Colorectal Cancer Update: 2004 Shannon B. Holloway MHS RPA-C New York Presbyterian-Weill Cornell – Solid Tumor Service The Jay Monahan Center for Gastrointestinal.

Colorectal Cancer Update: 2004

Shannon B. Holloway MHS RPA-CNew York Presbyterian-Weill Cornell – Solid Tumor Service

The Jay Monahan Center for Gastrointestinal Health

Overview of Presentation

• Statistics

• Prevention & Screening

• Overview of the Major Therapeutic Agents

• Evolution of Colorectal Cancer Treatments

• What the Future Holds

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..

US Mortality, 2001

Source: US Mortality Public Use Data Tape 2001, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

• 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. Alzheimer’s disease 53,852 2.2•

Rank Cause of DeathNo. of deaths

% of all deaths

2004 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2004.

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 3%bile duct

Urinary bladder 3%

Kidney 3%

All other sites 21%

Change in the US Death Rates* by Cause, 1950 & 2001

* Age-adjusted to 2000 US standard population.Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3. http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf

21.8

180.7

48.1

586.8

193.9

57.5

194.4

245.8

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

1950

2001

Rate Per 100,000

Colorectal Cancer:Breakdown of Stage of Diagnosis and

Survival Times

0102030405060708090

100

Stage 1 Stage 2 Stage 3 Stage 4

CRC Stage atDiagnosis

Five-Year Survivalby Stage

American Cancer Society

Screening Recommendations for Colorectal Cancer, 2003

Feca l O ccult B lood T est andFlexib le S igm oidoscopy

Annua lly a nd Every 5 yearsR espectively

Flexib le S igm oidoscopyEvery 5 yea rs

Feca l O ccult B lood T est(FO B T )

Annua lly

C olonoscopyEvery 10 yea rs

Double Contrast Barium Enem a(DCBE)

Every 5 Years

W om en and Men> Age 50

Should fo llow one of these testing regim ens

Overview of Potential Risk FactorsColorectal Cancer

Dietary & Lifestyle

• Obesity

• Smoking

• Red Meat

• Alcohol

• Fruits & Vegetables

Overview of Risk FactorsColorectal Cancer

Inherited Disorders

- Familial Adenomatous Polyposis (FAP)

- Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Colorectal Cancer :TNM & Duke’s 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

Current Anti-Cancer Approaches

Surgery

Chemo-therapy

Radiation

Hormonaltherapy

Targetedtherapy

Remove known tumor masses

Kill rapidly dividing tumor cells, including tumor cells in adjacent tissues

Kill rapidly dividing tumor cells

Inhibit the growth and survival of hormone-dependent tumor cells

Specifically inhibit processes required for tumor cell growth

CRC Treatment by Stage

S tag e IS u rg ery

S tag e IIS u rg ery an d C h em oth erap y

P lu s R ad ia tion

S tag e IIIS u rg ery an d C h em oth erap y

P lu s R ad ia tion

S tag e IVP rim ary C h em oth erap y,R esec tion an d R ad ia tionwh en p oss ib le /in d ica ted

R ec ta l C an cerTrea tm en t M od a lity

S tag e IS u rg ery

S tag e IIS u rg ery

(C h em oth erap y C on trovers ia l)

S tag e IIIS u rg ery an d C h em oth erap y

S tag e IVP rim ary C h em oth erap y,R esec tion an d R ad ia tionwh en p oss ib le /in d ica ted

C o lon C an cerTrea tm en t M od a lity

CellularDedifferentiation

GrowthDysregulation

UnlimitedCell Division

Angiogenesis

Loss ofApoptosis

Invasion andMetastasis

Natural History of Cancer

Molecular Events in CancerAberrant

Signal Transduction

Secretion ofAutocrine

Growth Factors

Secretion ofMatrix Metalloproteinases

Expression of OncogenesLoss of Tumor Suppressor Genes

Secretion of Angiogenic

Growth Factors

Dysregulation of Growth Factors

or Receptors

1994

Fluorouracil(5FU)

2000

Fluorouracil(5FU)

Irinotecan(Camptosar)

Irinotecan(Camptosar)

Capecitabine(Xeloda)

