neoplasie del colon-retto

Neoplasie del Colon-retto

The therapeutic spectrum in adjuvant colon cancer and neoadjuvant rectal

cancer: Chair’s welcome

Alberto SobreroOspedale San Martino

Genoa, Italy

Adjuvant chemotherapy of colon cancer: steps ahead

1990 1991 20041992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

5-FU/LEV

5-FU/LV

6 months Elderly as well

Stage II

XelodaFOLFOX

Neoadjuvant chemoradiation:treating early to optimize outcomes

Neoadjuvant chemoradiation improves1

– downstaging

– surgical resection

– sphincter-sparing surgery

1Bosset JF et al. J Clin Oncol 2005;23:5620–7

“It’s time we pay more, not less, attention to the concept of cure and give our patients the benefit of the doubt”

De Vita, Nature Clin Pract, Feb 2006

New treatments, new hope

Evolving choices in adjuvantcolon cancer

Joe McKendrickBox Hill Hospital, Box Hill, Victoria, Australia

Adjuvant chemotherapyfor colon cancer

Colon cancer

– common

– increasing

– costly

Adjuvant therapy reduces burden of disease

Advances in the adjuvant treatment of stage III CRC

3-year overall survival (%)100

80

60

401980 1985 1990 1995 2000 2005

Surgery alone

Efficacy of adjuvant chemotherapyin colon cancer widely accepted

1990 Intergroup study1

– 5-FU/levamisole improves survival in surgically resected stage III colon cancer

– 16% absolute reduction in risk of death

Efficacy of adjuvant chemotherapy in stage III colon cancer widely accepted by early 1990s

Adoption of adjuvant therapy slow and not universal

Toxicity a significant issue

Conflicting opinion about stage II disease1Moertel CG et al. N Engl J Med 1990;322:352–8

5-FU-based adjuvant chemotherapy:early modifications and improvements

NSABP C-03,1 IMPACT,2 INT0089,3 NSABP C-04,4 QUASAR5

– no advantage gained by adding levamisole to 5-FU/LV

– low dose leucovorin (LV) is adequate

– 6 months’ therapy as good as 12 months’ therapy

– weekly therapy equivalent to monthly

1Wolmark N et al. J Clin Oncol 1993;11:1879–87; 2IMPACT investigators. Lancet 1995;345:939–443Haller DG et al. J Clin Oncol 2005;23:8671–8; 4Wolmark N et al. J Clin Oncol 1999;17:3553–9

5QUASAR Collaborative Group. Lancet 2000;355:1588–96

Roswell Park regimen: equivalent efficacy with distinct safety profiles

No improvement in DFS or OS with Roswell Park versus Mayo Clinic regimen1

For Mayo Clinic, major toxicity is myelosuppression2

For Roswell Park, major toxicity is diarrhea3

Need to improve safety of 5-FU-based therapy

1Haller DG et al. J Clin Oncol 2005;23:8671–82Haydon A. Intern Med J 2003;33:119–24

3Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)

Similar efficacy with infused 5-FU/LV versus bolus

Disease-free survival: stage III

0 0.5 1.0 1.5 2.0 2.5 2.8

Hazard ratio = 1.2795% CI (0.87–1.86)Log-rank p=0.21

1.0

0.8

0.6

0.4

Probability

Years

Hazard ratio = 1.02595% CI (0.78–1.35)Log-rank p=0.86

Overall survival: stage III

Years

André T et al. J Clin Oncol 2003;21:2896–903

0 0.5 1.0 1.5 2.0 2.5 2.8

Mayo (n=256)

LV5FU2 (n=257)

Better toxicity profile withLV5FU2 versus Mayo

Grade 3 / 4 adverse events (% of patients)

LV5FU2 (n=452)

Bolus 5-FU/LV (n=453)

