Colorectal Cancer Update: 2004

1
Colorectal Cancer Update 2004
Shannon B. Holloway MHS RPA-C New York
Presbyterian-Weill Cornell Solid Tumor
Service The Jay Monahan Center for
Gastrointestinal Health
2
Overview of Presentation

• Statistics
• Prevention Screening
• Overview of the Major Therapeutic Agents
• Evolution of Colorectal Cancer Treatments
• What the Future Holds

3
Colorectal Cancer Overview

• 148,000 new cases annually in United States
• Third-leading cause of cancer death (57,100 per
  year)
• Unresectable disease is generally fatal
• Until recently, chemotherapy has been perceived
  by some as affording only modest clinical benefit

Cancer Facts Figures, 2003. American Cancer
Society..
4
US Mortality, 2001
No. of deaths
of all deaths
Rank
Cause of Death

• 1. Heart Diseases 700,142 29.0
• 2. Cancer 553,768 22.9
• 3. Cerebrovascular diseases 163,538 6.8
• 4. Chronic lower respiratory diseases 123,013
  5.1
• 5. Accidents (Unintentional injuries) 101,537
  4.2
• 6. Diabetes mellitus 71,372 3.0
• 7. Influenza and Pneumonia 62,034 2.6
• 8. Alzheimers disease 53,852 2.2

Source US Mortality Public Use Data Tape 2001,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2003.
5
2004 Estimated US Cancer Deaths
Men290,890
Women272,810

• 25 Lung bronchus
• 15 Breast
• 10 Colon rectum
• 6 Ovary
• 6 Pancreas
• 4 Leukemia
• 3 Non-Hodgkin lymphoma
• 3 Uterine corpus
• 2 Multiple myeloma
• 2 Brain/ONS
• 24 All other sites

Lung bronchus 32 Prostate 10 Colon
rectum 10 Pancreas 5 Leukemia 5 Non-Hodgkin 4
lymphoma Esophagus 4 Liver intrahepatic 3bil
e duct Urinary bladder 3 Kidney 3 All other
sites 21
ONSOther nervous system. Source American Cancer
Society, 2004.
6
Change in the US Death Rates by Cause, 1950
2001
Rate Per 100,000
1950 2001
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
Age-adjusted to 2000 US standard
population. Sources 1950 Mortality Data -
CDC/NCHS, NVSS, Mortality Revised. 2001 Mortality
DataNVSR-Death Final Data 2001Volume 52, No. 3.
http//www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03
.pdf
7
Colorectal CancerBreakdown of Stage of
Diagnosis and Survival Times
8
American Cancer SocietyScreening Recommendations
for Colorectal Cancer, 2003
9
Overview of Potential Risk FactorsColorectal
Cancer

• Dietary Lifestyle
• Obesity ??
• Smoking ?
• Red Meat ?
• Alcohol ?
• Fruits Vegetables ?

10
Overview of Risk FactorsColorectal Cancer

• Inherited Disorders
• Familial Adenomatous Polyposis (FAP)
• Hereditary Nonpolyposis Colorectal Cancer
  (HNPCC)

11
Colorectal Cancer TNM Dukes Staging Guidelines
American Joint Committee on Cancer TNM Staging System Duke American Joint Committee on Cancer TNM Staging System
Stage I (T1-2N0M0) A T1 Tumor invades submucosa T2 Tumor invades muscularis propria
Stage II A (T3N0M0) B (T4N0M0) B T3 Tumor invades through muscularis propria or into pericolic and perirectal tissues. T4 Invasion into adjacent organs/tissues /- visceral invasion
Stage III A (T1-2N1M0) B (T3-4N1M0) C (TanyN2M0) c N1 Metastatis in 1-3 regional lymph nodes N2 Metastatis into 4 regional lymph nodes
Stage IV(TanyNanyM1) Presence of Metastatic Disease
12
Current Anti-Cancer Approaches
13
CRC Treatment by Stage
14
Natural History of Cancer
Cellular Dedifferentiation
Growth Dysregulation
Loss of Apoptosis
Invasion and Metastasis
Unlimited Cell Division
Angiogenesis
15
Molecular Events in Cancer
Dysregulation of Growth Factors or Receptors
Aberrant Signal Transduction
Secretion of Autocrine Growth Factors
Secretion of Angiogenic Growth Factors
Secretion of Matrix Metalloproteinases
Expression of Oncogenes Loss of Tumor Suppressor
Genes
16
1994
Fluorouracil (5FU)
17
2000
Irinotecan (Camptosar)
Fluorouracil (5FU)
18
Irinotecan (Camptosar)
Oxaliplatin (Eloxatin)
Cetuximab (Erbitux)
2004
Fluorouracil (5FU)
Capecitabine (Xeloda)
Bevacizumab (Avastin)
19
1994 Overall Survival Metastatic Disease
10 months
20
2004 Overall Survival Metastatic Disease
25 months
21
Cytotoxic Chemotherapy
22
Fluorouracil (5-FU)
23
Fluorouracil (5FU)

