Advances in the adjuvant treatment of colorectal cancer Stefano Cascinu Clinica di Oncologia Medica...

Advances in the adjuvant treatment of colorectal cancer

Stefano CascinuClinica di Oncologia Medica

Ancona

COLON CANCER2004

COLON CANCER2004

Estimated New Cases in Europe and Estimated New Cases in Europe and ItalyItaly

DeathDeath

UE: 213.000 110.000UE: 213.000 110.000

I: 32.000 16.000 I: 32.000 16.000

ADJUVANT CT VS CONTROL: AGE < vs > 70 YRS

Sargent 2001

1990 FU/levamisole better than surgery alone

1994 FU/LV better than surgery alone

1996 FU/LV better than FU/levamisole

1996 6 months FU/LV = 12 months FU/LV

1996 Levamisole unnecessary

1996 HD LV = LD LV

1998 Weekly = monthly schedules

2001 Elderly benefit from therapy

ADJUVANT COLON CANCER:ADJUVANT COLON CANCER:

MAIN STEPS FROM 1990 to 2002MAIN STEPS FROM 1990 to 2002

Infusional 5-FU?Intraportal + systemic 5-FU?Oral fluoropyrimidines?Oxaliplatin?Irinotecan

ADJUVANT COLON CANCER :ADJUVANT COLON CANCER :

Questions answered from 2002:

Open questions on Open questions on adjuvant therapy adjuvant therapy

Patient selectionStage CStage B2

Treatment choice

MOSAICMOSAICMOSAICMOSAIC

2246 Patients

Stage III 60%

FOLFOX-4

LV5FU2

RANDOM

André T, NEJM 2004

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

MOSAIC: DFS in stage IIIMOSAIC: DFS in stage IIIMOSAIC: DFS in stage IIIMOSAIC: DFS in stage III

DFS 3-y

FOLFOX4 72.2%

LV5FU2 65.3%

Hazard ratio: 0.76 (0.62 – 0.92)

24% risk reduction for stage III patients

Benefit of Adjuvant CT in stage Benefit of Adjuvant CT in stage IIIIII

Benefit of Adjuvant CT in stage Benefit of Adjuvant CT in stage IIIIII

Bolus 5FU

FOLFOX4

Relative Risk Reduction

40% +24%

Absolute Benefit 13% +7%

Number Needed to Treat

8:1 5:1

N. of Recurrence Saved

1/4 1/2.5

Trial Pts Treatment Data

MOSAIC224

6FOLFOX-4 x 6 mos5FULV2 x 6 mos

3-y DFS4-y DFSSafety

NSABP C-07

2407

FLOX x 6 mos Bolus 5FULV w x 6

mos

3-y DFSSafety

ROCHE NO1696

8

1886

XELOX x 6 mosBolus 5FULV w/q4w x

6 mosSafety

Trials evaluating LOHP in the Trials evaluating LOHP in the adjuvant settingadjuvant setting

Trials evaluating LOHP in the Trials evaluating LOHP in the adjuvant settingadjuvant setting

ROCHE NO16968ROCHE NO16968ROCHE NO16968ROCHE NO16968

1886 Patients

Stage III

XELOX q3w x6 mos

Bolus 5FU/LV qw or q4w x6 mos

RANDOM

Schmoll, PASCO 2005

Grade 3/4 AEs (%) 5FU/LV XELOXFOLFO

X*Diarrhea 17.1 15.6 10.8Stomatitis 7.9 0.6 2.7Nausea 3.9 4.1 5.1Vomiting 2.5 5.0 5.8Neurosensory 0 8.1 12.4HFS 0.2 3.6 2.0Neutropenia 10.9 5.3 41.1Febrile Neutropenia 3.8 0.2 1.8Treatment related Deaths