Bevacizumab(Avastin)

Fluorouracil(5FU)

Oxaliplatin(Eloxatin)

Cetuximab(Erbitux)

2004

1994Overall Survival

Metastatic Disease

10 months

Henrick et al. Proc Am Soc Clin Oncol.2004;23:249 Absract 3517

2004Overall Survival

Metastatic Disease

25 months

Cytotoxic Chemotherapy

Fluorouracil(5-FU)

Fluorouracil (5FU)

Indication for Use:

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

Fluorouracil (5FU)

• Administration– IV Bolus– Continuous Infusion

• Target– Thymidylate Synthase (TS)

• Mechanism of Action– Prevents DNA replication, causes RNA/DNA

strand breaks

Fluorouracil (5FU)

• IV Bolus Side Effects– Diarrhea– N/V– Stomatitis

• Continuous Infusion Side effects– Stomatitis– Diarrhea– Hand-Foot Syndrome

The Meta-Analysis Group in Cancer

The Meta-Analysis Group. J Clinical Oncol.1998;16:301-308

Meta-Analysis of 5FU Bolus vs Infusional

6 Trials (N=1219) Bolus Infusional

Response Rate 14% 22%

Median Survival 11.3 12.1

Neutropenia 31% 4%

Hand-Foot Syndrome 13% 34%

Irinotecan(Camptosar)

Irinotecan (Camptosar)

Indications for use:

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

Irinotecan – Pro-drug Topoisomerase-1 Inhibitor

Irinotecan hydrochloride

N NC

O

O N

N O

O

O

C 2H

O C 2H

C 3H

H C 3H

SN-38

N N-HHO

N

N O

O

O

C 2H

O C 2H

C 3H

H C 3H

+

CarboxylesterasesC 2O

Piperidinopiperidine +

Irintotecan (Camptosar)

• Administration– IV

• Target– Topoisomerase 1

• Mechanism of Action– Prevents religation and single-strand DNA breaks

Irinotecan (Camtosar)

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

Doulliard&

Saltz

Pharmacia 0038 Phase III Trial of First-line Irinotecan + 5-FU/LV

Schema

RANDOMI

Z ATION

Single-agent irinotecan Irinotecan 125 mg/m2 over 90 minutesWeekly 4 0f 6 weeks

Single-agent irinotecan Irinotecan 125 mg/m2 over 90 minutesWeekly 4 0f 6 weeks

IFL Irinotecan 125 mg/m2 over 90 minutesLeucovorin 20 mg/m2 IV bolusFluorouracil 500 mg/m2 IV bolusWeekly 4 0f 6 weeks

IFL Irinotecan 125 mg/m2 over 90 minutesLeucovorin 20 mg/m2 IV bolusFluorouracil 500 mg/m2 IV bolusWeekly 4 0f 6 weeks

Saltz LB et al. N Engl J Med. 2000;343:905.

N=226

N=226

N=231

5-FU/LV (Mayo)Leucovorin 20 mg/m2 IV bolusFluorouracil 425 mg/m2 IV bolusd 1-5 q4wk

Median SurvivalIrinotecan plus bolus 5-FU/LV

p<0.042p<0.042

Irinotecan/5-FU/LV (N=231)Irinotecan/5-FU/LV (N=231)

5-FU/LV (N=226)5-FU/LV (N=226)

14.8 mo14.8 mo

12.6 mo12.6 mo

MonthsMonths

Pro

bab

ilit

yP

rob

abil

ity

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0

00 66 1212 1818 2424 3030

Saltz Saltz et alet al. . N Engl J Med N Engl J Med 343:905, 2000.343:905, 2000.

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. 2000;343:905.

Capecitabine(Xeloda)

Capecitabine (Xeloda)

Indication for use:

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

XELODA® (capecitabine) Chemical Structure

XELODAXELODA

NN

NN

OOOO

NH-CO-O-CNH-CO-O-C55HH1111

FF

HH33CC

HOHO OHOH

NNHH

HNHN

OO

FF

5-FU5-FU

OO

Capecitabine (Xeloda)

• Administration– Oral

• Target– Thymidylate Synthase

• Mechanism of Action– Prevents DNA Replication

Capecitabine (Xeloda)

• Side Effects– Palmar-Plantar Erythrodysesthesia (PPE) or

Hand-Foot Syndrome– Diarrhea– Nausea & Vomiting– Interaction with warfarin

Van Cutsem and Hoff

Phase II Study1: Results

• Response rates of 21%–24% 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. 2000;18:1337-1345.

