Herceptin®

Targeted Therapy for HER2 Positive Breast Cancer

Prof B.KleinHead of OncologyHasharon hospital

HER2 terminology

Human Epidermal growth factor Receptor-2

Also known as

– neu (rat gene)

– c-erbB-2

HER2 protein = p185HER2

The HER gene family

GENEHER1

(c-erbB-1)

LIGAND EGF TGF-

Beta cellulin Heparin-binding growth factor Amphiregulin

Epiregulin

NeuregulinsNeuregulins

HER2(c-erbB-2)

HER3(c-erbB-3)

HER4(c-erbB-4)

EGF = epidermal growth factorTGF- = transforming growth factor alpha

?

Role of HER2 in breast cancer (I)

HER2 is an oncogene involved in abnormal cell growth

HER2 gene amplification --> protein overexpression --> activated HER2 receptors --> abnormal cell growth

Role of HER2 in breast cancer (II)

HER2 gene amplification or receptor overexpression occurs in approximately 25% of metastatic breast cancers

HER2-positive tumours are associated with poor prognosis and shortened disease-free/overall survival

HER2 receptor provides an extracellular targetfor novel and specific anticancer treatment(monoclonal antibodies)

Transmembrane structure of HER2 monomer

Extracellular domain(632 amino acids)Ligand-binding site

Intracellular domain(580 amino acids)Tyrosine kinase activity

Transmembrane domain(22 amino acids)

Cytoplasm

Plasmamembrane

HER2 receptor dimer transmembrane signal transduction pathway

Signaltransductionto nucleus

Nucleus

Binding site

Tyrosinekinase activity

Cytoplasm

Plasmamembrane

Growth factor

Gene activationCELL

DIVISION

Indicators of increased HER2 production

1 = gene copy number2 = mRNA transcription3 = cell surface receptor protein expression4 = release of receptor extracellular domain

Normal Amplification/Overexpression

Cytoplasm

HER2 receptorprotein

Cytoplasmicmembrane

Nucleus

HER2 DNA

HER2mRNA

1

2

3

4

Positive HER2 status rates in various tumour types in different studies

Tumour type(no. of samples)

HER2 proteinoverexpression (range)

Breast cancer (n=2111) 17–37%

Ovarian (n=73) 32%

Gastric (n=459) 12–55%

NSCLC (n=207) 27–56%

Mesenchymal (n=94) 37%

Bladder (n=141) 36%

Oesophageal (n=25) 60–73%

Salivary (n=27) 32–62%

Hynes NE, Stern DF. Biochim Biophys Acta 1994; 1198: 165–184

HER2-Driven Metastatic Breast CancerA Distinctly Aggressive Disease

In adjuvant and metastatic settings, patients with HER2-driven disease experience inferior survival and a poor response to chemotherapy and hormonal therapies.1,2

References: 1. Paik S, Hazan R, Fischer ER, et al. J Clin Oncol. 1990;8:103-112. 2. Ross JS, Fletcher JA. Am J Clin Pathol. 1999;112 (suppl 1):S53-S67.

Assays for determination of HER2 status

Detection methodHER2 macromolecule

detected Assay measures

IHC Protein Overexpression

FISH DNA Amplification

ELISA Protein Circulating shedHER2 receptors

Western blot Protein Overexpression

Northern blot mRNA Overexpression

Southern, slot blots DNA Amplification

RT-PCR DNA AmplificationIHC = immunohistochemistryFISH = Fluorescence in situ hybridisationELISA = Enzyme-linked immunosorbent assay

HER2-positive IHC stain

2+ 3+ 0 1+

IHC Images courtesy of MJ Kornstein, MD, Medical College of Virginia

HER2-positive FISH stain

IHC scoring and criteria for anti-HER2 therapy

IHC score

Anti-HER2 eligibility

0 Not eligible

1+ Not eligible

2+ Eligible

3+ Eligible

Herceptin (trastuzumab) – humanised anti-HER2 monoclonal antibody

• High affinity (Kd=0.1nM) and specificity

• 95% human, 5% murine -->

decreased potential for immunogenicity

Herceptin® in MBC

Pivotal phase III trial Herceptin® in combination with

chemotherapy (H0648g)