0.5 0.7 0.5

ROCHE NO16968: SAFETYROCHE NO16968: SAFETYROCHE NO16968: SAFETYROCHE NO16968: SAFETY

* Data from MOSAIC trial

NSABP C-07NSABP C-07NSABP C-07NSABP C-07

2407 Patients

Stage III 71%

FLOXqw x6 mos

FU/LVqw x6 mos

RANDOM

Wolmark N, PASCO 2005

MOSAIC(FOLFOX4)

C-07(FLOX)

3-y DFS 78% 77%

Absolute Benefit

+5% +5%

HR 0.77 0.79

Diarrhea g3-4 11% 36%

Deaths 0.5% 1.2%

NSABP C-07 vs MOSAICNSABP C-07 vs MOSAICNSABP C-07 vs MOSAICNSABP C-07 vs MOSAIC

ADJUVANT CT FOR STAGE III

COLON CANCER TODAY …

ADJUVANT CT FOR STAGE III

COLON CANCER TODAY …

Study Author N Treatment Arms 5-y DFS

GERCORAndrè2003

9055FULV2 x 6-9mFU/LV q4w x 6-9m

67%67%

INT-0153Poplin 2005

9405FU PVI/Lev x 6m FU/LV/Lev q4w x 6m

63%61%

SAFFAChau2005

8015FU PVI x 3mFU/LV q4w x 6m

73%67%

X-ACTTwelves

20051987

Capecitabine x 6mFU/LV q4w x 6m

64%60%

NSABP C-06

Wolmark

20051608

UFT/LV x 6mFU/LV qw x 6m

67%68%

Adjuvant Infusional or Oral Adjuvant Infusional or Oral 5FU 5FU

Adjuvant Infusional or Oral Adjuvant Infusional or Oral 5FU 5FU

Advantages

• Toxicity ( ↓ diarrhea, stomatitis, neutropenia)

• Duration (3 months 5FU PVI)

• Compliance (oral 5FU)

Disadvantages

• Efficacy ( = 5FU/LV)

• CVC complications (infusional 5FU)

• Compliance (oral 5FU)

Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU Adjuvant Infusional or Oral 5FU

Heterogeneous prognosis of stage III

Weakness of FOLFOX

Patients’ characteristics/preferences

Why consider a monotherapy? Why consider a monotherapy?

Prognostic factors for stage IIIPrognostic factors for stage III

T, N, grade

Number of N removed/examined

MSI, TGF-1 RII, 18q LOH

TS, TP, DPD, p53

LDH-5, FLK-1

Gene signature

Known

Unknown

Green FL, Ann Surg 2002

Prognosis of stage III patientsPrognosis of stage III patients

Gill S, J Clin Oncol 2004

5y-DFS of resected colon cancer5y-DFS of resected colon cancer

Weakness of FOLFOXWeakness of FOLFOX

Toxicity

Long term safety

• Neurotoxicity

• Secondary leukemia

Long term efficacy

• 3-y DFS vs 5-y OS

NCI Gr 3 (%) FOLFOX4 LV5FU2

Thrombocytopenia 1.7 0.4

Neutropenia 41.1 4.7

Febrile neutropenia 0.7 0.1

Neutropenic sepsis 1.1 0.1

Diarrhoea 10.8 6.7

Stomatitis 2.7 2.2

Vomiting 5.9 1.4

Allergy 3.0 0.2

Alopecia (Gr 2) 5.0 5.0

All cause mortality 0.5 0.5

MOSAIC: toxicityMOSAIC: toxicity

0

2

4

6

8

10

12

14

Pati

en

ts w

ith

Gra

de 3

Neu

rop

ath

y (

%)