Neutropenia 7 16

Diarrhea 4 9

Mucositis 2 7

Nausea / vomiting* 1 3

All toxicities 11 26

*Not significant André T et al. J Clin Oncol 2003;21:2896–903

Issues with central venous catheters

Additional costs

Inconvenient for patients

Need for invasive surgical procedure

– possible complications include infections,bleeding, pneumothorax, deep-vein thrombosisand pulmonary embolism1,2

– varying level of risk (7–20%) but base rate of complications unavoidable regardless of center/experience3

1Kuter DJ. Oncologist 2004;9:207–162Verso M et al. J Clin Oncol 2003;21:3665–75

3Sobrero A and Sciallero S. Ann Oncol 2005;16:521–2

Xeloda is established in MCRC and should simplify complex adjuvant treatments

Xeloda is effective and well tolerated in MCRC

– can replace 5-FU as monotherapy and in combination regimens

– convenient home-based oral therapy

Potential to translate these advantages into adjuvant setting

Benefit of adjuvant therapy forstage II patients not always clear

Relatively few stage II patients have been randomized

Lower risk of recurrence

Contradictory meta-analyses

– IMPACT meta-analysis concluded no advantagein 1 025 patients1

– NSABP pooled data analysis showed improvedevent-free and overall survival in 1 565 patients2

1IMPACT. J Clin Oncol 1999;17:1356–632Mamounas E et al. J Clin Oncol 1999;17:1349–55

QUASAR: adjuvant chemotherapy significantly reduces recurrence in stage II

Chemotherapy 78.0Observation 73.8

Hazard ratio = 0.78(95% CI: 0.67–0.91)

p=0.001

5-year RFS (%)

Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9 10

Years

Relapse-free survival (%)

QUASAR: adjuvant chemotherapy improves overall survival in stage II

Years

Gray RG et al. J Clin Oncol 2004;23:245s (Abst 3501)

ChemotherapyObservationp=0.04

100

80

60

40

20

00 1 2 3 4 5 6 7 8 9 10

Survival (%)

Dutch trial of 5-FU/LEV suggested improved OS for stage II

Taal B et al. Br J Cancer 2001;85:1437–43

100

80

60

40

20

00 1 2 3 4 5 6

5-FU/LEV (n=233)

Control (n=235)

Years

Overall survival (%)

Should high-risk stage II patientsbe offered adjuvant chemotherapy?

Some high-risk patients may benefit from adjuvant chemotherapy1

– obstruction or perforation

– venous or lymphatic invasion

– perineural invasion

– tumor adherence

Better prognostic factors could aid in patient selection

– Biomarker data collection incorporated in most ongoing studies

1NCCN Clinical Practice Guidelines in Oncology v.2.2004

Patients who could benefit are still denied adjuvant therapy

Indication of benefit of adjuvant therapy in stage II1–5

– small but significant benefit of chemotherapy

High-risk stage II patients may benefit as much as some stage III patients

Older patients and some minorities less likely to receive chemotherapy6,7

– toxicity concerns

1Gray RG et al. J Clin Oncol 2004;22:245s (Abst 3501)2Taal BG et al. Br J Cancer 2001;85:1437–43; 3IMPACT. J Clin Oncol 1999;17:1356–63

4Gill S et al. J Clin Oncol 2004;22:1797–806; 5Figueredo A et al. J Clin Oncol 2004;22:3395–4076Sargent DJ et al. N Engl J Med 2001;345:1091–7

7Grothey A et al. Proc Am Soc Clin Oncol 2002;21:129a (Abst 512)

