The treatment of metastaticcolorectal cancer in 2007

Prof Eric Van Cutsem, MD, PhD

Gastrointestinal Oncology Unit

University Hospital Gasthuisberg

Leuven - Belgium

CRC is a major health concern

• Life-time risk for CRC 4–6%1

• Worldwide– Third most common cancer2

– > 1000 000 new cases2

– Second leading cause of cancer death (~529 000)2

• 400 000/year patients in Europe develop CRC2

• 25% present with metastatic disease

• 40–50% eventually develop metastatic disease

• > 200 000 deaths/year in Europe2

1. Winawer S, Fletcher R, et al. Gastroenterol 2003: 124; 544-60 2. GLOBOCAN. http://www-dep.iarc.fr 2002

First-lineSecond-

lineThird-

lineAdjuvantDiagnosis

Neo-adjuvant/Surgery

Maximising patient outcomes in CRC Maximising patient outcomes in CRC

• Colorectal cancer treatment in a context of Continuum of Care:

– Treatment Plan throughout the continuum of care, based on best available evidence

– More effective drugs now available and trend towards a targeted and possibly “tailored” therapy

– Multi-Disciplinary Approach: i.e. resection of liver metastases

Goldberg R, Rothenberg M, Van Cutsem E et al. Oncologist 2007

Colorectal liver metastases

• Disease is limited to the liver:- Unresectable liver metastases

– Neoadjuvant or induction chemotherapy followed by resection if response

– Resectable liver metastases• Neoadjuvant and/or adjuvant chemotherapy

The role of neo-adjuvant and adjuvant chemotherapy for livermetastases of

colorectal cancer

Patterns of resectability in patients with CRC liver metastases

Metastatic CRC

85% unresectable 15% resectable

• 10-20% potentially resectable• 80-90% never resectable

neoadjuvant chemotherapy to increase resectability?

• Class I

• Class II

neoadj. and/or adjuv. CT to

increase cure rate?

5-Yr Survival after resection of CR Livermetastases

22%35%25%25%33%39%25%26%32%37%38% 34%58%41%58%

5%0%5%3%--

5%4%2%0%

2.8%0%

0.8%-

1%-

2596080141859219280

1818204

1001235257133615190

198119861987198719881991199219921994199920002002200220032004

FosterIwatsukiNordlingerAdsonHughesScheeleRosenAFCGayowskiFongMinigawaErcolaniChotiAdamAbdalla

SurvivalOp. Mort.PatientsYearAuthors

EORTC 40983: Study design

Randomize

SurgeryFOLFOX4 FOLFOX4

Surgery

6 cycles

(3 months)

N=364 patients with < 4

resectable livermetastases

6 cycles

(3 months)

Nordlinger B et al, Proc ASCO 2007

EORTC 40983: Results

P=0.0250.73(0.55-0.97)

+9.2%(33.2% to 42.4%)

152151All resectedPatients

P=0.0410.77 (0.60-1.00)

+8.1%(28.1% to 36.2%)

171171All eligiblePatients

P=0.0580.79(0.62-1.02)

+7.2%(28.1% to 35.4%)

182182All patients

P-valueHazardRatio

(Confidence Interval)

% absolute difference

in 3-year PFS

N pts Surgery

N ptsCT

Nordlinger B et al, Proc ASCO 2007

Progression-free survival in eligible patients

HR= 0.77; CI: 0.60-1.00, p=0.041

Periop CT

28.1%

36.2%

+8.1%At 3 years

(years)0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :125 171 83 57 37 22 8115 171 115 74 43 21 5

Surgery only

Nordlinger B et al, Proc ASCO 2007

Cytotoxic chemotherapy formetastatic CRC

Survival

Med (mo) 1 yr (%) 2 yr (%)

– Best Supp. Care 6 < 30 < 10– 5-FU + FA 11-12 45 20-30

• Capecitabine 12 50 20-30 • Irinotecan 18 60-70 30-40• Oxaliplatin 18 60-70 30-40

TheThe issues issues thatthat face us to face us to achieveachieve a a continuum continuum ofof carecare

1st line chemo 3rd line chemo2nd line chemo

1st 1st biologicbiologic 2nd 2nd biologicbiologic

HowHow to to startstart??

AtAt progressionprogressionchange change chemochemo,,

biologicbiologic or or bothboth??

IndependentIndependentsequencessequences??