Pivotal Herceptin® combination therapy trial (H0648g): design and enrolment

No prior anthracyclines Prior anthracyclines

Paclitaxel(n=96)

Herceptin® + paclitaxel(n=92)

AC(n=138)

Herceptin® + AC(n=143)

Metastatic breast cancer HER2 overexpression No prior CT for MBC Measurable disease KPS 60%

Eligible patients (n=469)

AC = doxorubicin/epirubicin + cyclophosphamide, CT = chemotherapy, MBC = metastatic breast cancer

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25 30 35 40 45 50

Pro

bab

ilit

y o

f su

rviv

al

20.3 25.1

Herceptin® + CT

CT alonep<0.05

Time (months)CT patients treatedwith Herceptin® after 24% 62% 65% 72%disease progression

Pivotal Herceptin® combination therapy trial (H0648g): overall survival – all patients

Cut-off October 1999 ASCO 2000

Herceptin® + CT

CT alone

p<0.05

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.020 29

0 5 10 15 20 25 30 35 40 45 50

Time (months)

Pro

bab

ilit

y o

f su

rviv

al

Mass R et al. Proc ASCO 2000;19:Abstract 291

Pivotal Herceptin® combination therapy trial (H0648g): overall survival – IHC 3+ patients

45%

Pivotal Herceptin® combination therapy trial (H0648g): conclusions

Herceptin® in combination with chemotherapy improves TTP and overall survival

A survival benefit is seen even though 72% ofchemotherapy-alone patients received Herceptin®

after disease progression

Adding Herceptin® to paclitaxel – increases median survival from 18.4 to 22.1 months

in all patients and from 18 to 25 months in IHC 3+ patients

– increases TTP from 3.0 to 6.9 months in all patientsand from 3.0 to 7.1 months in IHC 3+ patients

First-line Herceptin® monotherapy Phase II trial (H0650g)

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Pro

bab

ilit

y

Duration of survival (months since randomisation)

Median survival: 24.4 months

First-line Herceptin® monotherapy (H0650g): survival in all enrolled patients

Vogel CL, et al. J Clin Oncol 2002;20:719–26

First-line Herceptin® monotherapy (H0650g): summary

Herceptin® is active as a single agent in patientswith no prior chemotherapy for metastatic disease

Response rates with 2mg/kg and 4mg/kg are similar

Well tolerated with favourable safety profile

– severe adverse events are infrequent

Vogel CL, et al. J Clin Oncol 2002;20:719–26

Tolerability of Herceptin®

Tolerability of Herceptin®

Common side effects

Well tolerated

Lacks the usual chemotherapy-related toxicities

Mild infusion-related symptoms occur in 40% of patients with the first infusion (fever, chills)

Serious adverse events

Exacerbation of anthracycline-related cardiotoxicity

Rare, severe, infusion-related reactions

Tolerability of Herceptin® (cont’d)

In clinical trials to date:

Side effects have been generally mild-to-moderate

Side effects tend to occur with the first infusion and are easily manageable

No unexpected side effects have been observed since the retrospective observation of cardiac events in the pivotal trials

Herceptin® does not exacerbate chemotherapy-related side effects

Incidence of Herceptin® associated cardiotoxicity in the pivotal trials: retrospective analysis

In a retrospective analysis of safety data from the pivotal trials, only 66 of 447 patients (15%) developed symptomatic heart failure

Cardiac dysfunction is most common in patients receiving Herceptin® in combination with anthracyclines

Cardiotoxicity is manageable with standard medication and patients at risk can usually be identified prior to therapy

Cook-Burns N. Oncology 2001;61(Suppl. 2):58–60

Tykerb Profile

– Belongs to the 4-anilinoquinazoline class of tyrosine kinase inhibitors

– Binds reversibly to the cytoplasmic ATP-binding site of the kinase, thereby preventing receptor phosphorylation and activation