• Indication for Use
• In neo-adjuvant, adjuvant therapy and as a
  component in therapy for metastatic colorectal
  cancer

24
Fluorouracil (5FU)

• Administration
• IV Bolus
• Continuous Infusion
• Target
• Thymidylate Synthase (TS)
• Mechanism of Action
• Prevents DNA replication, causes RNA/DNA strand
  breaks

25
Fluorouracil (5FU)

• IV Bolus Side Effects
• Diarrhea
• N/V
• Stomatitis
• Continuous Infusion Side effects
• Stomatitis
• Diarrhea
• Hand-Foot Syndrome

26
The Meta-Analysis Group in Cancer
27
Meta-Analysis of 5FU Bolus vs Infusional
6 Trials (N1219) Bolus Infusional
Response Rate 14 22
Median Survival 11.3 12.1
Neutropenia 31 4
Hand-Foot Syndrome 13 34
28
Irinotecan (Camptosar)
29
Irinotecan (Camptosar)

• Indications for use
• First or second-line therapy in combination with
  5FU for metastatic colorectal cancer

30
Irinotecan Pro-drug Topoisomerase-1 Inhibitor
C
H
3
C
H
O
2
N
N
O
N
O
C
O
O
N
O
H
C
H
C
H
2
3
Irinotecan hydrochloride
Carboxylesterases
C
O
2
C
H
3
C
H
O
2
HO
N
N-H
N
O

O
N
O
H
C
H
C
H
2
3
SN-38
Piperidinopiperidine
31
Irintotecan (Camptosar)

• Administration
• IV
• Target
• Topoisomerase 1
• Mechanism of Action
• Prevents religation and single-strand DNA breaks

32
Irinotecan (Camtosar)

• Side Effects
• Late-Onset Diarrhea
• Neutropenia
• Nausea/Vomiting

33
Doulliard Saltz
34
Pharmacia 0038 Phase III Trial of First-line
Irinotecan 5-FU/LV
Schema
R A N D O M I Z A T I O N
IFL Irinotecan 125 mg/m2 over 90
minutes Leucovorin 20 mg/m2 IV bolus Fluorouracil
500 mg/m2 IV bolus Weekly 4 0f 6 weeks
N226
N226
5-FU/LV (Mayo) Leucovorin 20 mg/m2 IV
bolus Fluorouracil 425 mg/m2 IV bolus d 1-5 q4wk
Single-agent irinotecan Irinotecan 125 mg/m2
over 90 minutes Weekly 4 0f 6 weeks
N231
Saltz LB et al. N Engl J Med. 2000343905.
35
Median SurvivalIrinotecan plus bolus 5-FU/LV
14.8 mo
plt0.042
12.6 mo
Saltz et al. N Engl J Med 343905, 2000.
36
0038 Phase III Trial of First-line Irinotecan
5-FU/LV
Results
IFL
5-FU/LV
Irinotecan
RR
39
21
18
TTP (mo)
7.0
4.3
4.2
Overall Survival (mo)
14.8
12.6
12.0
Saltz LB et al. N Engl J Med. 2000343905.
37
Capecitabine (Xeloda)
38
Capecitabine (Xeloda)

• Indication for use
• First-line treatment for metastatic colorectal
  cancer when treatment with fluoropyrimidine
  therapy alone is preferred

39
XELODA (capecitabine) Chemical Structure
NH-CO-O-C5H11
F
O
N
F
HN
O
N
O
H3C
O
N H
HO
OH
XELODA
5-FU
40
Capecitabine (Xeloda)

• Administration
• Oral
• Target
• Thymidylate Synthase
• Mechanism of Action
• Prevents DNA Replication

41
Capecitabine (Xeloda)

• Side Effects
• Palmar-Plantar Erythrodysesthesia (PPE) or
  Hand-Foot Syndrome
• Diarrhea
• Nausea Vomiting
• Interaction with warfarin