Van Cutsem E. Editorial J Clin Oncol. 2006

Sistin Chape: UniversalJudgement of Michelangelo

The emerging Integrated Circuit of

the Cell

J. FOLKMAN: 1971The Angiogenic Switch and

Antiangiogenic Therapy

SomaticMutation

SmallAvascular

Tumor

Tumor Secretion of Proangiogenic

Factors Stimulates Angiogenesis

Rapid Tumor Growth and Metastasis

Angiogenic Inhibitors May Reverse this

Process

Tumour blood vesselsNormal blood vessels

Maturation/stabilisation factors present

Basal integrin expression

Less dependent on cell survival factors

Less permeable

Leaky

Preferential expression of �v�3, �v�5, and �5�1 integrins

Fewer supporting cells

Growth and survival factors (e.g., VEGF) present

Supporting cells present

Tumour vasculature resulting from VEGF-mediated angiogenesis is abnormal

Jain., Semin Oncol 2002;29 (Suppl. 16):3–9; Carmeliet, Nat Med 2003;9:653–60;Lee et al., J Biol Chem 2003;278:5277–84

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

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

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

.... .....

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

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

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

Maturation factors present

Normal and Tumor VasculatureTumor Blood VesselsNormal Blood Vessels

Reduced integrinexpression

Minimally dependent oncell survival factors

.... ..... Less permeable

Leaky

Preferential expression of

αvβ3 αvβ5 & α5β1integrins

Fewer pericytes

Growth and survival factors (eg, VEGF)

present

.... .....

Supporting pericytespresent

Blau and Banfi. Nat Med. 2001;7:532.Jain. Nat Med. 2001;7:987.

Tumor Vasculature is AbnormalNormal colon Nearby colorectal cancer

Tumor vasculature is dilated, highly chaotic, and tortuous, with a lack of hierarchicalvessel arrangement

Carmeliet P, et al. Nature 2000;407:249–57Konerding et al; Microenvironment of Human Tumors 2002

Anti-VEGF

Reducesinterstitial fluid pressure

vessel density

Increasesdrug delivery

Anti-VEGF antibody ‘normalises’the tumour vasculature

Jain R. Nature Med 2001;7:987–9; Willett CG, et al. Nat Med 2004;10:145–7; Tong R, et al, Cancer Res 2004;64:3731–6

VEGFVEGFVEGF VEGF

receptorreceptor--22

Cation Cation channelchannel

↑↑ PermeabilityPermeability

Antibodies inhibiting VEGFAntibodies inhibiting VEGF(e.g. (e.g. bevacizumabbevacizumab))

Antibodies inhibiting Antibodies inhibiting VEGF receptorsVEGF receptors

Soluble VEGF receptorsSoluble VEGF receptors(VEGF(VEGF--TRAP)TRAP)

Small-moleculesinhibiting VEGF receptors

(TKIs)(e.g. PTK-787)

RibozymesRibozymes((AngiozymeAngiozyme))

– P– PP–

P–

– P– P

P–P–

– P– P

P–P–

Migration, permeability, DNA synthesis, survivalMigration, permeability, DNA synthesis, survival

LymphangiogenesisLymphangiogenesisAngiogenesisAngiogenesis

Agents targeting the VEGF pathway

Clinical Results in Metastatic ColorectalCancer

Bevacizumab in combination with chemotherapy in metastastic CRC

– pivotal trial: IFL: increased activity in first line– 5-FU/FA monotherapy: increased activity in first line– FOLFOX: increased activity in second line– Oxaliplatin based: increased activity in first line

– Cetuximab +/- irinotecan: high activity in irinotecan refractoryCRC

– Bolus 5-FU/FA plus bevacizumab: not active in irinotecan and oxaliplatin refractory CRC

Median progression-free survival6.2 vs 10.6 monthsHR=0.54 p<0.0001

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Superior PFS + OS with 1st line IFL + bevacizumab vs IFLPr

obab

ility

of b

eing

pro

gres

sion

free

1.0

0.8

0.6

0.4

0.2

00 10 20 30

Time (months)

IFL + bevacizumabIFL + placebo

6.2m 10.6mPr

obab

ility

of s

urvi

val

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Time (months)

IFL + bevacizumabIFL + placebo

15.6m 20.3m

Median survival 15.6 vs 20.3 monthsHR=0.66 p<0.001

Bevacizumab: Safety Overview

Bevacizumab does not increase chemotherapy related toxicities.