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 1–14 followed by a 7-day rest period

– Mayo Clinic regimen: leucovorin (LV) 20 mg/m2 + 5-FU 425 mg/m2 (IV bolus), days 1–5 every 4 weeks

1. Hoff PM, et al. J Clin Oncol. 2001;19:2282-2292.

2. Van Cutsem E, et al. J Clin Oncol. 2001;19:4097-4106.

Efficacy of XELODA® (capecitabine) vs 5-FU/LV in Metastatic Colorectal Cancer

XELODAXELODA 5-FU/LV5-FU/LV(n=302)(n=302) (n=303)(n=303)

Overall Response Rate (%, 95% C.I.)Overall Response Rate (%, 95% C.I.) 21 (16–26)21 (16–26) 11 (8–15)11 (8–15)

((PP-value)-value) 0.00140.0014

Time to Progression (median, days, 95% C.I.)Time to Progression (median, days, 95% C.I.) 128 (120–136)128 (120–136) 131 (105–153)131 (105–153)

Hazard Ratio (XELODA/5-FU/LV)Hazard Ratio (XELODA/5-FU/LV) 0.990.99

95% C.I. for Hazard Ratio95% C.I. for Hazard Ratio (0.84–1.17)(0.84–1.17)

Survival (median, days, 95% C.I.)Survival (median, days, 95% C.I.) 380 (321–434)380 (321–434) 407 (366–446)407 (366–446)

Hazard Ratio (XELODA/5-FU/LV)Hazard Ratio (XELODA/5-FU/LV) 1.001.00

95% C.I. for Hazard Ratio95% C.I. for Hazard Ratio (0.84–1.18)(0.84–1.18)

Phase III Phase III –– Study 1 Study 1Phase III Phase III –– Study 1 Study 1

00 55 1010 1515 2020 2525 3030 3535 4040 4545

Est

imat

ed P

roba

bilit

yE

stim

ated

Pro

babi

lity

Time (months)Time (months)

5-FU/LV5-FU/LV12.812.8

XELODAXELODA12.912.9

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

XELODA (n=603) XELODA (n=603)

5-FU/LV (n=604)5-FU/LV (n=604)

Median (CI)Median (CI)XELODA:XELODA: 12.9 (12.0–14.0)12.9 (12.0–14.0)5-FU/LV:5-FU/LV: 12.8 (11.8–14.0)12.8 (11.8–14.0)

Hazard ratio = 0.96Hazard ratio = 0.96(0.85–1.08)(0.85–1.08)

Log-rankLog-rankP=P=0.480.48

Phase III Studies in First-line Treatment of MCRC: Overall Survival, Integrated Analysis1

1. Twelves C. Eur J Cancer. 2002;38(suppl):S15-S20.

Pat

ient

s (%

)P

atie

nts

(%)

XELODA (n=596)XELODA (n=596)

5-FU/LV (n=593)5-FU/LV (n=593)

00

1010

2020

3030

4040

5050

6060

7070

DiarrheaDiarrhea StomatitisStomatitis Hand-footHand-foot NauseaNausea VomitingVomiting AlopeciaAlopecia FatigueFatiguesyndromesyndrome

**

**

**

**

**

Phase III Studies in First-line Treatment of MCRC: Most Common Treatment-Related Adverse Events

20%, Integrated Analysis1 (Total)

1. Twelves C, et al. Eur J Cancer. 2002;38 (suppl):S15-S2.

*P*P<0.001<0.001

CapeOX regimen (Tabernero, ASCO 02)

capecitabine 1,000 mg/m2 twice daily

Days 1–14 Rest

1 8 15 21

oxaliplatin

130 mg/m2

(2-hour infusion)

Day

repeated every 3 weeks

RR 45%*

PFS 7.6 months

Overall Survival 19.5 months

Grade 3 toxicity: 7% neutropenia, 13% nausea/vomiting, 16% diarrhea, 16% neuropathy

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

(N=96 pts)

Van Cutsem E et al. Proc ASCO. 2003;22 (abstr 1023).