Factors that may influence treatment decisions with adjuvant chemotherapy

Benefit torisk ratioBenefit torisk ratio

Healthcareproviders

Healthcareproviders

Treatment costsTreatment costs Resourceuse

Resourceuse

PatientsPatientsImpact onlifestyle

Impact onlifestyle

ConvenienceConvenience

TreatmentoutcomesTreatmentoutcomes

EfficacyEfficacy ToxicityToxicity

Patientcharacteristics

Patientcharacteristics

AgeAgeDisease

stageDisease

stage

PreferencePreference

Comorbiditiese.g. diabetes, impaired

cardiac function

Comorbiditiese.g. diabetes, impaired

cardiac function

BiomarkersBiomarkers

Redefining adjuvant therapies

Improve efficacy with new agents

Reduce toxicity

Prospective identification of high-risk stage II patients

Tailor to ensure all patients can benefit

– effective, well-tolerated, convenient therapy

With Xeloda’s approval, the need for an effective, well-tolerated, convenient and cost-effective therapy may be addressed

The next level in adjuvant treatment: new chemotherapy combinations

Alberto SobreroOspedale San Martino

Genoa, Italy

Combinations in adjuvant chemotherapy: recent evidence

1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)2Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500); 3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500)

4Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8); 5Ychou M et al. Proc ASCO 2005 (Abst 3502)

NR = not reported

DFS

hazard ratio

p value OS

hazard ratio

p value

MOSAIC 0.77 <0.001 0.91 NR

NSABP C-072 0.79 <0.004 NR NR

Oxaliplatin combinations

Irinotecan combinations

3CALGB89803 NR 0.80 NR 0.81

PETACC-34 0.89 0.091 NR NR

ACCORD25 1.19 0.22 NR NR

1

MOSAIC: superior DFS withFOLFOX versus LV5FU2 in stage III

Months

FOLFOX4 (n=672) 72.2%

LV5FU2 (n=675) 65.3%

3-year DFS

Estimated probability

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60

André T et al. N Engl J Med 2004;350:2343–51

Hazard ratio (95% CI) 0.76 (0.62–0.92)

NSABP C-07: superior DFS with FLOX versus 5-FU/LV in stage III

Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500)

Estimated probability1.0

0.9

0.8

0.7

0.6

0.50 1 2 3 4

Years

FLOX (n=272)

76.5%5-FU/LV (n=332)

71.6%

Hazard ratio (95% CI)0.79 (0.67–0.93)

p<0.004

3-year DFS

The strength of MOSAIC: clinically relevant absolute benefit is increasing

4-year DFS (%)1 3-year DFS (%)2

II and III 6.8* 5.1*

III N1 7.0 –

III N2 12 –

III 8.7* 6.3*

II 3.8 2.7

High-risk stage II 5.4 5.1

1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501)2André T et al. N Engl J Med 2004;350:2343–51*p<0.05

FLOX vs FOLFOX: no difference in DFS

NSABP C-07 MOSAIC

3-year DFS (%) 76.5 78.2

Hazard ratio 0.79 0.77

Difference 4.9 5.1

FOLFOX versus LV5FU2: grade 3/4 adverse events

†

*12% grade 4†Not reported

Neutro

penia

Throm

bo-

cyto

penia

Diarrh

ea

Vomiti

ng

Neuro

pathy

(sen

sory

)

Nause

a

Allerg

ic

reac

tion

Febril

e

neutro

penia

FOLFOX4 (n=1 108)

LV5FU2 (n=1 111)

Patients (%)

*

André T et al. N Engl J Med 2004;350:2343–51

45

40

15

10

5

0

Irinotecan has significant benefitsin MCRC

Regimen N PR PFS OS Author

Douillard/AIO + Irinotecan

338 23%35%

4.46.7

14.117.4

Douillard Lancet 2000

FL (Saltz) + Irinotecan

440 21%39%

4.37.0

12.614.8

SaltzNEJM 2000

AIO + Irinotecan

430 34%62%

6.48.5

16.920.1

KöhneJCO 2005

CALGB89803: DFS not improvedwith IFL in stage III colon cancer

1.0

0.8

0.6

0.4

0.2

0.0

Proportion disease free

0 12 24 36 48 60Months

p=0.80

5-FU/LV (Roswell Park regimen)IFL

Saltz L et al. J Clin Oncol Proc ASCO 2004;22:14S (Abst 3500)