42
Van Cutsem and Hoff
43
Phase II Study1 Results

• Response rates of 2124 achieved with all three
  XELODA regimens
• The intermittent monotherapy regimen was chosen
  for phase III trials based on its higher
  dose-intensity, lower potential for toxicity, and
  the prospect of drug-free days

1. Van Cutsem E, et al. J Clin Oncol.
2000181337-1345.
44
Phase III Studies XELODA (capecitabine) vs
5-FU/LV in First-line Treatment of Metastatic
Colorectal Cancer

• Two phase III trials with identical protocols
• Study 1 was conducted in the Americas1
• Study 2 was conducted in Europe, Israel,
  Australia, New Zealand, and Taiwan2
• Patients were randomized to
• XELODA 1,250 mg/m2 twice daily (2,500 mg/m2
  total daily dose), days 114 followed by a 7-day
  rest period
• Mayo Clinic regimen leucovorin (LV) 20 mg/m2
  5-FU 425 mg/m2 (IV bolus), days 15 every 4 weeks

45
Efficacy of XELODA (capecitabine) vs 5-FU/LV in
Metastatic Colorectal Cancer
Phase III Study 1
XELODA 5-FU/LV (n302) (n303)
Overall Response Rate (, 95 C.I.) 21
(1626) 11 (815) (P-value) 0.0014 Time to
Progression (median, days, 95 C.I.) 128
(120136) 131 (105153) Hazard Ratio
(XELODA/5-FU/LV) 0.99 95 C.I. for Hazard
Ratio (0.841.17) Survival (median, days, 95
C.I.) 380 (321434) 407 (366446) Hazard Ratio
(XELODA/5-FU/LV) 1.00 95 C.I. for Hazard
Ratio (0.841.18)
46
Phase III Studies in First-line Treatment of
MCRC Overall Survival, Integrated Analysis1
1.0 0.8 0.6 0.4 0.2 0
XELODA (n603) 5-FU/LV (n604)
Median (CI) XELODA 12.9 (12.014.0) 5-FU/LV 12
.8 (11.814.0) Hazard ratio 0.96(0.851.08) Log
-rankP0.48
Estimated Probability
5-FU/LV 12.8
XELODA 12.9
0 5 10 15 20 25 30 35 40 45
Time (months)
1. Twelves C. Eur J Cancer. 200238(suppl)S15-S20
.
47
Phase III Studies in First-line Treatment of
MCRC Most Common Treatment-Related Adverse
Events ?20, Integrated Analysis1 (Total)
XELODA (n596) 5-FU/LV (n593)

Plt0.001

Patients ()



Diarrhea Stomatitis Hand-foot Nausea Vomiting Alo
pecia Fatigue syndrome
1. Twelves C, et al. Eur J Cancer. 200238
(suppl)S15-S2.
48
CapeOX regimen (Tabernero, ASCO 02)
1 8 15 21
Day
oxaliplatin 130 mg/m2(2-hour infusion)
capecitabine 1,000 mg/m2 twice daily
Days 114
Rest

repeated every 3 weeks
49
Capecitabine/Oxaliplatin Phase II Trial in
First-line Colorectal Cancer
Oxaliplatin 130 mg/m2 day 1 plus Capecitabine
1000 mg/m2 b.i.d. every 3 wks (N96 pts)

• RR 45
• PFS 7.6 months
• Overall Survival 19.5 months
• Grade ? 3 toxicity 7 neutropenia, 13
  nausea/vomiting, 16 diarrhea, 16 neuropathy

Based on independent response review
Van Cutsem E et al. Proc ASCO. 200322 (abstr
1023).
50
Oxaliplatin (Eloxatin)
51
Oxaliplatin (Eloxatin)

• Indications for use
• Treatment of metastatic colorectal cancer in
  combination with infusional 5FU

52
OxaliplatinMolecular Structure
53
Oxaliplatin (Eloxatin)

• Administration
• IV
• Target
• DNA
• Mechanism of Action
• Prevents Replication and Transcription of DNA