– Works inside the cell

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Tykerb

Tykerb is an oral small-molecule dual inhibitor of ERBB1 and ERBB2

tyrosine kinases:

Tykerb is an oral small-molecule dual inhibitor of ERBB1 and ERBB2

tyrosine kinases:

Primary endpoint: TTPSecondary endpoints: OS, PFS, ORR

Tykerb1250 mg/day po daily

Capecitabine 2000 mg/m2/day,

days 1-14, q 21 days

Capecitabine 2500 mg/m2/day

days 1-14, q 21 days

EGF100151: Phase III Trial of Capecitabine ± Tykerb in Advanced or Metastatic Breast Cancer

Eligibility criteria

•Progressive MBC or stage IIIB/IIIC LABC with T4 lesion

•HER2 overexpression (IHC3+ or 2+ and FISH+)

•Unlimited prior therapies, but no prior capecitabine

•Prior therapies must include:

•Herceptin in metastatic setting

•Anthracycline and taxane in either metastatic or adjuvant setting

RANDOMIZE

Endpoints

Primary

– Time to tumor progression (TTP) as assessed by independent review committee based on ITT

Secondary

– Overall survival

– Progression-free survival (PFS)

– Overall response

– Clinical benefit rate

– Toxicity

Time to Progession as Assessed by IRC

Xeloda

Tykerb + Xeloda

0.00004P-value (log-rank, 1-sided)

72 49Progressed or died

19.136.7Median TTP, wk

161163No. of pts

0.49 (0.34, 0.71)Hazard ratio (95% CI)

0.2

0.4

0.6

0.8

0.0

1.0

0

Cu

mu

lati

ve P

rog

ress

ion

-Fre

e

10 20 30 40 50 60

Time (weeks)

70

Herceptin® in the adjuvant setting

Targeting HER-2 in the Adjuvant Setting

George W. Sledge MD

Indiana University Cancer Center

MonthsMonths

0.2

0

0.4

0.6

0.8

1.0

FISH+

Months

0.2

0

0.4

0.6

0.8

1.0 Trast. + CT (n = 176)

CT (n = 169)

Pro

bab

ility

of

surv

ival

RR = 0.71p = 0.007

0 10 20 30 40 50

20.0 mo

26.2 mo

FISH–

RR = 1.11p = NS

0 10 20 30 40 50

19.8 mo24.0 mo

Trast. + CT (n = 50)

CT (n = 56)

Trastuzumab Combination Pivotal Trial: Overall Survival

Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

NSABP B-31

NCCTG N9831

Arm 1Arm 2

Arm A

Arm B

Arm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 80 mg/m2/wk x 12= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Control: ACT

Investigational: ACT+H

NSABP B-31/N9831 Joint Analysis: Statistical Analysis

Decision to perform joint analysis occurred following trial design and initiation

Analysis performed before either trial completed accrual, resulting in premature trial closure and short median follow-up

Does not include all randomized patients Primary endpoint = disease-free survival, whereas the original B-31

primary endpoint was OS

DESIGN OF THE HERA TRIALDESIGN OF THE HERA TRIAL

Women with HER2 POSITIVE invasive Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmedbreast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy radiotherapy

StratificationStratificationStratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,

age, regionage, region

RandomizationRandomizationRandomizationRandomization

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 2 years3 weekly x 2 years

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 1 year3 weekly x 1 year

ObservationObservation

HERA Trial: Design Elements

Randomized patients received trastuzumab following completion of chemotherapy

DFS was primary endpoint Most patients did not receive a taxane In contrast to Joint Analysis, HERA included a

relatively large percentage of node-negative patients (about 1/3)

Very short median f/u (1 year following randomization)

Questions Asked Does adjuvant trastuzumab improve disease-free

survival? Should we give trastuzumab with chemotherapy or

following chemotherapy? What is the appropriate duration of trastuzumab

therapy? What is the price of trastuzumab therapy?

Does adjuvant trastuzumab improve disease-free survival?