13%

5%

1%0.5%*

During Treatment

28-DayFollow up

6-MonthFollow up

18-MonthFollow up

MOSAIC: Incidence of Grade 3 NeuropathyMOSAIC: Incidence of Grade 3 Neuropathy

Andrè T, NEJM 2004 * 4% grade 2-3

Median DI: 820 mg/sqm

Atypical cumulative neurotoxicity• Rare situation described with cumulative doses > 1000

mg/sqm

• Presentation: Lhermitte’s sign/Urinary retention

• Involvement of dorsal root, spinal cord and parasympathetic

“Coasting” phenomenon• 10-15% of patients symptoms emerge or worsen after

oxaliplatin discontinuation

• This toxicity is not adequately described

• In the MOSAIC 12 patients developed grade 3 sensor

neurotoxicity after the end of treatment

OXALIPLATIN CRHONIC NEUROTOXICITYOXALIPLATIN CRHONIC NEUROTOXICITY

Taleb S, Cancer 2002

Oxaliplatin-Related Acute Myelogenous Leukemia

Oxaliplatin-Related Acute Myelogenous Leukemia

• 56-year-old woman• FOLFOX-4 (12 cycles)• FOLFOX-6 + BV (9 cycles)

• 65-year-old woman• Irinotecan (3 cycles)• FOLFOX-4 (3 cycles)

Merrouche Y, Ann Oncol 2005Carneiro BA, Oncologist 2006

3-y DFS as surrogate of 5-y OS3-y DFS as surrogate of 5-y OS

Sargent D, J Clin Oncol 2005

Analisys of 18 randomized trials (5FU-based)

What does DFS means?What does DFS means?

1) Disease Relapse

2) Death from any cause

3) Second colorectal cancer

4) Second non colorectal cancer

• Sargent: 1+2

• MOSAIC, X-ACT: 1+2+3

• PETACC-3, ACCORD: 1+2+3+4

What does DFS means?What does DFS means?

1) Disease Relapse

2) Death from any cause

3) Second colorectal cancer

4) Second non colorectal cancer

• Sargent: 1+2

• MOSAIC, X-ACT: 1+2+3

• PETACC-3, ACCORD: 1+2+3+4

RFS

Trial TreatmentStag

ePatients

CALGBC89803

IFLBolus 5FU/LV w

III 1246

ACCORD2FOLFIRI5FULV2

III HR

400

PETACC-3FOLFIRI or AIO-

IRI5FULV2 or AIO

III 2111 No benefit in DFS Excessive toxicity with IFL

Trials evaluating IRINOTECAN in Trials evaluating IRINOTECAN in the adjuvant settingthe adjuvant setting

Trials evaluating IRINOTECAN in Trials evaluating IRINOTECAN in the adjuvant settingthe adjuvant setting

Neutropenia Febrile neutropenia Death during treatment

43%

4% 2.8%5%

1% 1%0

10

20

30

40

50

Pat

ien

ts (

%)

P < .00001

P < .0005 P < .008

LV5FU2 + Irinotecan

LV5FU2 alone

Saltz LB, PASCO 2004

CALGB C89803: IFL vs FLCALGB C89803: IFL vs FL

PETACC-3: FOLFIRI-AIOIRI vs FLPETACC-3: FOLFIRI-AIOIRI vs FL

Results Stage III

HR P-value

DFS 0.89 0.091

RFS 0.86 0.045

Van Cutsem E, PASCO 2005

PETACC-3: FOLFIRI-AIOIRI vs FLPETACC-3: FOLFIRI-AIOIRI vs FL

Results Stage III

HR P-value

DFS 0.89 0.091

RFS 0.86 0.045

Risk adjusted for T and N

HR P-value

DFS 0.85 0.021

RFS 0.82 0.009Van Cutsem E, PASCO 2005

PETACC-3 vs MOSAIC: toxicityPETACC-3 vs MOSAIC: toxicity

Grade 3/4 AEs (%) FOLFIRI FOLFOXDiarrhea 11.9 10.8Stomatitis 1.4 2.7Nausea 5.1 5.1Vomiting 5.8 5.8Neurosensory NR 12.4HFS NR 2.0Neutropenia 28.2 41.1Febrile Neutropenia 0.3 1.8Treatment related Deaths