54
Oxaliplatin (Eloxatin)

• Side Effects
• Acute Neuropathy
• Cumulative Neuropathy
• Nausea
• Diarrhea

55
N9741
56
N9741 Schema

• 798 stage IV patients

IFL
(n264) Irinotecan 125 mg/m2 over 90
minutes Leucovorin 20 mg/m2 IV bolus Fluorouracil
500 mg/m2 IV bolus Weekly 4 0f 6 weeks
RANDOMI ZAT ION
FOLFOX4 (n269) ELOXATIN 85 mg/m2 over 2
hours d 1 LV 200 mg/m2 IV over 2 hours d 1,2 5-FU
400-mg/m2 bolus for 2-4 minutes d 1,2 5-FU
600-mg/m2 continuous infusion over 22 hours d
1,2 q2wk
IROX
(n265) ELOXATIN 85 mg/m2 d 1 CPT-11
200 mg/m2 d 1 q3w
57
N9741Overall Survival
FOLFOX vs IFL p0.0001 Hazard ratio 0.66
IROX vs IFL p0.04 Hazard ratio 0.80
19.5
20
17.4
14.8
15
Median survival (months)
10
5
0
IFL
FOLFOX
IROX
58
N9741One Year Survival
72
80
67
59

60
40
20
IFL
FOLFOX
IROX
59
N9741Confirmed Response Rates
FOLFOX vs IFL p0.002
FOLFOX vs IROX p0.03
50
45
40
34
31
30

20
10
0
IFL
FOLFOX
IROX
60
N9741 Time to Progression
FOLFOX vs IFL p0.0014 Hazard ratio 0.72
IROX vs IFL pgt 0.50 Hazard ratio 1.02
10
8.7
8
6.9
6.5
Median TTP(months)
6
4
2
0
IROX
IFL
FOLFOX
2-sided p values
61
N9741 Phase III Trial of First-line IFL vs FOLFOX
vs IROX
Conclusions

• FOLFOX significantly more active than IFL and
  IROX in first-line therapy
• Toxicity less with FOLFOX than IFL regimen except
  for peripheral sensory neuropathy
• Many patients received irinotecan after FOLFOX
• IFL uses 5-FU bolus while FOLFOX uses 5-FU
  infusion
• A new standard of care for first-line therapy

Goldberg RN et al. Proc ASCO. 200322 (abstr
1009).
62
Tournigand
63
Tournigand Study DesignRandomized, Multicentric,
Open-label, Prospective, Phase III Trial
Until progression
Arm A (n113)
FOLFIRI
FOLFOX6
Until progression
CPT-11 180 mg/m2 IV LV 200 mg mg/m2 over 2
hours d1, 5FU 2400-3000 mg/m2 over 46 hours
R
Until progression
FOLFOX6
FOLFIRI
Until progression
Arm B (n113)
Eloxatin 100 mg/m2 IV LV 200 mg mg/m2 over 2
hours d1, 5FU 2400-3000 mg/m2 over 46 hours
64
Tournigand Study Results
Arm A
Arm B
FOLFIRI
FOLFOX6
FOLFOX6
FOLFIRI
P Value
ORR (CR),
56 (3)
15
54 (5)
4
0.68
ORR SD,
79
63
81
35
0.65
Median TTP, mos
14.4
11.5
0.9
Median OS, mos
20.4
21.5
2-year Survival,
41
45
65
Tournigand StudyTime to Progression
1.0
FOLFIRI / FOLFOX
0.8
FOLFOX/FOLFIRI
FOLFIRI/FOLFOX
Median (months) Events/patients Median follow-up
11.5 9.2-14.6
14.4 12.5-17.0
0.6
Probability
85/109
86/111
18.6 months
0.4
FOLFOX/FOLFIRI
0.2
Log-rank p.065
0.0
6
12
18
24
30
36
0
Months
66
Median OS Correlates With Availability of All
Effective Drugs

• Patients OS
• Author Study With 3 Drugs (mo)
• Saltz 2000 5 14.8
• Douillard 2000 16 17.4
• de Gramont 2000 29 16.2
• Giacchetti 2000 60 19.4
• Tournigand 2001 68 21.0
• Goldberg 2003 70 19.5
• Grothey 2002 75 21.4

67
Monoclonal Antibodies Targeted TherapyIn
Oncology
68
Goals for Monoclonal Antibodies

• Activity
• High specificity for a target critical to tumor
  growth and survival
• Able to achieve meaningful clinical benefit
• Utility
• Can be used as single agent or in combination
• Minimal overlapping toxicities
• Potential targets present across tumor types and
  stages of disease

Weiner LM. Semin Oncol. 199926(suppl 12)41-50
Breedveld FC. Lancet. 2000355735-740 Reff ME,
Hariharan K, Braslawsky G. Cancer Control.
20029152-166 Herbst RS, Shin DM. Cancer 2002
941593-1611 Carter P. Nat Rev Cancer.
20011118-129. Review.
69
Antibody Function

• Antibodies have two major functions
• Recognize and bind antigen
• Induce immune responses after binding

