335-42.
Copyright Mass Med Soc

14. VEGFR Tyrosine Kinase Inhibitors in CRC:
Over 10,000 CRC Patients Treated on Negative Trials!
Agent AKA mCRC Trials CRC Patients
Cediranib AZD2171 2 Phase III 3,194
Semaxinib SU5416 2 Phase III 2,084
Vatalanib PTK787 2 Phase III 2,050
Sunitinib SU11248 Phase III 1,623
Brivanib BMS-582664 Phase III 926
Sorafenib BAY 43-9006 Phase IIB 814
Vandetanib ZD6474 Phase IIB 356
Axitinib AG-013736 Phase IIB 299
Linifanib ABT-869 Phase IIB 147
Vargateg BIBF 1120 Phase II 166
Tivozanib AV-951 Phase II 80
Motesanib AMG-706 Phase IB 148
Pazopanib GW786034 Phase IB 94
Clinicaltrials.gov; Slide courtesy of Scott Kopetz

15. Mode of Action of Regorafenib
• Regorafenib inhibits multiple cell-
signaling kinases:
– Angiogenic
• VEGFR1–3, TIE2
– Stromal
• PDGFR-β, FGFR
– Oncogenic
• KIT, PDGFR, RET
• T1/2 in man: approx. 26-28 hrs
– Two major metabolites (M2,
M5) are pharmacologically
active
Wilhelm SM et al. Int J Cancer 2011

16. Toxicity (>10% patients, any grade, related)
Patients D/C treatment due to AEs: 8.2% (R) versus 1.2%(P)
Grothey, GI Symposium 2012, J Clin Oncol 30, 2012 (suppl 4; abstr LBA385)
Adverse event, %
Regorafenib
N=500
Placebo
N=253
All
grades
Grade 3 Grade 4 Grade 5 All
grades
Grade 3 Grade 4 Grade 5
Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0
Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0
Hypertension 27.8 7.2 0 0 5.9 0.8 0 0
Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0
Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0
Anorexia 30.4 3.2 0 0 15.4 2.8 0 0
Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0
Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0
Fever 10.4 0.8 0 0 2.8 0 0 0
Nausea 14.4 0.4 0 0 11.1 0 0 0
Bleeding 11.4 0.4 0 0.4 2.8 0 0 0
Voice changes 29.4 0.2 0 0 5.5 0 0 0
Weight loss 13.8 0 0 0 2.4 0 0 0

17. Regorafenib:
Overall survival (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final
analysis)
1.00
0.50
0.25
0
0.75
200100500 150 300250 400350 450
Days from randomization
Survivaldistributionfunction
Placebo N=255
Regorafenib N=505
Median 6.4 mos 5.0 mos
95% CI 5.9–7.3 4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
Regorafenib Placebo
Grothey et al, ASCO GI 2012
42 days!

18. Aflibercept
Another Approach to Targeting Angiogenesis
• Soluble fusion protein
• Consists of portions of the extracellular domains of
human VEGFR1 and VEGFR2 fused to a human IgG1
Fc portion
• Binds all VEGF-A isoforms, VEGF-B, and PlGF
• High affinity: Binds VEGF-A and PlGF more tightly
than native receptors
• Half-life ~ 17 days
Van Cutsem et al, 2011.

19. Aflibercept: MOA Comparison
Courtesy of Philip Philip.
Cell membrane
VEGF-A
VEGF-R1
(Flt-1)
Migration
Invasion
Survival
VEGF-R3
(Flt-4)
Lymphangio-
genesis
VEGF-R2
(KDR/Flk-1)
Proliferation
Survival
Permeability
PlGF
VEGF-B
VEGF-C
VEGF-D
Functions Bevacizumab
VGX-100
Ramucirumab
CT-322
IMC-18F1
Aflibercept
TB403
XXX
VEGFR
TKIs

20. “VELOUR” trial
Similar Combination Approach as Bev
- Aflibercept (VEGF Trap) in colorectal cancer
- Multiple centers in Australia, China, Europe, Japan, and
North America
mCRC after
failure of an
oxaliplatin-based
regimen
N=1200
Placebo
+ FOLFIRI
(n=605)
R
Aflibercept 4 mg/kg IV
+ FOLFIRI
(n=611)
Primary Endpoint: Overall Survival (OS)
1:1
Note: 30% had received prior bevacizumab
Van Cutsem et al, 2011.
(FOLFIRI= infusional 5FU/IRI/LV)

