Each summer, the American Society for Clinical Oncology holds the world’s largest conference for cancer researchers, doctors and other medical professionals. Results from clinical trials and other studies are released, which give scientists a fresh look at treatments that may or may not hold great promise in the march toward a cure for cancer. Dr. Axel Grothey of the Mayo Clinic will explain what science is now telling us about colorectal cancer and how it may impact your treatment in the near future.

1. Welcome!
What's New in Colorectal Cancer Research?
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3. Fight Colorectal Cancer
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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
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7. Fight Colorectal Cancer
Dr. Axel Grothey
Professor of Oncology
Mayo Clinic
www.FightColorectalCancer.org www.CCAlliance.org
877-427-2111 877-422-2030

8. Colorectal Cancer
Updates ASCO 2012
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester

9. Disclosures
• Consulting activities
(honoraria went to the Mayo Foundation)
• Amgen
• Bayer
• Pfizer
• Roche/Genentech
• BMS
• Imclone/Eli-Lilly
I WILL include discussion of investigational or off-label use of a
product in my presentation.

10. Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005
Best supportive care (BSC)
5-FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab
median overall survival

12. First-line Bevacizumab in
Metastatic Colorectal Cancer: OS
AVF2107g[1] NO16966[2] BICC-C[3] TREE-2[4]
30 28.0
26.0 27.0
† 23.1
25
*
20.3 19.9 21.3
19.2
20.7
20 17.6
OS (Mos)
15.6
15
10
5
0
*P < .001; †P = .0769
1. Hurwitz H, et al. N Engl J Med. 2004;350:2335. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.
3. Fuchs C, et al. ASCO 2007. Abstract 4027. 4. Hochster, et al. ASCO 2006. Abstract 3510.

13. AIO 0504 / Roche ML18147
Multinational European Trial
Any-OX Any-IRI
+ BEV + BEV
R R
Any-IRI Any-OX
Any-IRI Any-OX + BEV
+ BEV
N = 820 Accrual completed May 31, 2010
Primary EP: OS

14. Bevacizumab (BEV) plus chemotherapy (CT)
continued beyond first progression in patients
with metastatic colorectal cancer (mCRC)
previously treated with BEV + CT: Results of a
randomised phase III intergroup study – TML
(ML18147)
D Arnold1, T Andre2, J Bennouna3, J Sastre4, P Österlund5, R Greil6
E Van Cutsem7, R von Moos8, I Reyes-Rivera9, B Bendahmane10, S Kubicka11
on behalf of the AIO, GERCOR, FFCD, UNICANCER GI, TTD, GEMCAD and AGMT groups
1Hamburg, Germany; 2Paris, France; 3Nantes, France; 4Madrid, Spain
5Helsinki, Finland; 6Salzburg, Austria; 7Leuven, Belgium; 8Chur, Switzerland
9South San Francisco, USA; 10Basel, Switzerland; 11Reutlingen, Germany

15. ML18147 study design (phase III)
Standard second-line CT
(oxaliplatin or irinotecan-
BEV + standard
based) until PD
first-line CT (either
oxaliplatin or PD Randomize 1:1
irinotecan-based) BEV (2.5 mg/kg/wk) +
standard second-line CT
(n=820) CT switch:
(oxaliplatin or irinotecan-
Oxaliplatin → Irinotecan based) until PD
Irinotecan → Oxaliplatin
Primary endpoint • Overall survival (OS) from randomization
Secondary endpoints • Progression-free survival (PFS)
included • Best overall response rate
• Safety
Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)
• First-line PFS (≤9 months, >9 months)
• Time from last BEV dose (≤42 days, >42 days)
• ECOG PS at baseline (0/1, 2)
Study conducted in 220 centres in Europe and Saudi Arabia

16. Main eligibility criteria
Inclusion
• Patients ≥18 years with histologically confirmed diagnosis of mCRC
• Eastern Cooperative Oncology Group (ECOG) PS 0–2
• PD (≥1 measurable lesion according to RECIST v1 assessed by
investigator, documented by CT or MRI), ≤4 weeks prior to start of
study treatment
• Previously treated with BEV plus standard first-line CT, not candidates
for primary metastasectomy
Exclusion
• Diagnosis of PD >3 months after last BEV administration
• First-line patients with PFS in first-line of <3 months
• Patients receiving <3 consecutive months of BEV in first-line