Bevacizumab has specific side effects: – Hypertension– Proteinuria– Thromboembolic events: arterial– Bleeding: minor mucosal (epistaxis) and major hemorrhage (non small

cell lung cancer)– Gastrointestinal perforation– Wound healing/postoperative bleeding

Kabbinavar F et al. J Clin Oncol 2003;21:60–5Hurwitz H et al. NEJM 2004;350:2335–42

Giantonio BJ, et al. Presented at: 2005 Gastrointestinal Cancers Symposium; 27–29 January 2005; Hollywood, FL, USA. Abstract 169a

Arterial thromboembolic events*

Risk factors for arterial thromboembolic events included– history of prior arterial thromboembolic events such as stroke or heart attack– age of 65 years or older

Arterial events included in analysis– CVA (stroke), transient ischemic attack, subarachnoid hemorrhage– myocardial infarction, angina (unstable angina), arterial thrombosis and other arterial

thromboembolic events

4.5% (45/1004)2.0% (15/741)Arterial TE events

0.8% (8/1004)0.4% (3/741)Mortality

bevacizumab plus chemotherapy

Chemotherapy alone

*Pooled analysis of five randomised trials

EGFR pathway inhibition

pEGFR

pMAPK

Ki67

p27

pEGFR

pMAPK

Ki67

p27

pAkt

1

K

2

KShc

PI3KShc

Grb2

Grb2Ras

Sos

Sos

Raf

MEK1/2

Akt

MAPK

Cell cycleprogression

Survival Proliferation

PTEN

GSK-3mTOR FKHR

Bad

D1 Cyclin

p27

SKIN TUMOR

Tabernero J et al 2003

Tyrosine kinaseinhibitors

(gefitinib, erlotinib,CI-1033, EKB-569, …)

Monoclonalantibodies

(cetuximab, panitumumab, matuzumab, ...)

Signal Transduction

R R

Ligand

K K

Anti-EGF Receptor Therapies

CELL MEMBRANECELL MEMBRANE

Cetuximab +/- irinotecan in irinotecan refractory CRC: Response Ratio

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)

Perc

enta

gecetuximab + irinotecan

(n=218)cetuximab (n=111)

***

* p=0.0074; ** p<0.001; [] = 95% CI

Cunningham D … Van Cutsem E. N Engl J Med 2004

Panitumumab PD Follow-up6.0 mg/kg Q2W+ BSC

BSC PD Follow-up

RRAANNDDOOMMIIZZEE

Optional Optional Panitumumab Panitumumab

Crossover StudyCrossover Study

Stratification:Stratification:•• ECOG score: 0ECOG score: 0--1 vs. 21 vs. 2•• Geographic regionGeographic region

PanitumumabPanitumumab in in mCRCmCRC: phase 3 trial: phase 3 trial

1:1

Key inclusion:Key inclusion:•• Disease progression on CT scan Disease progression on CT scan

after after fluoropyrimidinefluoropyrimidine, , irinotecanirinotecanand and oxaliplatinoxaliplatin

•• EGFrEGFr membrane staining on membrane staining on ≥≥ 1% 1% tumor cellstumor cells

Van Cutsem E et al. J Clin Oncol 2007

Even

t-fre

e Pr

obab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

Hazard ratio=0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testp < 0.000000001

ProgressionProgression--Free SurvivalFree Survival

Panitumumab

BSC

Patients at risk:PanitumumabBSC

231 118 49 31 13 5 1232 75 17 7 3 1 1

Primary Analysis, All RandomizedAnalysis Set, Central Radiology Van Cutsem E et al. J Clin Oncol 2007

0%

10%

20%

30%

40%

50%

60%

KaplanKaplan-- Meier ProgressionMeier Progression--Free Survival Rates at Free Survival Rates at Prespecified Time PointsPrespecified Time Points

49%49%

30%30%35%35%

14%14%

26%26%

9%9%5%5%

18%18%

4%4%1%1%1%1% 1%1%

4%4%

10%10%

Panitumumab (N=231)Panitumumab (N=231)BSC (N=232)BSC (N=232)

Wk 8Wk 8 Wk 12Wk 12 Wk 16Wk 16 Wk 24Wk 24 Wk 32Wk 32 Wk 40Wk 40 Wk 48Wk 48

Primary Analysis, All Randomized Analysis Set, Central Radiology

% P

rogr

essi

on F

ree

(95

% C

I)

Patients at risk:Patients at risk:PanitumumabPanitumumabBSCBSC

118118 4949 3131 1313 55 117575 1717 77 33 11 11

76763131

Van Cutsem E et al. J Clin Oncol 2007

EGFR-inhibitor induced skin reactions

1 2 3 4 5 6 7 8 9

Descriptionof severe cases

THERAPY SUGGESTIONS

Post inflammatory effectsAcne-like rash

paronychia

dry skin

Topical anti-acne creams (drying effect)

+/- tetracyclines

+/- antihistamines

pruritus

Pulse dye laser Emollients Hydrocolloid dressing

or

Propylene glycol+/-acetylsalicyl

Anti-septic soaks

Silver nitrate (pyogenicgranuloma)

fissura

S Segaert & E Van Cutsem, Ann Oncology 2005

Study: 9923 0141 BOND Saltz (2001)1 Saltz (2004)2 Cunningham Van Cutsem Xiong (2004)5 Kies (2002)6

(2004)3 (2004)4

Correlation of rash and survival after treatment with cetuximab

1. Saltz et al. Proc ASCO 2001. 2. Saltz et al. J Clin Oncol 2004. 3. Cunningham D…Van Cutsem E. N Engl J Med 2004. 4. Van Cutsem et al. EORTC/NCI Geneva 2004.