21. VELOUR trial
Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611
PT, SOC, HLT* All Grades Grade 3/4 All Grades Grade 3/4
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia**
Complicated neutropenia
56.3 29.5
2.8
67.8 36.7
5.7
Asthenic conditions (HLT) 50.2 10.6 60.4 16.9
Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7
Thrombocytopenia** 33.8 1.7 47.4 3.3
Infections (SOC) 32.7 6.9 46.2 12.3
Decrease appetite 23.8 1.8 31.9 3.4
Weight decreased 14.4 0.8 31.9 2.6
Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8
Skin hyperpigmentation 2.8 0 8.2 0
Dehydration 3.0 1.3 9.0 4.3
PL: 12.1% AFL: 26.6%
AEs leading to treatment discontinuation
Van Cutsem et al, 2011.

22. “VELOUR” trial: Overall Survival
Cut-off date = February 7, 2011; Median follow-up = 22.28 mos
Van Cutsem et al, 2011.
6 weeks longer OS
Not compared to bevacizumab

23. Issues Regarding Angiogenesis Inhibitors
– Most medical oncologists believe that utilization of AIs
is relevant throughout the course of advanced CRC
(when risks are acceptable)
– Bevacizumab can be used with chemotherapy and the
reason aflibercept is not being routinely used is related
to unfamiliarity and concerns regarding the toxicity
data
– For some reason, although regorafenib was active in
refractory patients, drugs that are similar have not
worked with chemotherapy
– Among those involved in clinical research (like me), we
are worried that patients will get regorafenib rather
than be offered a clinical trial

24. Can Biomarkers Help Us Select the
Patients Most Likely to Benefit from
Targeted Therapies ?

25. Biomarker = Toxicity (mechanism based)
Biological effect
Efficacy
Pharmacodynamic biomarker: Associated with drug
effect
Example: skin rash with EGFR inhibitor, or inhibition of p-ERK with MEK
inhibitor
Predictive biomarker: Predicts outcome to therapy
Example: Her2/Neu amplification by FISH for trastuzumab
Prognostic biomarker: Associated with outcome,
independent of therapy
Example: VEGF expression
Biomarkers: Introduction

26. Biomarkers for Bevacizumab in CRC
• Although there are biomarkers associated with the PD
effects of bevacizumab, to date to no predictive
biomarkers have been identified
• This is likely due to the complex interaction of the
tumor and microenvironment
• Studies are ongoing to determine whether the PD
biomarkers such as high blood pressure and MRI can
be used to identify patients deriving clinical benefit

27. EGFR Antibodies Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
Akt
Raf
MEK
MAPK
Cell Motility
MetastasisAngiogenesis
Proliferation
Cell survival
DNA
PTEN
Ras
Slide courtesy of Axel Grothey
Targeting the EGFR in CRC

28. Cetuximab +/- Irinotecan
PFS
p<0.001
Cunningham, NEJM 2004
Note: overall survival curves were nearly identical (likely due to crossover)

29. What About Biomarkers and EGFR Antibodies in
CRC?

30. Did staining for EGFR matter? NO!
Courtesy of DakoCytomation, 2004
21% 25%
23%
Response Rates

31. EGFR Signaling Cascade and KRAS
Akt
SOS
FOS Myc
P13K
FKHR
mTOR
PTEN
MEK 1/2
MAPK
BAD
GSK-3
Shc
Grb-2
Ras
Raf
Jun
p27
Cyclin D-1
Ligand
Signal
Adapters
and Enzymes
Signal
Cascade
EGFR dimer
Transcription
Factors
STAT
Inhibitors upstream may be
ineffective
Karapetis WGIC 2008