Disease-Free Survival

87%87%85%85%

67%

75%

N EventsACT 1679 261ACTH 1672 134

%

HR=0.48, 2P=3x10-12

ACACTHTH

ACT

Years From Randomization B31/N9831

DISEASE-FREE SURVIVALDISEASE-FREE SURVIVAL

Months from randomizationMonths from randomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents2-yr2-yr

DFS %DFS % HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54[0.43, 0.67][0.43, 0.67]<0.0001<0.0001

220220 77.477.4

Trastuzumab 1 yrTrastuzumab 1 yr

ObservationObservation

% alive and % alive and disease disease

freefree

10010090908080707060605050404030302020101000

No. No. at riskat risk

Joint Analysis Results

DDFS HR = 0.47 2p = 8 X 10 -10

OS HR = 0.67 2p = 0.015

HERA Results

DDFS HR = 0.51 p < 0.0001OS HR = 0.76 p = 0.26

Should we give trastuzumab with chemotherapy or following

chemotherapy?

•Preclinical data suggests that trastuzumab may amplify chemotherapy’s pro-apoptotic effects•Synergistic activity predicted in preclinical models for some chemotherapy agents•Cardiotoxicity concerns when trastuzumab given in proximity to anthracyclines

Should we give trastuzumab with chemotherapy or following

chemotherapy?

Trastuzumab following chemotherapy improves DFS and DDFS (HERA)

Concurrent chemotherapy plus trastuzumab may be superior to sequential therapy (N9831)

Concurrent therapy a la N9831 associated with greater cardiotoxicity

Disease-Free Survival: Control vs Sequential

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

YearsNumber of patients followedA 979 629 353 168 15B 985 637 403 169 20

AC AC →→ T TEvents=117Events=117

Hazard ratio=0.87Hazard ratio=0.87Stratified logrank Stratified logrank 2P2P=0.2936=0.2936

AC AC ->-> T T ->-> H HEvents=103Events=103

%

Disease-Free Survival: Concurrent vs. Sequential

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

monthsNumber of patients followedB 842 501 285 162 20C 840 520 285 178 17

AC AC ->->T T ->->HH events=84events=84

Stratified logrankStratified logrankPP=0.0114=0.0114

AC AC ->->T + H -> HT + H -> HEvents = 53Events = 53

%

What is the appropriate duration of trastuzumab therapy?

Unknown (HERA 1 vs. 2y pending) Current data supports one year of therapy Current data supports initiation of therapy for up to

six months following completion of chemotherapy or radiation therapy

Could we get by with less trastuzumab (i.e. with chemotherapy alone)?

Does adjuvant trastuzumab improve disease-free survival?

YES

What is the price of trastuzumab therapy?

Cardiac toxicity (CHF) can be a consequence of using trastuzumab close to doxorubicin

Rate = 3.3-4.3% for AC->TH vs. 0-0.5% for AC->T (N9831/B-31); Rate = 0.5-2.2% when given post-chemotherapy (HERA/N9831)

Degree of reversibility is uncertain and requires further follow-up; long-term effects unknown

While benefits far outweigh the risk, the price is real and should be discussed with patients

Can Doxorubicin Be Eliminated?

HER2 +FISH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 Year Trastuzumab

N=31501 Year Trastuzumab

ACT

ACTH

TCH

BCIRG 006

LVEF Declines by NYHA Class

AC-T AC-TH TCH

>10%, <LLN 9 34 7

>15%, <LLN 6 25 4

Grade 3/4 CHF 1 18 1

Implication: Trastuzumab per se is not cardiotoxic; it becomes so when it keeps company with DOX

Phase III Trial Comparing AC-T with AC-TH and with TCH

in the Adjuvant Treatment of HER2 positive Early Breast Cancer Patients:

First Interim Efficacy Analysis

Study sponsored by Sanofi-AventisSupport from Genentech

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M,

Falkson C, Pinter T, Fornander T, Shiftan T, Valero V, Von Minckwitz G, Mackey J, Tabah-Fisch I, Buyse M,

Lindsay MA, Riva A, Bee V, Pegram M, Press M, Crown J, on behalf of the BCIRG 006 Investigators.