PETACC-3: DFS not significantly improved with FOLFIRI in stage III

Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8)

1.0

0.9

0.8

0.7

0.6

0.5

0.0

Estimated probability

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48Months

FOLFIRI (n=1 044) 63.35-FU/LV (n=1 050) 60.3

Hazard ratio (95% CI)0.89 (0.77–1.11)

p=0.091

3-year DFS

ACCORD2: DFS not improved with FOLFIRI in high-risk colon cancer

Ychou M et al. J Clin Oncol 2005;23 (Abst 3502)

Estimated probability1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5 6

LV5FU2

60%FOLFIRI

51%

Hazard ratio (95% CI)1.19 (0.90–1.59)

p=0.22

3-year DFS

Years

Xeloda has the potential to replace5-FU in adjuvant combinations

Xeloda is at least as effective as 5-FU/LV with

– significantly superior relapse-free survival

– trends to improved disease-free and overall survival

– consistent benefits in all efficacy endpoints

XELOX has similar high efficacy and favorable safety profile compared with FOLFOX in metastatic CRC

Xeloda is the optimal fluoropyrimidine partner to simplify complex combination regimens

XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) versus 5-FU / LV

1º endpoint: DFS – XELOX >5-FU/LV – minimal absolute difference targeted: 6%

2º endpoints: survival, tolerability, convenience, pharmacoeconomics

Recruitment completed: September 2004

XELOX 24 weeks

Bolus 5-FU/LV Mayo Clinic

or Roswell Park

24 or 32 weeks

Chemotherapy-naïve, stage III

colon cancer n=1 886

XELOX is an ideal combination in the adjuvant setting

1Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)

XELOXA1

Grade 3/4 toxicities XELOX 5-FU/LV

Diarrhea 19 20

Stomatitis <1 8

Nausea 5 4

Vomiting 6 3

Neurosensory 11 0

HFS 5 <1

Neutropenia 8 15

Febrile neutropenia <1 4

XELOX is an ideal combination in the adjuvant setting

1Schmoll H-J et al. Proc ASCO GI 2006 (Abst 278)2André T et al. N Engl J Med 2004;350:2343–51

3Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update)

XELOXA1 MOSAIC2 NSABP C-073 Grade 3/4 toxicities 5-FU/LV FOLFOX FLOX

Diarrhea 20 12 36

8 3 NR

Nausea 4 5 15

Vomiting 3 6 12

Neurosensory 0 12 8

HFS <1 2 NR

Neutropenia 15 41 5

Febrile neutropenia 4 2 NR

XELOX

19

<1

5

6

11

5

8

<1

Stomatitis

UK QUASAR2: adjuvant Xeloda± Avastin

1º endpoint: DFS– minimal absolute difference targeted: 6%

2º endpoints: 5-year overall survival, safety, health economics Recruitment opened 2005

Xeloda 8 cycles (24 weeks)

Xeloda8 cycles (24 weeks)

Avastin 7.5mg/kg

16 cycles (48 weeks)