*Based on independent response review

Oxaliplatin(Eloxatin)

Oxaliplatin (Eloxatin)

Indications for use:

Treatment of metastatic colorectal cancer in combination with infusional 5FU

OxaliplatinMolecular Structure

Oxaliplatin (Eloxatin)

• Administration– IV

• Target– DNA

• Mechanism of Action– Prevents Replication and Transcription of DNA

Oxaliplatin (Eloxatin)

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

N9741

798 stage IV patients 798 stage IV patients

N9741: Schema

FOLFOX4 (n=269)ELOXATIN 85 mg/m2 over 2 hours d 1LV 200 mg/m2 IV over 2 hours d 1,25-FU 400-mg/m2 bolus for 2-4 minutes d 1,25-FU 600-mg/m2 continuous infusion over 22 hours d 1,2q2wk

FOLFOX4 (n=269)ELOXATIN 85 mg/m2 over 2 hours d 1LV 200 mg/m2 IV over 2 hours d 1,25-FU 400-mg/m2 bolus for 2-4 minutes d 1,25-FU 600-mg/m2 continuous infusion over 22 hours d 1,2q2wk

RRAANNDDOOMMIIZZAATTIIOONN

RRAANNDDOOMMIIZZAATTIIOONN

IROX IROX (n=265)(n=265)ELOXATIN 85 mg/mELOXATIN 85 mg/m22 d 1 d 1CPT-11 200 mg/mCPT-11 200 mg/m22 d 1 d 1q3w q3w

IFL (n=264)Irinotecan 125 mg/m2 over 90 minutesLeucovorin 20 mg/m2 IV bolusFluorouracil 500 mg/m2 IV bolusWeekly 4 0f 6 weeks

20

10

0

IFL FOLFOX

5

15 14.8

19.5

Median survival (months)

N9741Overall Survival

FOLFOX vs IFL p=0.0001 Hazard ratio= 0.66

17.4

IROX

IROX vs IFLp=0.04

Hazard ratio= 0.80

40

IFL FOLFOX

20

60

59%

72%

%

N9741One Year Survival

67%

IROX

80

N9741Confirmed Response Rates

40

20

0IFL FOLFOX

10

3031%

45%

%

FOLFOX vs IFL *p=0.002

50

34%

IROX

FOLFOX vs IROX *p=0.03

N9741: Time to Progression

* 2-sided p values

10

8

6

2

0IFL FOLFOX

4

6.9

8.7

Median TTP

(months)

FOLFOX vs IFL *p=0.0014Hazard ratio 0.72

IROX

6.5

IROX vs IFL *p> 0.50Hazard ratio 1.02

• 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

Conclusions

Goldberg RN et al. Proc ASCO. 2003:22 (abstr 1009).

N9741 Phase III Trial of First-line IFL vs FOLFOX vs IROX

Tournigand

Tournigand Study DesignRandomized, Multicentric, Open-label,

Prospective, Phase III Trial

Until progression

FOLFIRI FOLFOX6

R

FOLFOX6 FOLFIRI

CPT-11 180 mg/m2 IV + LV 200 mg mg/m2 over 2 hours d1, 5FU 2400-3000 mg/m2 over 46 hours

Eloxatin 100 mg/m2 IV + LV 200 mg mg/m2 over 2 hours d1, 5FU 2400-3000 mg/m2 over 46 hours

Until progression

Until progression

Until progression

Arm B(n=113)

Arm A(n=113)

Tournigand Study Results

Arm A Arm BFOLFIRI FOLFOX6 FOLFOX6 FOLFIRI P

Value

ORR (CR), % 56 (3) 15 54 (5) 4 0.68

0.65

0.9

Median TTP, mos14.4 11.5

2-year Survival, %41 45

ORR + SD, % 79 63 81 35

Median OS, mos 20.4 21.5

18.6 months

11.5 [9.2-14.6]14.4 [12.5-17.0]