0.3 0.5

Patients preference/attitudesPatients preference/attitudes

www.adjuvantonline.com

5FU basedFOLFOX

Patients preference/attitudesPatients preference/attitudes

Stefano Bollani … … il jazzista che ama divertire la gente …

Gino Castaldo, La Repubblica 2005

Completion of Therapy by Medicare

Patients With Stage III Colon Cancer

Completion of Therapy by Medicare

Patients With Stage III Colon Cancer

3193 stage III colon cancer patients recorded in 1992 –

1996 SEER program

Risk of cancer-related mortality was significantly lower

among those completing chemotherapy (5FU based)

• relative risk = 0.79 (0.69-0.89)

Factors associated with incomplete adjuvant CT

• Physical frailty

• Treatment complications

• Lack of social and psychological support.

Dobie S, JNCI 2006

Relative risks of adjuvant CT completionRelative risks of adjuvant CT completion

Dobie S, JNCI 2006

Age

Marital status

Comorbidities

MOSAIC: pazienti MOSAIC: pazienti anzianianziani

Nessuna differenza tra pazienti con piu’o meno di 65 anni

Author (year)(Ref.)

Number patients

Oxaliplatin/

5FU dose

Neurotoxicity (grade 1-4)

Neurotoxicity (grade 3-4)

Patients younger than 70 yearsDe Gramont (00) (8)

210 85 mg/m2 5FU ci

68% 18%

Andre’ (99) (20)

97 85 mg/m25FU ci

94% 28%

Goldberg (04) (7)

254 85 mg/m2 5FU ci

- 18%

Maindrault (01) (21)

48 130 mg/m25FU ci

97% 11%

Hochster (03) (6)

42 85 mg/m2 5FU bolus

36% 12% 

Ravaioli (03) (5)

45 130 mg/m2 5FU bolus

42% 2.2%

Rothenberg (03) (22)

152 85 mg/m2 5FU ci

51% 5%

Patients older than 70 yearsDe Gramont (00)(8)

43 85 mg/m2 5FU ci

96 21%

Andre (99)(20)

18 85 mg/m2 5FU ci

45% 29%

Aparicio (03)(12)

44 85 mg/m2 5FU ci

- 16%

Adjuvant CT for stage IIIAdjuvant CT for stage III

FOLFOX-4 is the reference treatment

Assessment of long term safety/efficacy is mandatory

Monotherapy could be a reasonable choice considering:

• Risk of recurrence

• Patients characteristics

• Patients preference/attitudes

Ongoing studies for stage IIIOngoing studies for stage III

Study Treatment Arms Duration

AVANTFOLFOXFOLFOX + bevacizumabXELOX + bevacizumab

6 months1 year1 year

NSABP C-08FOLFOXFOLFOX + bevacizumab

6 months1 year

PETACC-8FOLFOXFOLFOX + cetuximab

6 months6 months

INT-0147FOLFOXFOLFOX + cetuximab

6 months6 months

ITALYFOLFOX/XELOXFOLFOX/XELOX

6 months3 months

Stage II patients – to Stage II patients – to

treat ?treat ?

-mf-

COLON CANCERCOLON CANCER20042004

COLON CANCERCOLON CANCER20042004

Estimated New Cases in Europe and ItalyEstimated New Cases in Europe and Italy

N- T 3-4 (15-28%)N- T 3-4 (15-28%)

UE: 213.000UE: 213.000 31.950-59.64031.950-59.640

I: 32.000 4800- 8960I: 32.000 4800- 8960

DeathsDeaths

UE: 110.000 UE: 110.000

I: 16.000I: 16.000

Stage II

CURED 70%CURED 70%

UE: 22.365-41748UE: 22.365-41748

Italy: 3.360-6.272Italy: 3.360-6.272

RELAPSED: 30%RELAPSED: 30%

UE:9.585-17.892UE:9.585-17.892

Italy: 1.440-2.688Italy: 1.440-2.688

AJCC Cancer StagingAJCC Cancer Staging Colorectal Cancer 2002 Colorectal Cancer 2002