17. Demographic and baseline characteristics:
Randomized patients
CT BEV + CT
Characteristic (n=411) (n=409)
Male, % 63 65
Age, median years 63 63
ECOG performance status, %
0 43 44
1 52 51
2 5 5
First-line PFS, %
≤9 months 56 54
>9 months 44 46
First-line CT, %
Irinotecan-based 58 59
Oxaliplatin-based 42 41
Patients were accrued between February 2006 and June 2010

18. Demographic and baseline characteristics:
Randomized patients (cont‟d)
CT BEV + CT
Characteristic (n=411) (n=409)
Duration from last BEV dose to
randomisation, %
≤42 days 77 77
>42 days 23 23
Patient populationa, %
AIO 32 32
ML18147 68 68
Liver metastasis only, %
No 71 73
Yes 29 27
No. of organs with metastasis, %
1 39 36
>1 61 64
aPatientpopulation refers to sequential enrolment of patients in original AIO study and
subsequent enrolment in ML18147 when study was transferred to Roche

19. Second-line chemotherapy during study:
Randomized patients
CT BEV + CT
Second-line CT regimen, % (n=407) (n=407)
Irinotecan-based CT 43 42
FOLFIRI 14 16
LV5FU2 + CPT11 (Douillard regimen1) 7 7
XELIRI 12 12
Other regimens 10 7
Oxaliplatin-based CT 57 58
FOLFOX4 / mFOLFOX4 18 19
FOLFOX6 13 16
FUFOX 9 6
XELOX 11 14
Other regimens 6 4
1. Douillard et al. Lancet 2000;355:1041–7

20. OS: ITT population
1.0 CT (n=410)
BEV + CT (n=409)
0.8
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
0.6
OS estimate
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
0.4 p=0.0211 (log-rank test)
0.2
9.8 mo 11.2 mo
0
0 6 12 18 24 30 36 42
No. at risk Time (months)
CT 410 293 162 51 24 7 3 2
BEV + CT409 328 188 64 29 13 4 1
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

21. Subgroup analysis of OS: ITT population
Category Subgroup n HR (95% CI)
All All 819 0.81 (0.69–0.94)
Patient populationa AIO 260 0.86 (0.67–1.11)
ML18147 559 0.78 (0.64–0.94)
Gender Female 294 0.99 (0.77–1.28)
Male 525 0.73 (0.60–0.88)
Age <65 years 458 0.79 (0.65–0.98)
≥65 years 361 0.83 (0.66–1.04)
ECOG performance status 0 357 0.74 (0.59–0.94)
≥1 458 0.87 (0.71–1.06)
First-line PFS ≤9 months 449 0.89 (0.73–1.09)
>9 months 369 0.73 (0.58–0.92)
First-line CT Oxaliplatin-based 343 0.79 (0.62–1.00)
Irinotecan-based 476 0.82 (0.67–1.00)
Time from last BEV ≤42 days 630 0.82 (0.69–0.97)
>42 days 189 0.76 (0.55–1.06)
Liver metastasis only No 592 0.81 (0.67–0.97)
Yes 226 0.79 (0.59–1.05)
No. of organs 1 307 0.83 (0.64–1.08)
with metastasis >1 511 0.77 (0.64–0.94)
HR 0 1 2
aPatient
population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when
study was transferred to Roche. All patients listed under AIO were included in primary analysis

22. PFS: ITT population
1.0 CT (n=410)
BEV + CT (n=409)
0.8
PFS estimate
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78)
0.6 p<0.0001 (log-rank test)
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
0.4 p<0.0001 (log-rank test)
0.2
4.1 mo 5.7 mo
0
0 6 12 18 24 36
Time (months)
No. at risk
CT 410 119 20 6 4 0
BEV + CT 409 189 45 12 5 2
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

23. Best overall response: Measurable disease
population
CT BEV + CT
Outcome (n=406) (n=404)
Respondersa, n (%) 16 (3.9) 22 (5.4)
p-value 0.3113
Complete response, n (%) 2 (<1) 1 (<1)
Partial response, n (%) 14 (3) 21 (5)
Stable disease, n (%) 204 (50) 253 (63)
Disease control rate, n (%) 220 (54) 275 (68)
p-valueb <0.0001
PD, n (%) 142 (35) 87 (22)
Missingc, n (%) 44 (11) 42 (10)
aPatientswith a best overall response of confirmed complete or partial response
bThis analysis was not prespecified
cIncludes „not-evaluable‟ or „no tumour assessment‟ following baseline visit

