Axel GrotheyProfessor of Oncology

Mayo Clinic, Rochester, Minnesota, USA

Vice Chair and Director of Cancer Treatment of the North Central Cancer Treatment Group (NCCTG)

Co-chair of the gastrointestinal program of NCCTG

Former Senior Consultant and Head of the Oncological Research Laboratory at the Martin-Luther-University in Halle, Germany

Prior posts at the MD Anderson Cancer Center, Houston, USA and the University of Essen and University of Bochum, Germany

Author of many papers in English and German

Mayo Clinic, Rochester

Mounting evidence in early CRC

Axel GrotheyMayo Clinic, Rochester,

Minnesota, USA

Adjuvant chemotherapy of colon cancer: steps ahead

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

5-FU/LV 1-year superior to surgery alone

Bolus 5-FU/LV superior to

surgery alone

6- and 12-month equivalent

Elderly benefitas well

Stage II

Capecitabine

FOLFOX better than LV5FU2

LV5FU2 equivalent to bolus 5-FU/LV

20062005

5-FU = 5-fluorouracilLV = leucovorin

Stage II colon cancer:a heterogeneous population

In 2007, approximately 80,000 patients will be diagnosed with either stage II or III colon cancer in the USA

28% of diagnosed colon cancer patients

Wide spectrum of disease1

– IIa: T3, N0, M0

– IIb: T4, N0, M0

5-year disease-free survival2

– IIa: 65–73%

– IIb: 51–60%

25–30% of stage II patients will relapse within 5 years1AJCC Cancer Staging Handbook, 6th ed

2Gill S, et al. J Clin Oncol 2004;22:1797–806

Who should be offered adjuvant therapy of colon cancer?

All patients with stage III tumours

Patients with ‘high-risk’ stage II tumours according to– clinico-pathological parameters

• T4 tumours• obstruction/perforation• lymphatic or vascular invasion• undifferentiated histology• <10 (12) lymph nodes examined

– molecular parameters? (in trials)

Adjuvant therapy for stage II colon cancer

The role of adjuvant therapy for patients with stage II disease is controversial– studies have confirmed the benefits of treatment in

stage III disease1,2

A number of factors may influence adjuvant treatment decisions – treatment outcomes, patient characteristics,

comorbidities, convenience, costs, etc.

The evidence for adjuvant treatment of stage II colon cancer comes from >13,500 patients– relative risk reduction between 14% and 31%

1Jessup JM, et al. JAMA 2005;294:2758–602de Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)

5-FU-based adjuvant therapyfor colon cancer

5-FU: historical standardin the adjuvant setting

1IMPACT Investigators, Lancet 1995;345:939–442Wolmark N, et al. J Clin Oncol 1993;11:1879–87

3QUASAR Group. Lancet 2000;355:1588–964André T, et al. J Clin Oncol 2003;21:2896–903

3-year disease-free survival (%)

Observation1

5-FU/high-dose LV (Mayo)2

5-FU/low-dose LV (Mayo)3

LV5FU24

Stage II and III colon cancer patients

6 months 5-FU/LV (Mayo)1

55 60 65 70 75

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

Van Cutsem E, et al. J Clin Oncol 2005;23:(Suppl. 16):3s (Abstract LBA8)

1.0

0.9

0.8

0.7

0.6

0.5

0

Est

imat

ed p

rob

abil

ity

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

FOLFIRI 1,044 63.35-FU/LV 1,050 60.3

HR=0.89 (95% CI: 0.77–1.11)

p=0.091

3-year DFS (%)

DFS = disease free survivalHR = hazard ratio; CI = confidence interval

n

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

Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6

HR=1.19(95% CI: 0.90–1.59)

p=0.22

Years

Est

imat

ed p

rob

abil

ity

FOLFIRI 51LV5FU2 60

3-year DFS (%)

CALGB 89803: DFS and OS not improvedwith IFL in stage III colon cancer

Saltz L, et al. J Clin Oncol 2007;25:3456–61OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n d

isea

se-f

ree

Pro

po

rtio

n s

urv

ivin

g0 1 2 3 4 5 6 7

Years

0 1 2 3 4 5 6 7

Years

n Events

FU/LV 629 227IFL 635 248

p (stratified) = 0.85 (1-sided)

n Events

FU/LV 629 171IFL 635 181

p (stratified) = 0.74 (1-sided)