81% 77%53-68% 46-61% 27-64% 21-59%

LOW vs HIGH

LOW vs HIGH

LOW vs HIGH

T1-2,N1T3-4,N1any T,N2

IIIAIIIBIIIC

82% 79%74% 70%

LOW vs HIGH

LOW vs HIGH

T3,N0T4,N0

IIAIIB

5yrs DFS (Surgery +CT)

GradingAJCC Stage2002

TNM Stage

Adjuvant chemotherapy for Adjuvant chemotherapy for stage II colon cancerstage II colon cancer

PROS

NSABP metanalysis

GILL (ASCO 2003)

Dutch trial

CONS

IMPACT metanalysis

Seer – Medicare data

INT 0035QUASARQUASAR

CCOPEBC Meta-analysis CCOPEBC Meta-analysis 20042004

4187 pts with stage II colon cancer from 18 RCT

Mortality RR 0.70 (95 % CI = 0.44 – 1.11 p.13)

I.P. 5-FU(5 RCT)

Mortality RR 0.86 (95 % CI = 0.73 – 1.01 p.07)

FU + LEV + FUFA(8 RCT)

Mortality RR 0.90 (95 % CI = 0.71 – 1.13 p.35)

FU + LEV(3 RCT)

Mortality RR 0.87 (95 % CI = 0.75 – 1.01 p.07)Global

Figueredo A, JCO 2004Figueredo A, JCO 2004

ASCO guidelines for stage II ASCO guidelines for stage II colon cancercolon cancer

ASCO guidelines for stage II ASCO guidelines for stage II colon cancercolon cancer

“High risk”

NCDBNCDB35787 pts35787 pts

NCDBNCDB35787 pts35787 pts

1-2 Nodes Neg examined1-2 Nodes Neg examined 5 yrs OS = 64 %5 yrs OS = 64 %1-2 Nodes Neg examined1-2 Nodes Neg examined 5 yrs OS = 64 %5 yrs OS = 64 %

25 Nodes Neg examined25 Nodes Neg examined 5 yrs OS = 86 %5 yrs OS = 86 % 25 Nodes Neg examined25 Nodes Neg examined 5 yrs OS = 86 %5 yrs OS = 86 %

At least At least 1313 to be examined to be examinedAt least At least 1313 to be examined to be examined

• < 6 nodes< 6 nodes• TT44

• PerforationPerforation• GG33

• < 6 nodes< 6 nodes• TT44

• PerforationPerforation• GG33

JCO 2004JCO 2004JCO 2004JCO 2004

Disease Free Survival - Stage II Disease Free Survival - Stage II patientspatients

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50

Hazard ratio [95% CI]: 0.82 [0.57-1.17]Hazard ratio [95% CI]: 0.82 [0.57-1.17]

Probability

DFS (months)

20% risk reduction for stage II patients in the FOLFOX arm

FOLFOX (n=451) 86.6%LV5FU2 (n=448) 83.9%

3-year

HIGH RISK STAGE IIHIGH RISK STAGE II COLON CANCER: COLON CANCER: MOSAIC SUBPOPULATION DATAMOSAIC SUBPOPULATION DATA

HICKISH, ASCO 2004HICKISH, ASCO 2004

On the basis of the MOSAIC results, adjuvant therapy for stage II patients with FOLFOX FOLFOX provides an improvement of 3.8% in 4-provides an improvement of 3.8% in 4-year DFS compared with optimized year DFS compared with optimized (infusional) FU/LV therapy.(infusional) FU/LV therapy.