Stage II / IIIcolon cancer

n=3 510

AVANT: adjuvant FOLFOXvs XELOX ± Avastin

1º endpoint: DFS– minimal absolute difference targeted: 5.3%

2º endpoints include: overall survival and tolerability Started Q4 2004

XELOX plus

Avastin

FOLFOX

Chemotherapy-naïve,stage II / III

colon cancer n=3 450

FOLFOXplus

Avastin

Xeloda provides added advantagesin adjuvant combination regimens

Xeloda should be preferred to i.v. 5-FU/LV

– consistent efficacy benefits in stage III colon cancer

– more convenient for patient and physician

– reduces hospitalizations for adverse events

– cost-saving for most healthcare systems

Adjuvant XELOX has a favorable safety profile with less neutropenia than FOLFOX

Xeloda is an ideal backbone for future development

Landmark trials: adjuvantXeloda-based combinations

2004 2005 2006 2007 2008 2009 2010 2011

XELOXA final safety

XELOXA 1° efficacy

XELOXA survival follow-up

QUASAR2 last follow-up planned

AVANT 1° efficacy

AVANT survival follow-up

Avastin® therapy: the essential basis of first-line treatment regimens

Bruce GiantonioAbramson Cancer Center, The University of Pennsylvania,

Philadelphia, USA

Mode of action suggests Avastin can be combined with all first-line chemotherapy

Avastin’s unique mechanism of action is potentially exploited best when used with chemotherapy, but

– it shouldn’t be dependent upon any particular chemotherapy regimen

Efficacy data indicate that the magnitude of benefit achieved with Avastin is greatest when used with first-line chemotherapy

Clinically and statistically significant survival benefit is seen despite modest improvements in response rates

Treatment of metastatic CRC

CRC = colorectal cancer; IFL = irinotecan, 5-fluorouracil (5-FU)/leucovorin (LV); FOLFIRI = 5-FU/LV + irinotecan; XELIRI = Xeloda® + irinotecan; FOLFOX = 5-FU/LV + oxaliplatin; XELOX = Xeloda + oxaliplatin; BSC = best supportive care

Metastatic CRC

IFL/FOLFIRI/XELIRI

5-FU or Xeloda FOLFOX or XELOX

Irinotecan +cetuximab

FOLFOX BSC/FOLFOX/FOLFIRI

FOLFIRI 5-FU/LV

First-line

Second-line

Phase III trial of IFL ± Avastin (AVF2107g): survival

Median survivalIFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Avastin: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001

Pro

bab

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y o

f su

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al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Time (months)

IFL + Avastin

IFL + placebo

15.6 20.3

Hurwitz H, et al. N Engl J Med 2004;350:2335–42CI = confidence interval; HR = hazard ratio

Phase III trial of IFL ± Avastin: progression-free survival

Median progression-free survivalIFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + Avastin: 10.6 (95% CI: 9.0–11.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001

Pro

bab

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f b

ein

g

pro

gre

ssio

n-f

ree

1.0

0.8

0.6

0.4

0.2

00 10 20 30

Progression-free survival (months)

6.2 10.6

IFL + Avastin

IFL + placebo

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

Use of Avastin with FOLFIRI-based therapy

Avastin has proven efficacy in combination with IFL

Studies of IFL and FOLFIRI regimens suggest improved safety and comparable, if not superior, efficacy of FOLFIRI

Based on what we know, it is expected that Avastin will enhance efficacy when combined with FOLFIRI

Phase II trial of Avastin plus FOLFIRI: preliminary efficacy and safety results

Avastin plus FOLFIRI appears to be well tolerated with comparable efficacy1

It is expected that progression-free survival will surpass the 8.5 month median progression-free survival reported for FOLFIRI alone2 and be at least equivalent to the 10.6 months reported for IFL plus Avastin3

Incidence of adverse events is lower than that reported with IFL plus Avastin – no grade 3/4 diarrhoea versus 32%1

1Hoff PM, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 252. Available at http://www.asco.org. Accessed 28 February 2006

2Tournigand C, et al. J Clin Oncol 2004;22:229–37 3Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Phase IV trial of Avastin plus irinotecan (AVIRI): study design

Primary endpoint: progression-free survival

Secondary endpoints: overall survival, overall response rate, duration of response and safety

Data available: 2006

Patients with previously untreated

metastatic CRC (n=202)

Avastin 5mg/kg every 2 weeks + FOLFIRI

Planned trial of Avastin plus FOLFIRI/ XELIRI: ACCORD 13 (MEXICO)

Primary endpoint: progression-free survival Secondary endpoints: overall survival, overall response rate,

duration of response and safety

Patients with untreated

metastatic CRC(n=140)