FU/LVIFL

FU/LVIFL

MOSAIC: superior DFSwith FOLFOX4 in stage III

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

FOLFOX4 1, 123 72.2LV5FU2 1, 123 65.3

3-year DFS (%)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48 54 60

Months

HR=0.76 (95% CI: 0.62–0.92)p=0.002

Est

imat

ed p

rob

abil

ity

n

Disease stage4-year DFS

relative benefit (%)1

3-year DFS relative benefit (%)2

II and III 6.8* 5.1*

III N1 7.0 –

III N2 12.0 –

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(Suppl. 16)246s (Abstract 3501) 2André T, et al. N Engl J Med 2004;350:2343–51

*p<0.05

MOSAIC: consistent benefitin DFS with FOLFOX4 versus LV5FU2

MOSAIC: OS for stage II and stage III patients

Data cut-off: January 2007

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96

HR (95% CI)

Stage II 1.00 (0.71–1.42)

Stage III 0.80 (0.66–0.98)

0.1%0.1%

4.4%4.4%

p=0.996

p=0.029

De Gramont A, et al. J Clin Oncol 2007;25(Suppl. 18)165s (Abstract 4007)

NSABP C-07: superior DFSwith FLOX in stage II/III combined

Kuebler JP, et al. J Clin Oncol 2007;25:2156–8

1.0

0.9

0.8

0.7

0.6

0.50 1 2 3 4

Years

FLOX 1,200 76.55-FU/LV 1,207 71.6

3-year DFS (%)

HR=0.79 (95% CI: 0.67–0.93)p<0.004E

stim

ated

pro

bab

ilit

y

n

Adjuvant combination therapy: summary

Data from MOSAIC and NSABP C-07 suggest that– oxaliplatin plus 5-FU/LV significantly improves DFS

in patients with stage II and III colon cancer– oxaliplatin plus 5-FU/LV significantly improves OS

in patients with stage III colon cancer

Data from PETACC-3, ACCORD and CALGB 89803 suggest that– addition of irinotecan to LV5FU2 may reduce risk

of recurrence in patients with stage III colon cancer– there is no clear significant benefit for irinotecan in

the adjuvant setting

Capecitabine: the potential agent of choice for adjuvant therapy

IntestineLiver

Capecitabine

5'-DFCR

5'-DFUR

CyD

5'-DFCR

5'-DFUR

5-FU

Tumour >> healthy tissueCapecitabine

CyD

CE

5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesterase

Capecitabine mode of action:TP-activation – proof of concept at last?

Thymidinephosphorylase (TP)

X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer

Primary endpoint: non-inferiority in DFS

Secondary endpoint: OS

Bolus 5-FU/LV5-FU 425mg/m2 +

LV 20mg/m2 days 1–5 q4w

Capecitabine1,250mg/m2 b.i.d. days 1–14 q3w

Chemonaïve stage IIIresection 8 weeks

n=1, 004

n=983

RANDO MISATION

Data cut-off: January 2007b.i.d. = twice daily

Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB)

X-ACT: 5-year DFS (median follow-up 6.8 years)

5-year

DFS (%)

Capecitabine 1, 004 60.8

5-FU/LV 983 56.7

1.0

0.8

0.6

0.4

0.2

00 6 42 48 78 96

Months

HR=0.88 (95% CI: 0.77–1.01)NI margin 1.20

12 18 24 30 36 54 60 66 72 84 90

ITT population

Est

imat

ed p

rob

abil

ity

ITT (intent-to-treat) population; NI = non-inferiorityTwelves C, et al. Eur J Cancer Suppl

2007;5:1 (Abstract 1LB)

102

n

Test of non-inferiority p<0.0001Test of superiority p=0.0682

X-ACT: 5-year OS (median follow-up 6.8 years)

HR=0.86 (95% CI: 0.74–1.01)NI margin 1.14

ITT population

0 6 42 48 78 96

Months

12 18 24 30 36 54 60 66 72 84 90 102

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

rob

abil

ity

Test of non-inferiority p=0.000116Test of superiority p=0.06

5-year

OS (%)

Capecitabine 1, 004 71.4

5-FU/LV 983 68.4

n

Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB)

X-ACT: improved efficacy with capecitabine(5-year OS subgroup analysis)

ITT population

Male

Female

<40

40–69 years old

70

pN1

pN2

Baseline CEA <ULN

Baseline CEA >ULN

n

Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB)

HR (95% CI)