32. Randomized Trial Results
Median PFS (Cetux- or Pmab- containing arms)
Study Treatment
Total Pts
MT WT
Amado
2008
P versus BSC
(3rd line)
427
7.4 wks
HR 0.99
12.3 wks
HR 0.45
Karapetis
2008
C versus BSC
(no X-over)
394 1.9 mos
3.7 mos
HR 0.40
Van Cutsem
2008
FOLFIRI +/- C
(1st line)
540
7.6 mos
HR 1.07
9.9 mos
HR 0.68
Bokemeyer
2008
FOLFOX +/- C
(1st line)
233
5.5 mos
HR 1.83
7.7 mos
HR 0.57
C = cetuximab; P = panitumumab; BSC = best supportive care

33. Amgen “408” Trial
This trial was important because it had a
placebo arm
Patients had to be “EGFR positive,” defined as >1% tumor
cells staining by IHC
Pretreated with 5-FU, oxaliplatin, irinotecan
Previously treated
metastatic
colorectal cancer
N=463
Panitumumab 6 mg/kg
Q2 weeks
Best Supportive Care
OptionalCrossover
Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007

34. PFS by treatment overall
Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007
Resulted in FDA
approval of
panitumumab
for use in 3rd
line setting

35. Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008
PFS by treatment within KRAS groups
Note: The BSC arms look similar indicating lack of impact on prognosis
KRAS MT
KRAS WT
BSC
BSC

36. KRAS and Panitumumab
Waterfall plot shows
responses (tumor
shrinkage) were
confined to Ras WT
patients
Mut WT
Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008

37. Mechanism-based toxicity:
Skin Rash with EGFR Blockade
This is a pharmacodynamic biomarker- is it predictive?

38. M Peeters et al, Cancer, 2009
More severe skin toxicity
and associated
symptoms led to
prolonged survival in this
subset analysis
Grade 2+ skin toxicity
Greater skin toxicity
symptoms
Skin Rash: Maybe necessary but not
sufficient for antitumor activity

39. Summary and Lessons Learned with EGFR Inhibitors in CRC
• EGFR-targeted antibodies have very modest single-agent activity
in refractory CRC but appear to improve responses to
chemotherapy
• Biomarker studies have demonstrated that benefit is restricted
to KRAS WT patients
• Surprisingly, no benefit was observed in the adjuvant studies
• Ongoing questions remain regarding the extent to which
immune mechanisms contribute to antitumor effects and how
to integrate skin rash data in dosing decisions
• The EGFR TKIs (oral drugs) have not exhibited activity in CRC

40. What About the Combination of
Biologics- is More Better????

41. PACCE Trial:
Randomized phase III trial of 1000 patients comparing
chemo/Bev with or without panitumumab
Previously
untreated
metastatic
colorectal cancer
N=1000
5-FU/Oxali/Bev
N=800
5-FU/Irino/Bev
N=200
Hecht, World GI 2007
+ panitumumab
+ panitumumab
(alone)
(alone)

42. PACCE Trial
Progression-Free Survival
Hecht, World GI 2007
Months
413 267 92 21 3
410 298 96 21 1
0 5 10 15 20
Pmab+bev/Ox-CT N
bev/Ox-CT N
Patients at risk:
# PFS events
(%)
Median
(95%CI), mos
206 (50) 9.0 (8.5-10.4)
172 (42) 10.5 (9.7-11.6)
Pmab+bev/Ox-CT
Bev/Ox-CT
HR= 1.29 (95% CI: 1.05-1.58)
ProportionProgression-Free
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ITT set
Control group did better!

43. TCGA Data: Many Pathways to Target

44. Conclusions
• Novel biological agents targeting the EGFR and VEGF pathways
have extended survival and provided new options for CRC
patients with advanced disease
• Unfortunately, these results have not translated to adjuvant
therapy and the reasons for this are not well understood
• Biomarkers have been instrumental in further defining a
potentially responsive patient population
• These results, along with the issues of combining “double
biologics” in unselected patients, are driving the field forward
towards personalized therapy and more rational combinations
• Despite the advances in therapy, more effective agents are
needed and luckily drug development is robust, but very
dependent on clinical trials

45. Thank You- Questions?

46. Fight Colorectal Cancer
CONTACT US
Fight Colorectal Cancer
1414 Prince Street, Suite 204
Alexandria, VA 22314
(703) 548-1225
Toll-Free Answer Line: 1-877-427-2111
www.FightColorectalCancer.org
Email us: Info@FightColorectalCancer.org