Avastin 5mg/kg every

2 weeks + FOLFIRI

Avastin 7.5mg/kg every

3 weeks + XELIRI

Duration of treatment 24 weeks

Avastin 7.5mg/kg

every 3 weeks

Avastin 7.5mg/kg

every 3 weeks

PD

PD

PD = progression of disease

Avastin can be combined with IFL/FOLFIRI/XELIRI-based therapy

Metastatic CRC

IFL/FOLFIRI/XELIRI

5-FU or Xeloda FOLFOX or XELOX

Irinotecan +cetuximab

FOLFOX BSC/FOLFOX/FOLFIRI

FOLFIRI 5-FU/LV

First-line

Second-line

Combined analysis of Avastin plus 5-FU-based regimens: overall survival

Su

rviv

al (

%)

100

80

60

40

20

00 10 20 30 40

Time (months)

Median survival: 14.6 vs 17.9 monthsHR=0.74, p=0.0081

5-FU/LV/Avastin 5mg/kg

5-FU/LV or IFL

14.6 17.9

Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12

Combined analysis of Avastin plus 5-FU-based regimens: progression-free survival

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

100

80

60

40

20

00 10 20 30

Time (months)

Median progression-free survival: 5.6 vs 8.8 monthsHR=0.63, p=0.0001

5-FU/LV/Avastin 5mg/kg

5-FU/LV or IFL

5.6 8.8

Kabbinavar FF, et al. J Clin Oncol 2005;23:3706–12

Xeloda in metastatic CRC: significantly superior response rate versus bolus 5-FU/LV

Xeloda (n=603)

Bolus 5-FU/LV (n=604)

p value

Response rate (%) 26 17 <0.0002

Time to progression (months) 4.6 4.7 0.9535

Overall survival (months) 12.9 12.8 0.48

Van Cutsem E, et al. Br J Cancer 2004;90:1190–7

The efficacy of Xeloda versus bolus 5-FU/LV was similar to infusional 5-FU/LV versus bolus 5-FU/LV

Preclinical evidence for the use of Avastin with Xeloda-based therapy

Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45 (Abstract 2203)*Sub-maximum effective doses

Combining Avastin and Xeloda resulted in a greater duration of tumour inhibition than with either agent alone

Mea

n t

um

ou

r vo

lum

e (m

m3 )

2,000

1,750

1,500

1,250

1,000

750

500

250

0

Control

Avastin*

Xeloda*

Avastin* + Xeloda*

0 7 14 21 28 35 42 49 56 63Day

Ongoing/planned trials of Xeloda plus Avastin in first-line metastatic CRC

MAX (ML18513); randomised phase II/III trial (n=333) – patients with previously untreated metastatic CRC will be

randomised to receive one of three regimens until disease progression• Xeloda• Avastin 7.5mg/kg every 3 weeks plus Xeloda• Avastin 7.5mg/kg every 3 weeks plus Xeloda plus mitomycin C

Several other trials of Avastin plus Xeloda are planned, including– ML18524, open label study comparing the effect of three

chemotherapy regimens (n=300) – ML18799, phase II trial (n=80)– ML19823, phase II trial in elderly patients (n=60)

Avastin can be combined with 5-FU/LV- or Xeloda-based therapy

Metastatic CRC

IFL/FOLFIRI/XELIRI

5-FU or Xeloda FOLFOX or XELOX

Irinotecan +cetuximab

FOLFOX BSC/FOLFOX/FOLFIRI

FOLFIRI 5-FU/LV

First-line

Second-line

Phase III trial of Avastin plus FOLFOX in second line (E3200): overall survival

Pro

bab

ility

of

surv

ival

1.0

0.8

0.6

0.4

0.2

0

Time (months)AliveDead MedianTotal

A: FOLFOX4 + Avastin 289 246 43 12.9

B: FOLFOX4 290 257 33 10.8C: Avastin 243 216 27 10.2

HR=0.76

A vs B: p=0.0018

B vs C: p=0.95

Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

10.2 12.9

10.8

0 3 6 9 12 15 18 21 24 27 30 33 36

Phase III trial of Avastin plus FOLFOX in second line (E3200): progression-free survival