On the basis of these findings, with an admitted uso OFF Label between-trial extrapolation, the best estimate is that FOLFOX improves DFS by 6% to 7% improves DFS by 6% to 7% compared with surgery alonecompared with surgery alone in patients with stage II disease Grothey and Sargent, JCO

2005

22 novembre 200522 novembre 2005United States Pharmacopeia USPUnited States Pharmacopeia USP

Indica l’impiego del FOLFOX stadio IIIndica l’impiego del FOLFOX stadio IICome trattamento applicabile off-labelCome trattamento applicabile off-label

USP non FDA USP non FDA Ma spesso le assicurazioni rimborsano Ma spesso le assicurazioni rimborsano

sulla base delle sue indicazionisulla base delle sue indicazioni

ProspettivaProspettiva

Individuare i pazienti ad alto rischio per trattare solo quelli.

Ottimizzazione benefici

Riduzione costi

Riduzione tossicità

THE MEDICAL ALGORITHMS PROJECTTHE MEDICAL ALGORITHMS PROJECTWWW.MEDALREG.COM/REGISTRATION/SELECTION.PHPWWW.MEDALREG.COM/REGISTRATION/SELECTION.PHP

CRC : HAZARD RATI O PER GLI STADI I ICRC : HAZARD RATI O PER GLI STADI I I

FATTORE HR 95% CI p

PERITONEO + 2.88 1.7 - 4.9 .0001

INVAS. VENOSA 2.70 1.6 - 4.5 .0001

MARGINE + 2.61 1.4 - 4.8 .002

PERFORAZIONE 9.43 3.3 - 27.0 .0001

CRC : SCORE PER GLI STADI I ICRC : SCORE PER GLI STADI I I

FATTORE STATO PUNTI

PERITONEO + SI 1 NO 0

INVAS. VENOSA SI 1 NO 0

MARGINE + SI 1 NO 0

PERFORAZIONE SI 2 NO 0

CRC : I NDI CE PROGNOSTI CO PER GLI STADI I ICRC : I NDI CE PROGNOSTI CO PER GLI STADI I I

SCORE 5 YRS OS 95% CI

0 94% 85- 98

1 79% 70- 86

2 54% 40- 66

3- 5 30% 8- 57

Prognostic factorsPrognostic factors

COX COX MultivariateMultivariate AnalysisAnalysis ( 74 ( 74 ptspts ))

0,980.34,2.840,99Tumor size

0,980.25,6.081,22Grade

0,270.60,6.321,94T stage

0,610.95,1.030.99Age

P value95% CIHRFactor

0,980.34,2.840,99Tumor size

0,980.25,6.081,22Grade

0,270.60,6.321,94T stage

0,610.95,1.030.99Age

P value95% CIHRFactor

23- gene signature 0,17 0.06,0.51 0,001

Nucleus

Antireceptor Antibodies

± Toxins

Tyrosine Kinase Inhibitors

Hormone Agonists/ Antagonists

Farnesyl Transferase

Inhibitors

Apoptosis Agonists

Antisense

Angiogenesis Inhibitors (Angiostatin, Endostatin

& Anti-VEGF)

Metalloproteinase Inhibitors

Matrix Degradation(Collagenases,Gelatinases &Stromelysins)

Immune System Activation (Vaccines, Monoclonal antibodies)

Tumor Cell

Growth Factor Receptors

Intracellular Signaling Molecules

AntimetabolitesMicrotubule inhibitors

Targeted Therapies

Select studies of angiogenic factors and Select studies of angiogenic factors and their role in colon cancer progression and their role in colon cancer progression and

metastasismetastasisFACTOR N° K-PZ. ASSOCIATIONS STUDY

Angiogenin 65 MVD Etoh (200)

Angiomodulin 89 Poor prognosis Adachi (2001)

Interleukine-10 53 Poor prognosis Kawakami (2001)

PD-ECGF 96 Thrombospondin expr less MVD Takahashi (1996)

Thrombospondin-1 150 MVD, PD-ECGF in infiltrat. cells Maeda (2001)

Thrombospondin-2 61 Smaller MVD, fewer hepatic recurr. Tokunaga (1999)