24. Grade 3–5 adverse events (incidence ≥2%)
in any arm: Safety population
CT BEV + CT
Adverse event, % (n=409) (n=401)
Neutropenia 13 16
Leukopenia 3 4
Diarrhoea 8 10
Vomiting 3 4
Nausea 3 3
Abdominal pain 3 4
Subileus <1 2
Asthenia 4 6
Fatigue 2 4
Mucosal inflammation 1 3
Dyspnoea 3 2
Pulmonary embolism 2 3
Polyneuropathy 2 3
Neuropathy peripheral 2 1
Hypokalaemia 2 2
Decreased appetite 2 1

25. Adverse events of special interest to BEV:
Safety population
CT BEV + CT
(n=409) (n=401)
Patients, % All grades Grade 3–5 All grades Grade 3–5
AEs of special interest to BEV 21 6 41 12
Hypertension 7 1 12 2
Proteinuria 1 – 5 <1
Bleeding/haemorrhage 9 <1 26 2
Abscesses and fistulae – – 1 <1
GI perforation <1 <1 3 2
Congestive heart failure <1 <1 <1 –
VTE 4 3 6 5
ATE 1 <1 <1 <1
Wound-healing
<1 <1 1 <1
complications
RPLS – – – –
ATE: arterial thromboembolic events; GI: gastrointestinal; RPLS: reverse posterior leukoencephalopathy
syndrome; VTE: venous thromboembolic events

26. Conclusions
• First randomized clinical trial that prospectively investigated the
impact of continued VEGF inhibition with BEV beyond first
progression
• Study confirms that continuing BEV beyond first progression
while modifying CT is beneficial for patients with mCRC and
leads to a significant improvement in OS and PFS
• This provides a new second-line treatment option for patients
who have been treated with BEV + standard CT in first line while
maintaining an acceptable safety profile
• Findings indicate a potential new model for treatment
approaches through multiple lines and this is currently being
investigated in other tumour types

27. Large molecule VEGF inhibitors
PlGF VEGF-A VEGF-C,
VEGF-B Bevacizumab VEGF-D
Ramucirumab
Aflibercept
(VEGF Trap)
Functions
VEGF-R1 VEGF-R2 VEGF-R3
(Flt-1) (KDR/Flk-1) (Flt-4)
Migration Proliferation Lymphangio-
Invasion Survival genesis
Survival Permeability

28. 28
EFC10262: VELOUR
Phase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Aflibercept 4 mg/kg
600 pts IV
+ FOLFIRI q 2 weeks
mCRC after
failure of an
oxaliplatin R 1:1
based regimen
Placebo + FOLFIRI
Stratification factors: 600 pts
q 2 weeks
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
PIs: Allegra, Van Cutsem
30% of patients had prior BEV

29. VELOUR Study
• Overall results
• Adding aflibercept to FOLFIRI in mCRC patients previously treated
with an oxaliplatin-based regimen resulted in significant OS and PFS
benefits
OS PFS
Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

30. Overall Survival:
Stratified by Prior Bevacizumab – ITT Population

31. Progression-Free Survival:
Stratified by Prior Bevacizumab – ITT Population

32. Response Rates

33. Safety – Most frequent AEs, with ≥ 5% difference in incidence between
treatment arms, excluding anti-VEGF class events
Placebo, N = 605 Aflibercept N = 611
Safety Population, % of patients All All
Grade 3-4 Grade 3-4
Grades Grades
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia** 56.3 29.5 67.8 36.7
Complicated neutropenia 2.8 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 leading
AEs to treatment discontinuation:
4.3 0.5 11.0 2.8
erythrodysaesthesia
AFL: 26.6%
Skin hyperpigmentation 2.8 0 8.2 0
Dehydration
PL: 12.1% 3.0 1.3 9.0 4.3
Van Cutsem, et al. WCGC 2011

34. Cytokine increase on BEV therapy
Kopetz et al., JCO 2010

35. Regorafenib – A Multi-Kinase
Inhibitor
Cellular Phosphorylation Assays IC50 nM
VEGFR-2 Phosphorylation, 293 Cells 8
TIE2-Receptor Phosphorylation, CHO Cells 31
PDGFR-β Phosphorylation, Aortic SM Cells 90
mVEGFR3 Phosphorylation, 293 Cells 150
Mutant RET Phosphorylation, Thyroid TT Cells 10
Mutant c-KIT Phosphorylation, GIST 882 Cells 20
FGF-10 FGFR MCF-7 Cells 150-300
MAPK ERK-P HCC, HepG2 Cells 500
Cell Proliferation Assays IC50 nM
VEGF/HuVEC (2% FCS) BrdU 4
bFGF/ HuVEC (2% FCS) BrdU 120
PDGFBB/Aortic SM (0.1% BSA) BrdU 121
Thyroid TT RET C643W (10% FCS) 33
GIST 882 KIT K642E (10% FCS) 45
Breast, MDA MB 231 (10% FCS) 570
Melanoma, A375 (10% FCS) 900
HCC HepG2 (10% FCS) 560