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Carboplatin75 mg/m2 AUC 6

1 Year Trastuzumab

N=3,222

1 Year Trastuzumab

ACT

ACTH

TCH

Her2+(Central FISH)

N+or high risk N-

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

Slamon D., SABCS 2005

BCIRG 006

Stratified by Nodes and Hormonal Receptor Status

Disease Free Survival%

Dis

ea

se F

ree

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Year from randomization

77%

86%

80%

73%

84%

80%86%

93%

91%

Patients Events

1073 147 AC->T

1074 77 AC->TH

1075 98 TCH

HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001

HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002

The Angiogenic Switch

1-2 mm

Angiogenic

Switch

Small tumor• Nonvascular• “Dormant”

Larger tumor• Vascular• Metastatic potential

Normal and Tumor Vasculature

........................

.... ..... .... .....

........................

.... .....

........................

........................

........................

Maturation factors present

Normal Blood Vessels Tumor Blood Vessels

Reduced integrin expression

Less dependent on cell survival factors

.... ..... Less permeable

Leaky

Preferential expression of v3 v5 &

51 integrins

Fewer pericytes

Growth and survival factors (eg, VEGF)

present

.... .....

Supporting pericytes present

Agents Targeting the VEGF Pathway

VEGFR-2VEGFR-1P

PPPP

PPP

Endothelial cellSmall-molecule

VEGFR inhibitors (Vatalanib, sunitinib, sorafenib)

Anti-VEGFR antibodies(IMC-1121b)

Soluble VEGF

receptors(VEGF-TRAP)

VEGFAnti-VEGF antibodies

(bevacizumab)

Anti-VEGF antibody Avastin prevents the interaction of VEGF with its receptors

Avastin is a recombinant humanized monoclonal antibody to VEGF 93% human, 7% murine

Avastin binds VEGF, preventing interaction with its receptors and activation of downstream signalling pathways

This ultimately leads to vascular regression, leaving the tumour dormant

Avastin

– P– P

P– P–

VEGF

X

Growth

Proliferation

Migration

Survival

X

Phase III Trial With Bevacizumab Therapy in MCRC (AVF2107g)

*Third arm was discontinued after a predetermined interim safety analysis demonstrated the safety of therapy with 5-FU/LV/CPT-11 + bevacizumab.

†Patients receiving bevacizumab could continue therapy past disease progression in combination with second-line therapy.

IFL = bolus 5-FU/LV/irinotecanHurwitz et al. N Engl J Med 2004.

Previously untreated MCRC

(n=923)

PDIFL + placebo

(n=411)

PDFL + bevacizumab*(5 mg/kg, q2w) (n=110)

PDIFL + bevacizumab (5 mg/kg, q2w) (n=402)

Primaryend point:

Survival

RANDOM

IZATION

†

†

Phase III Trial of Bevacizumab in MCRC: Efficacy

IFL+ Placebo (n=411)

IFL+ Bevacizumab(n=402) P Value

Median survival (mo) 15.6 20.3 0.00004

PFS (mo) 6.24 10.6 <0.00001

ORR (%)

CR

PR

35

2.2

32.5

45

3.7

41.2

0.0036

Duration of resp. (mo) 7.1 10.4 0.0014

Hurwitz et al. N Engl J Med 2004

Phase III Trial of Bevacizumab in MCRC: Survival

HR=0.66, P=0.00004

Median survival: 15.6 vs 20.3 mo

Duration of survival (mo)

Pro

po

rtio

n s

urv

ivin

g

0.2

200 10 30 400

0.8

1.0

0.4

0.6

Treatment Group

IFL + placeboIFL + bevacizumab

Hurwitz et al. N Engl J Med 2004

Erbitux (cetuximab) - in colorectal cancer

- in head and neck cancer

- in lung cancer (NSCLC)

EGF, TGFAmphiregulin

-cellulinHB-EGF

EpiregulinHeregulins

NRG1-4Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

EGFR,HER1ErbB-1

HER2/neuErbB-2

HER3ErbB-3

HER4ErbB-4

C-terminus

100

100

100

44

82

33

36

59

24

48

79

28

The EGFR family and ligands

EGFR signalingActivation of EGFR stimulates all key processes involved in tumor growth

The EGFR is activated by growth factors (e.g. EGF and TGF-)

EGFR-activation leads to the building of receptor homo- or hetero-dimers

Receptor dimerization initiates an intracellular signaling cascade

Baselga et al. Eur J Cancer 2001; 37 (Suppl 4): S16.