Variable region
Constant region
Goldsby RA, Kindt TJ, Osborne BA, et al. Kubys
Immunology. New York, NYWH Freeman and Company
2003.
70
Bevacizumab (Avastin)
71
Bevacizumab (Avastin)

• Indication for use
• In combination with 5FU for first-line therapy
  for metastatic colorectal cancer

72
Bevacizumab (Avastin)

• Side Effects
• Hypertension
• GI Bleeds Perforation
• Thrombotic Events

73
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74
VEGF Activates Angiogenic Pathways
VEGF
VEGF
VEGF
Endothelial Cell
KDR-Flt 1
KDR-KDR
Flt 1-Flt 1
Actin cytoskeleton reorganization
FAK phosphorylation Paxillin phosphorylation Vincu
lin assembly
Gene induction
MMPs Flt 1
Growth mitosis
Cell modify migration
ANGIOGENESIS
75
Role of Anti-Angiogenic Agents

76
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77
Hurwitz
78
Avastin Phase III study regimens1
Reference 1. Avastin Prescribing Information.
Genentech, Inc. February 2004.
79
Avastin significantly extended median survival1

• 30 increase in median survival in combination
  with IFL vs IFL alone (N813)
• The survival benefit associated with Avastin was
  observed early in treatment and persisted
  throughout the course of the trial

Reference 1. Avastin Prescribing Information.
Genentech, Inc. February 2004.
80
Avastin significantly extended median
progression-free survival1

• 66 increase in median progression-free survival
  in combination with IFL vs IFL alone (N813)

References 1. Avastin Prescribing Information.
Genentech, Inc. February 2004. 2. Data on file
(SR1). Genentech, Inc.
81
Avastin significantly increased response rate1

• Although tumor shrinkage is not an expected
  outcome of anti-angiogenic therapy, response
  rate was significantly higher with Avastin plus
  IFL vs IFL alone

Reference 1. Avastin Prescribing Information.
Genentech, Inc. February 2004.
82
Clinical benefits in combination with 5-FU/LV1,2

• Pivotal Phase III colorectal cancer study
  included a group (Arm 3) receiving Avastin plus
  5-FU/LV

References 1. Avastin Prescribing Information.
Genentech, Inc. February 2004. 2. Data on file
(SR1). Genentech, Inc.
83
Cetuximab (Erbitux)
84
Cetuximab (Erbitux)

• Indications for use
• In combination with irinotecan for
  EGFR-expressing metastatic colorectal cancer that
  is refractory to irinotecan-based therapy or as a
  single agent in patients who are intolerant to
  irinotecan

85
Role of Epidermal Growth Factor Receptor (EGFR)
in Human Cancer

• EGFR critically regulates tumor cell division,
  repair, and survival, and is involved in tumor
  metastasis
• Binding of specific ligands to EGFR (eg, EGF,
  TGF-a) activates the receptor and triggers signal
  transduction cascades that affect cell
  proliferation
• Many human cancers express EGFR on the cell
  surface
• Inhibition of EGFR on tumor cells may inhibit the
  growth or progression of EGFR-expressing tumors

86
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87
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88
Cetuximab (Erbitux)

• Side Effects
• Acneform Rash
• Asthenia
• Hypersensitivity reactions

89
Bond
90
Bond Trial
Irinotecan Cetuximab
EGRF Patients with advanced CRC progressed on
or within 3 months of Irinotecan-based therapy
Randomization
Cetuximab
Irinotecan Cetuximab
91
BOND Trial Study with Cetuximab and Irinotecan
Cetuximab Monotherapy Cetuximab Irinotecan P Value
RR 10.8 22.9 0.007
Median TTP (Months) 1.5 4.1 lt0.001
Median Survival (Months) 6.9 8.6 0.48
92
Summary

• Monoclonal antibodies are excellent therapeutic
  agents in oncology
• Monoclonal antibody engineering has evolved over
  time
• Monoclonal antibodies with different isotypes
  have differential properties

Reff ME, Hariharan K, Braslawsky G. Cancer
Control. 20029152-166 Herbst RS, Shin DM.
Cancer 20021941593-1611 Goldsby RA, Kindt
TJ, Osborne BA et al. Kubys Immunology. New
York, NYWH Freeman and Company 2003 Breedveld
FC. Lancet. 2000355735-740 Weiner LM. Semin
Oncol. 199926(suppl 12)41-50.
93
What the future holdsIncorporation of
targeted therapies into standard cytotoxic
regimens.Microarray AnalysisInnovative
Screening Techniques
94
Thank You