85/109 86/111

Tournigand StudyTime to Progression

FOLFIRI/FOLFOX FOLFOX/FOLFIRI

FOLFIRI / FOLFOX

Median (months)

Events/patients

Median follow-up

Months

Log-rank p=.065

0.0

0.2

0.4

0.6

0.8

1.0

FOLFOX/FOLFIRI

6 12 18 24 30 360

Prob

abili

ty

Median OS Correlates With Availability of All Effective Drugs

% Patients OSAuthor 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

Monoclonal Antibodies: Targeted Therapy

In Oncology

– 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

Goals for Monoclonal Antibodies

Weiner LM. Semin Oncol. 1999;26(suppl 12):41-50; Breedveld FC. Lancet. 2000;355:735-740; Reff ME, Hariharan K, Braslawsky G. Cancer Control. 2002;9:152-166; Herbst RS, Shin DM. Cancer; 2002; 94:1593-1611; Carter P. Nat Rev Cancer. 2001;1:118-129. Review.

Antibodies have two major functions: • Recognize and bind antigen

• Induce immune responses after binding

Antibody Function

Constant region

Variable region

Goldsby RA, Kindt TJ, Osborne BA, et al. Kuby’s Immunology. New York, NY:WH Freeman and Company; 2003.

Bevacizumab(Avastin)

Bevacizumab (Avastin)

Indication for use:

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

Bevacizumab (Avastin)

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

VEGF Activates Angiogenic Pathways

VEGF VEGFVEGF

KDR-KDR KDR-Flt 1Flt 1-Flt 1

Actin cytoskeletonreorganization

Cell modify & migration

FAK phosphorylationPaxillin phosphorylation

Vinculin assembly Growthmitosis

Gene induction

MMPs

Flt 1

Endothelial Cell

ANGIOGENESIS

Role of Anti-Angiogenic Agents

Anti-angiogenesisapproaches Starve tumors of blood supply

Prevent vascular metastasis

Hurwitz

Avastin Phase III study regimens1

Reference1. Avastin Prescribing Information. Genentech, Inc. February 2004.

• 30% increase in median survival in combination with IFL vs IFL alone (N=813)

• The survival benefit associated with Avastin was observed early in treatment and persisted throughout the course of the trialReference

1. Avastin Prescribing Information. Genentech, Inc. February 2004.

Avastin significantly extended median survival1

Avastin significantly extended median progression-free survival1

• 66% increase in median progression-free survival in combination with IFL vs IFL alone (N=813)

References1. Avastin Prescribing Information. Genentech, Inc. February 2004.2. Data on file (SR1). Genentech, Inc.

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

Reference1. Avastin Prescribing Information. Genentech, Inc. February 2004.

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

References1. Avastin Prescribing Information. Genentech, Inc. February 2004.2. Data on file (SR1). Genentech, Inc.

Cetuximab(Erbitux)

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

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-) 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

Cetuximab (Erbitux)

• Side Effects– Acneform Rash– Asthenia– Hypersensitivity reactions

Bond

Bond Trial

EGRF+ Patientswith advanced

CRC progressedon or within 3

months of Irinotecan-based

therapy

Irinotecan +Cetuximab

CetuximabIrinotecan +Cetuximab

Randomization

Cunningham et al. Proc Am Soc Clin Oncol 2003;22:252 Absract 1012

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 <0.001

Median Survival

(Months)

6.9 8.6 0.48

• Monoclonal antibodies are excellent therapeutic agents in oncology

• Monoclonal antibody engineering has evolved over time

• Monoclonal antibodies with different isotypes have differential properties

Summary

Reff ME, Hariharan K, Braslawsky G. Cancer Control. 2002;9:152-166; Herbst RS, Shin DM. Cancer; 2002;1:94:1593-1611; Goldsby RA, Kindt TJ, Osborne BA et al. Kuby’s Immunology. New York, NY:WH Freeman and Company; 2003; Breedveld FC. Lancet. 2000;355:735-740; Weiner LM. Semin Oncol. 1999;26(suppl 12):41-50.

What the future holds:

Incorporation of targeted therapies into standard cytotoxic regimens.

Microarray Analysis

Innovative Screening Techniques

Thank You