UPAR 44 Fewer liver metast., better prognosis Nakata (1998)

VEGF 614 VEGF, vessel count Werther (2000)

VEGF 121 Poor prognosis Cascinu (2000)

VEGF 145+30 polyps

Poor prognosis Lee (2000)

VEGF 52 MVD, VEGFR-2 positivity metastas. Takahashi (1995)

VEGF 28 MVD, survival in node-negative Pz. Takahashi (1997)

MVD= microvessel density; PD-ECGF= plateled-derived endothelial cell growth factor; uPAR= urokinase-like plasminogen activator receptor; VEGF= vascular endothelial growth factor; VEGFR-2= vascular endothelial growth factor receptor 2.

Espressione del VEGF nella Espressione del VEGF nella neoplasia primitivaneoplasia primitiva

0 20 40 60 80

Follow-up (months)

% S

urvi

val

High VEGF

Low VEGF

P=0.0003

Takahashsi et al Arch surg 1997

Cascinu S, et al. Clin Cancer Res, 2000

Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)Hazard ratio = 0.66 (95% CI: 0.54–0.81)p<0.001

Pro

bab

ilit

y o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + bevacizumab

IFL + placebo

15.6 20.3

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

Phase III trial of IFL ± Phase III trial of IFL ± bevacizumab bevacizumab in metastatic CRC (AVF2107g): in metastatic CRC (AVF2107g): survivalsurvival

CI = confidence interval

Planned phase III trials of bevacizumab in adjuvant CRC

Trial n Cancer Treatment

NSABP C-08 2,500 Colon FOLFOX ± bevacizumab

BO17920 3,450 Colon FOLFOX vs FOLFOX + bevacizumab vs CapeOx + bevacizumab

QUASAR 2 3,750 CRC Capecitabine vs CapeIRI vs CapeIRI + bevacizumab

E5205 3,125 CRC FOLFOX-6 ± bevacizumab

CapeOx = capecitabine + oxaliplatinCapeIRI = capecitabine + irinotecan

BO17920 study design Randomised, open-label study

Primary endpoint: disease-free survivalSecondary endpoints: safety, overall survival350 centres in 36 countries

Duration of treatment phases 24 weeks 24 weeks

Bevacizumab alone(7.5mg/kg every

3 weeks)

Bevacizumab alone(7.5mg/kg every

3 weeks)

ObservationObservation

Bevacizumab alone(7.5mg/kg every

3 weeks)

Bevacizumab alone(7.5mg/kg every

3 weeks)

FOLFOX-4FOLFOX-4

FOLFOX-4 + bevacizumab(5mg/kg every

2 weeks)

FOLFOX-4 + bevacizumab(5mg/kg every

2 weeks)

XELOX + bevacizumab (7.5mg/kg every

3 weeks)

XELOX + bevacizumab (7.5mg/kg every

3 weeks)

Surgery for stage II + stage III colon cancer

(n=3,450)

Surgery for stage II + stage III colon cancer

(n=3,450)

FOLFOX6 + bevacizumab

5mg/kg every 2 weeks

Duration of treatment 24 weeks

Dukes’ C colon

cancer (n=2,500)

Observation

Bevacizumab 5mg/kg every 2

weeks

FOLFOX6 + placebo

24 weeks

Randomised, phase III trial of adjuvant bevacizumab plus FOLFOX6 (NSABP-C08): study design

AVF2107g: possiblebevacizumab-related toxicity

NB: not adjusted for different time on therapy

Patients (%)

IFL + placebo (n=397)

IFL + bevacizumab (n=393)

Bleeding Grade 3/4

2.5

3.1

Any thromboembolic event Arterial Venous

16.2 1.0

15.2

19.4 3.3

16.1

Deep thrombophlebitis Grade 3

6.3

8.9

Pulmonary embolus Grade 4

5.1

3.6

Any hypertension Grade 3

8.3 2.3

22.4 11.0

Any proteinuria Grade 2 Grade 3

21.7 5.8 0.8

26.5 3.1 0.8

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

Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery

ComplicationIFL/placebo(n=155) (%)