R

K

R

K

Cell surface R

K

R

K

Cell surface

SurvivalProliferation

Angiogenesis MetastasisCellular Responses

PI3K

Shc

Grb2 Ras Sos

Raf

MEK1/2

Akt

MAPK

PTEN

GSK-3mTOR FKHR BadIntra-CellularSignaling

NF-

[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]

p27

Gene Transcription/Cell Cycle Progression

Erbitux IgG1 monoclonal antibody Specific EGFR binding Prevents ligand binding to EGFR Higher affinity for EGFR compared to natural

ligands Blocks receptor dimerization, tyrosine kinase

phosphorylation, signal transduction Stimulates receptor internalization Fc region may induce antibody-dependent cell-

mediated cytotoxicity (ADCC) (immune response)

329 patients with mCRC progressed on or within3 months of irinotecan-based chemotherapy

2:1 RANDOMIZATION†

Erbitux**n = 111

Irinotecan* + Erbitux**n = 218

Irinotecan* + Erbitux**n = 56

on disease progression

* Same regimen as previously failed; ** initially 400 mg/m2 IV, then 250 mg/m2 IV weekly

The Erbitux ‘BOND’ I study: design

1° endpoint: RR

2 ° endpoint: TTP, OS, Safety

56[49-62]

23[18-29]

32[24-42]

11[6-18]

0

10

20

30

40

50

60

Response Rate Disease Control(CR+PR+SD)Endpoint

Pe

rce

nta

ge

Erbitux/Irinotecan n=218

Erbitux n=111

*

**

* p=0.0074; ** p<0.001; [ ] = 95% CICunningham D et al. NEJM 2004

Response rate: 23% vs 11% Disease control: 56% vs 32% PFS: 4.1 vs 1.5 months

Mono ComboN 111 218No. events 92 152Median 1.5 4.1

HR (95% CI): 0.54 (0.42; 0.71)p-value < 0.0001

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12Months

Pro

po

rtio

n

Progression-free survival

The The ErbituxErbitux ‘BOND’ I study ‘BOND’ I study::

BOND-2 Trial - Randomized Phase II

Irinotecan: same dose and schedule as beforeCetuximab: 400mg/m2 initial dose (week 1)

250mg/m2 qw (starting on week 2)Bevacizumab: 5mg/m2 q 2 wks

n=81

MCRC refractory to

irinotecan Cetuximab + bevacizumab +

irinotecan

Cetuximab + bevacizumab

Tox, RR, TTPR

Saltz et al., ASCO 2005

EGF-R expression not required

BOND-2 Trial - Efficacy (historic comparison with BOND-1)

BOND-1 BOND-2 BOND-1 BOND-2

C225C225+BEV

C225+CPTC225+CPT

+BEV

N pts 111 40 218 41

Previous Oxaliplatin (%) 64 90 62 85

RR (%) 11 20 23 37

TTP (mos) 1.5 5.6 4.1 7.9

Med. OS (mos) 6.9 -- 8.6 --

Saltz et al., ASCO 2005

Correlation of skin toxicity and efficacy

Maximum grade of skin reaction

Number of patients

Response (%)

mTTP* (months)

mOS** (months)

0 32 (14.7%) 6.3 1.4 3.0

1 58 (26.6%) 8.6 1.5 6.5

2 99 (45.4%) 27.3 4.2 10.3

3 29 (13.3%) 55.2 8.2 13.7

BOND combination arm: Erbitux + Irinotecan (n=218)

Skin reactions appear to be predictive for efficacy

Cunningham D et al. NEJM 2004