5. Xiong H et al. J Clin Oncol 2004. 6. Kies et al. Proc ASCO 2002.

Surv

ival

(mon

ths)

16

1412

10

86

4

2

0CRC CRC CRC CRC Pancreatic SCCHN

No reaction Grade 2Grade 1 Grade 3

CRYSTAL trial:Study design

Stratification factors:RegionsECOG PS

PopulationsRandomized patients n=1217Safety population n=1202ITT population: n=1198

FOLFIRI

irinotecan (180 mg/m2)+ 5-FU 400 mg/m2 bolus +

2400 mg/m2 as 46-hr continuous infusion)

+ FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1,then 250 mg/m2 weekly

+ irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus +

2400 mg/m2 as 46-hr continuous infusion)

+ FA every 2 weeks

REGFR-expressing

metastatic CRC

Van Cutsem E et al, Proc ASCO 2007

CRYSTAL trial: Primary endpoint PFS met ITT population independent review

Progression-free survival time (months)

PFS

estim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

HR = 0.851; 95% CI = [0.726-0.998]Stratified log-rank p-value = 0.0479

8.9 mo8.0 mo

FOLFIRI, n=599

Cetuximab + FOLFIRI, n=599

1-year PFS rate23% vs 34%

Subjects at riskFOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI

599 499 392 298 196 103 58 29 12 5 1Van Cutsem E et al, Proc ASCO 2007

CRYSTAL trial:Surgery with curative intent

2,5

1,5

6

4,3

0

1

2

3

4

5

6

7

Surgery with curativeintent

No residual tumor afterresection

Per

cent

age

(%)

*CMH test

n=599 / group n=599 / group

p=0.0034*

odds ratio 3.0

[95% CI: 1.4 - 6.5]

FOLFIRI alone Cetuximab + FOLFIRI

4.5

9.8

0

1

2

3

4

5

6

7

8

9

10

Perc

enta

ge (%

)n=134 / n=122

No residual tumor in patientswith liver metastases

ITT population(pre-planned)

Liver metastases only population(exploratory)

Van Cutsem E et al, Proc ASCO 2007

Phase 1–2 studies ongoing / plannedCombination with radiotherapyin rectal cancer

Studies ongoing / plannedAdjuvant treatment

Phase 2 studies show high resection rate of initially unresectable metastases

mCRC: liver metastases

Promising activity in phase 2 studiesFirst-line treatment

Proven activityChemorefractory patients

StatusClinical setting

ChallengesChallenges withwith EGFR EGFR inhibitorsinhibitors in CRC: in CRC: determiningdetermining the best the best treatmenttreatment strategiesstrategies

Tailored Treatment Tailored Treatment

PTEN

IL-8 VEGF

Ki67 p27Bcl-2 BclXl Angiogenesis

Can we find parameters to predict response to EGFR inhibitors?

FOLFOX /Xelox+

bevacizumab¹

FOLFOX /Xelox+

bevacizumab¹

FOLFIRI +bevacizumab¹

FOLFIRI +bevacizumab¹

No prioradjuvant therapy

Treatment Algorithm for Metastatic CRC

FOLFOX / Xelox

FOLFOX / Xelox

Irinotecan+ cetuximab

Irinotecan+ cetuximab

FOLFIRIFOLFIRI

FOLFIRIFOLFIRI

FOLFOX / Xelox

FOLFOX / Xelox

Irinotecan+ cetuximab

Irinotecan+ cetuximab

¹ if no cardiovascular contraindications

Capecitabine(5-FU/FA) ±

bevacizumab¹

Capecitabine(5-FU/FA) ±

bevacizumab¹

Individualisation of treatment in metastatic CRC with increasing number of active agents

Individual personal treatment

Tumor

TSTP

P53 MSI

Topo I

…..

Patient

Pharmacogenetic : cytotoxic metabolism

Novel targets: EGFR, VEGF, Cox-2, IGF…

Is progress made in chemotherapy and other treatments options of colon cancer? Yes

The dream ….

The reality ...