IFL/bevacizumab (n=150) n (%)

5-FU/LV/bevacizumab(n=37) (%)

Abscess 0 0 0

Perforatedlarge intestine

0 1 (0.67) 0

Perforated stomach ulcer

0 1 (0.67) 0

All types (total)

0 2 (1.3) 0Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530

Wound healing complications

Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery

(cont’d)

Haemorrhage

IFL/placebo (n=155)

n (%)

IFL/bevacizumab(n=150)

n (%)

5-FU/LV/bevacizumab(n=37) (%)

GI 1 (0.65) 0 0

Rectal 0 1 (0.67) 0

All types 1 (0.65) 1 (0.67) 0

Bleeding complications

Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3530

EGFR-targeting therapies

Tyrosine kinase inhibitors(gefitinib, erlotinib, CI-1033,

EKB-569, AEE788, GW572016, PKI-166)

Monoclonalantibodies

(cetuximab, ABX-EGF, EMD 72000, h-R3, MDX-447)

Signal Transduction

Ligands

R R

K K

Salomon (1995); Chow (1997)31-48%Bladder

Salomon (1995); Watanabe (1996);Rieske (1998)

40-63% Glioma

Bartlett (1996); Fischer-Colbrie (1997)35-70% Ovarian

Klijn (1992); Beckman (1996); Bucci (1997); Walker (1999)

14-91% Breast

Salomon (1995); Yoshida (1997)50-90% Renal Carcinoma

Fujino (1996); Rusch (1997);Fontanini (1998)

40-80% NSCLC

Salomon (1995); Uegaki (1997)Abbruzzese (2001)

30-95% 95%

PancreaticAdvanced Stage

Salomon (1995); Grandis (1996)80-100%Head and Neck

Salomon (1995); Messa (1998)Goldstein (2001); Cunningham (2003)

25-77% 75-82%

ColorectalColorectal – Advanced stage

References% EGFR (range)Tumor Type

EGFR Expression in Human Tumors

EGFR as a prognostic factor

EGFR expression mostly correlates with poor prognosis, EGFR expression mostly correlates with poor prognosis, decreased survival and/or increased metastasisdecreased survival and/or increased metastasis

EGFR expression also linked to reduced response, and/or EGFR expression also linked to reduced response, and/or increased resistance, to chemotherapyincreased resistance, to chemotherapy

Tumor Tumor typetype

PrognosiPrognosiss

SurvivalSurvivalRisk of Risk of

metastasmetastasisis

ReferencesReferences

ColorectalColorectal PoorPoor --IncreasIncreas

ededHemming Hemming

(1992)(1992)

Lung Lung (NSCLC)(NSCLC)

PoorPoorPoorPoor

Decreased Decreased OSOS--

--IncreasIncreas

eded

Ohsaki Ohsaki (2000)(2000)Pavelic Pavelic (1993)(1993)

Head & Head & Neck Neck (SCCHN)(SCCHN)

PoorPoor

Decreased Decreased DFSDFS

Decreased Decreased OSOS

--

Grandis Grandis (1998)(1998)Maurizi Maurizi (1996)(1996)

BOND study: grade 3/4 BOND study: grade 3/4 toxicitiestoxicities

Combination

Monotherapy

Diarrhea 45 (21%) * 2 (2%) Asthenia 29 (14%) 12 (10%) Neutropenia 20 (10%) * 0 (0%) Acneiform

rash20 (9%) 6 (5%)

Toxic effects were more frequent with the combination

Severity and incidence were similar to those expected with irinotecan alone

Cunningham D et al. NEJM 2004* p<0.001

Surgery for stage II + stage III colon

cancer ?

RANDOMIZATION

………….+ cetuximab

folfox

Cetuximab in adjuvant trials

EGFR status?