Pro

bab

ility

of

bei

ng

p

rog

ress

ion

-fre

e

1.0

0.8

0.6

0.4

0.2

0

Progression-free survival (months)0 2 4 6 8 10 12 14 16 18 20

CensFail MedianTotal273 228 45 7.2

273 241 32 4.8229 215 14 2.7

A: FOLFOX4 + Avastin

B: FOLFOX4C: Avastin

HR=0.64

A vs B: p<0.0001

B vs C: p<0.0001

2.7 7.24.8

Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine (TREE-2): study design

First-line metastatic CRC (n=223)

mFOLFOX6 + Avastin5mg/kg every 2 weeks

(n=75)

XELOX + Avastin7.5mg/kg every 3 weeks

(n=74)

bFOL + Avastin 5mg/kg every 2 weeks

(n=74)

PD

PD

PD

Primary endpoint: grade 3/4 toxicity Secondary endpoints include overall response rate, time to

progression and overall survival

Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at

http://www.asco.org. Accessed 28 February 2006mFOLFOX = modified FOLFOXbFOL = bolus 5-FU/LV + oxaliplatin

Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: overall response rate

0

10

20

30

40

50

60 TREE-1(without Avastin)1

TREE-2(with Avastin)2

Res

po

nse

rat

e (%

)

mFOLFOX6 bFOL XELOX

46.9

32.0

37.5

52.1

34.3

45.8

Regimen*

*Avastin is added to eachof the regimens in TREE-2

1Hochster HS, et al. J Clin Oncol 2005;23(June 1 Suppl.):249s (Abstract 3515)2Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium;

26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

Phase II trial of Avastin with oxaliplatin/ fluoropyrimidine: time to tumour progression

Pro

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pro

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ree

XELOX + Avastin

FOLFOX + Avastin

bFOL + Avastin

1.0

0.8

0.6

0.4

0.2

0

Time (months)0 5 10 15 20

Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

Phase II trial of Avastin with oxaliplatin/fluoropyrimidine: toxicity

40

30

20

10

0 Neutropenia Febrile Vomiting Dehydration Diarrhoea Grade 3 Bleeding Thrombo- neutropenia neurotoxicity embolic event

mFOLFOX6 + Avastin

bFOL + Avastin

XELOX + Avastin

Ove

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4 to

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ties

Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

Phase II trial of Avastin with three oxaliplatin/ fluoropyrimidine regimens: conclusion

Avastin given in combination with each of three oxaliplatin-fluoropyrimidine regimens is effective

and well tolerated

Hochster HS, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract 244. Available at http://www.asco.org. Accessed 28 February 2006

Phase II trial of XELOX plus Avastin (XELOX-A): study design

Primary endpoint: response rate

Secondary endpoints: safety and tolerability, time to progression, disease-free and overall survival

Exclusion criteria include: unstable or poorly controlled hypertension, arterial or venous thrombosis within the last 3 months, coagulopathy and anticoagulation therapy

Xeloda 1,000mg/m2 b.i.d. days 1–5 and days 8–12, every 2 weeks

oxaliplatin 85mg/m2 every 2 weeksAvastin 10mg/kg every 2 weeks

PD

Previously untreated

metastatic CRC (n=50)

Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)

Phase II trial of XELOX plus Avastin (XELOX-A): response rate

Response (RECIST criteria) n=30 (%) Complete response 1 (3)

Partial response 16 (53)

Stable disease 11 (37)

PD 2 (7)

Overall response rate* 17/30 (57)

Time to progression (months) 11.9 (9.8–∞)

*Overall response rate = complete response plus partial responseRECIST = Response Evaluation Criteria in Solid Tumors