36. CORRECT study design
R Regorafenib + BSC Primary
A 160 mg orally once daily
N
3 weeks on, 1 week off
Endpoint:
D
O OS
mCRC after M 90% power to
standard I 2:1
Z detect 33.3%
therapy A increase
T
I (HR=0.75), with
Placebo + BSC
O 1-sided overall
3 weeks on, 1 week off
N a=0.025
• 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

37. Overall survival (primary endpoint)
Regorafenib Placebo
1.00
Median 6.4 mos 5.0 mos
Survival distribution function
95% CI 5.9–7.3 4.4–5.8
0.75 Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
0.50
0.25
Placebo N=255
Regorafenib N=505
0
0 50 100 150 200 250 300 350 400 450
Days from randomization
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)

38. Progression-free survival
(secondary endpoint)
1.00
Regorafenib Placebo
Survival distribution function
Median 1.9 mos 1.7 mos
95% CI 1.9–2.1 1.7–1.7
0.75
Hazard ratio: 0.49 (95% CI: 0.42–0.58)
1-sided p-value: <0.000001
0.50
Placebo N=255
0.25 Regorafenib N=505
0
0 50 100 150 200 250 300 350
Days from randomization

39. Drug-related, treatment-emergent adverse events
occurring in ≥10% of patients at any grade
Regorafenib Placebo
Adverse event, %
N=500 N=253
All Grade Grade Grade All Grade Grade Grade
grades 3 4 5 grades 3 4 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 events
Adverse 11.4 0.4 0 0.4 2.8 0 0 0
leading to permanent
Voice changes 29.4 0.2
8.2%0 0 5.5 0 1.2%0 0
Tx discontinuation
Weight loss 13.8 0 0 0 2.4 0 0 0

40. Take-Home Messages: Optimized
Medical Therapy of Advanced CRC
1. Identify the goal of therapy
• For most patients gain of time and
maintaining QOL is more important
• Strength of BEV – duration of therapy
matters
• RR only matters for
• conversion therapy of liver metastases or
• if patient is symptomatic from his tumor
burden

41. Take-Home Messages: Optimized
Medical Therapy of Advanced CRC
2. Treat to progression – and beyond Be mindful
about toxicities, stop oxaliplatin before
neurotoxicity develops
• Some select patients can have CFI
3. Expose patients to all potentially active agents
• These agents are the oncologist‟s tools to
keep patients alive
• Use fluoropyrimidine-based combinations as
default backbone, reserve sequential single
agent therapy for select patients
4. We finally have new active agents in CRC:
Aflibercept and regorafenib

42. Bevacizumab vs EGFR Antibodies
in Advanced CRC - Simplified
Agent Strength Weakness
Bevacizumab • Delay in tumor • Limited single
progression agent activity
• Gain in time • Weak effect on RR
• Toxicity profile (per RECIST)
EGFR • Single agent activity • Gain in time to
antibodies • Consistent increase progression
in RR moderate
• Activity independent • Toxicity profile
of line of therapy
• Negative predictive
marker available

43. Example of Continuum of Care
FOLFOX-BEV KEY POINTS
x8
• For elderly patients consider
start of sequence with FP+/-
FP-BEV BEV
Until PD
if TTP of FP-BEV • First-line oxaliplatin-based
>6 mos therapy needs to be
“optimoxed”
FOLFOX-BEV
• Sequences of
FOLFOX -> FOLFIRI or
FOLFIRI -> FOLFOX
FOLFIRI-BEV
are interchangeable
if KRAS wt • BEV beyond progression
(BBP) supported by phase III
(Irino-) EGFR
results
mAb
• EGFR mAb retain their
activity in later lines of
Regorafenib therapy

44. Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005 2010 2015
BSC
35
5-FU
30
Irinotecan
Capecitabine
25 Oxaliplatin
OS (months)
Cetuximab
20 Bevacizumab
Panitumumab
15
Aflibercept
10 Regorafenib
5 median overall survival
0
1980 1985 1990 1995 2000 2005 2010 2015

45. COST of
CARE
The Elephant in the Room
PRESENTED BY:

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