Fernando N, et al. J Clin Oncol 2005;23(June 1 Suppl.):260s (Abstract 3556)

Ongoing phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (NO16966C)

2 x 2 factorial, randomised phase III trial

Primary objectives

– at least equivalent time to progression with XELOX (± Avastin) versus FOLFOX4 (± Avastin)

– superior time to progression with Avastin + XELOX/FOLFOX4 versus XELOX/FOLFOX4

Previously untreated

patients with metastatic CRC

(n=1,920)

Avastin 5mg/kg every

2 weeks (n=330)

Placebo (n=330)

Avastin 7.5mg/kg every

3 weeks (n=330)

Placebo (n=330)

FOLFOX4 (n=300)

XELOX (n=300)

DREAM study

mFOLFOX7 x6

mFOLFOX7 x6

XELOX4 x6

XELOX4 x6

mFOLFOX7 x6

mFOLFOX7 x6

XELOX4 x6

XELOX4 x6

Avastin

Avastin

AvastinPreviously untreated

patients with metastatic CRC

(n=640)

Primary endpoint: progression-free survival Secondary endpoints include: overall survival, response rate, duration of disease control,

tolerance and quality of life mFOLFOX7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day

AvastinAvastin +Tarceva®

Avastin AvastinAvastin +Tarceva

Ongoing phase IV optimisation trial (CONcePT) in first-line metastatic CRC

Primary endpoint: time to treatment failure

mFOLFOX7 + AvastinCONTINUOUS

oxaliplatin‘treat-to-failure’

± intravenous Ca/Mg

mFOLFOX7 + AvastinINTERMITTENT

oxaliplatinPatients with metastatic CRC

(n=532)

2x2 randomised, multicentre study

CONcePT: intermittent oxaliplatinStage 1 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m2

Stage 2 Avastin 5mg/kg CI 5-FU/LV

Stage 3 Avastin 5mg/kg CI 5-FU/LV Oxaliplatin 85mg/m2

CI = continuous infusion *Cumulative dose

x8 cycles, months 5–8

x8 cycles, months 1–4 Oxaliplatin 680mg/m2*

x8 cycles, months 9–12 Oxaliplatin 1,360mg/m2*

Avastin therapy: the essential basis of first-line treatment regimens

Metastatic CRC

Avastin + IFL/FOLFIRI/

XELIRI

Avastin + 5-FU or Xeloda

Avastin +FOLFOX or XELOX

Irinotecan +cetuximab

FOLFOX BSC/FOLFOX/FOLFIRI

FOLFIRI 5-FU/LV

First-line

Second-line

Large observational study of Avastin plus first-line chemotherapy for

metastatic CRC (BRiTE) Median progression-free survival is at least as good as that reported in

trial conditions despite the fact that this is a clinical practice population treated with many different chemotherapy regimens

Pro

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1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12 14 16 18 20

Time (months)

11.3

Kozloff M, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006;San Francisco, Ca. Abstract 247. Available at http://www.asco.org. Accessed 28 February 2006

Ongoing and planned trials of Avastin in CRC

Data from ongoing and planned trials are expected to support and investigate– optimisation of Avastin use with chemotherapy– optimisation of chemotherapy use with Avastin– incorporation of targeted agents with Avastin– activity of Avastin across multiple lines of therapy

• first-line use is currently recommended to maximise benefit

Studies are ongoing to examine continued efficacy after progression

Avastin in first-line treatment of metastatic CRC

Avastin has shown consistent efficacy improvements in metastatic CRC, regardless of the regimen with which it is combined

Metastatic CRC

Avastin + IFL/FOLFIRI/

XELIRI

Avastin + 5-FU or Xeloda

Avastin + FOLFOX or XELOX

Irinotecan + cetuximab

FOLFOX BSC/FOLFOX/FOLFIRI

FOLFIRI 5-FU/LV

First-line

Second-line