Favours capecitabine

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Favours 5-FU

1,987

1,074

912

76

1,513

396

1,389

593

1,672

155

CEA = carcinoembryonic antigenULN = upper limit of normal

Multivariate analysis of OS

Factor HR 95% CI p value

Age (years) 1.010 1.001–1.019 0.0238

Gender (female vs male) 0.770 0.654–0.908 0.0018

Regional lymph nodes (PN1 vs PN0, PN2, PNx) 0.577 0.489–0.682 <0.0001

Baseline CEA (< vs ULN) 0.401 0.320–0.503 <0.0001

Time from surgery to randomisation (days) 1.004 0.997–1.012 0.2418

Treatment effect (capecitabine vs 5-FU/LV) 0.828 0.705–0.971 0.0203

Twelves C, et al. N Engl J Med 2005;352:2696–704

Treatment duration and intensity

Capecitabine(n=995)

Bolus 5-FU/LV(n=974)

Completed full course of treatment (%) 84 88

Needed dose reduction (%) 42 44

Needed dose reduction, interruption or delay (%) 57 52

Twelves C, et al. N Engl J Med 2005;352:2696–704

Neutropenia

Nausea/

vomiti

ng

Stom

atitis

Diarrhoea

Febrile

neutropenia HFS

Pat

ien

ts (

%)

Scheithauer W, et al. Ann Oncol 2003;14:1735–43

**

* *

*p<0.001HFS = hand foot syndrome

Capecitabine (n=993)

5-FU/LV (n=974)

Grade 3/4 adverse events

X-ACT: improved safety with capecitabine50

40

30

20

10

0

X-ACT and MOSAIC: projection of OS in stage III patients

ITT population

Est

ima

ted

pro

bab

ilit

y

0 2 4 6 8

1.0

0.8

0.6

0.4

Years

X-ACT1

Bolus 5-FU/LV (n=983)

Capecitabine (n=1,004)

MOSAIC2

LV5FU2 (n=675)

FOLFOX (n=672)

1Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)

Est

ima

ted

pro

bab

ilit

y

1.0

0.8

0.6

0.4

Years0 2 4 6 8

X-ACT: 5-year survival update –conclusions

Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (p=0.06) in terms of 5-year OS

First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU

Capecitabine is known to be an effective/better tolerated alternative to bolus 5-FU/LV (Mayo Clinic) in the adjuvant treatment of stage III colon cancer

Chemo/radiotherapy-naïve

stage III colon cancer

Bolus 5-FU/LVMayo Clinic or Roswell Park

CAPOXCapecitabine 1,000mg/m2 b.i.d. days 1–15

Oxaliplatin 130mg/m2 day 1 q3w

Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

CAPOX: a new optionin the adjuvant setting

Primary endpoint: disease-free survival

n=944

n=942

RANDO MISATION

Grade 3/4 adverse events

Pat

ien

ts (

%)

CAPOX1 (n=938)

FOLFOX42 (n=1,108)

FLOX3 (n=1,200)

Cross-trial comparison*Not reported

Neutropenia

Nausea

Stom

atitis

Diarrhoea

Febrile

neutropenia HFS

Vomiti

ng

Neurosensory

1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51

3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)

*

Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX

* *

50

40

30

20

10

0

Before After Before After Before After

HFS Diarrhoea Stomatitis

Grade 2

Grade 3

Grade 4

Active patient management minimises adverse events: before and after dose modification

20

15

10

5

0

Cassidy J, et al. J Clin Oncol 2004;22(Suppl. 14):14s (Abstract 3509)

Cyc

les

(%)

Role of adjuvant anti-VEGF therapy

Rationale for anti-VEGF therapy in the adjuvant setting

The roles of angiogenesis and VEGF in colorectal tumour growth are well established1

Using anti-VEGF therapy such as bevacizumab when micrometastases are dormant and potentially reliant on VEGF may prevent the angiogenic switch,2 thereby improving outcomes

In preclinical studies, bevacizumab causes regression of human tumour xenografts,3–5 and a reduction in the number and size of liver metastases6

Bevacizumab may have a greater impact in earlier disease stages

1Bergers G, et al. Nat Rev Cancer 2003;3:401–10; 2Poon RT, et al. J Clin Oncol 2001;19:1207–25; 3Gerber HP, et al. Cancer Res 2000;60:6253–8; 4Wildiers H, et al.

Br J Cancer 2003;88:1979–86; 5Shen B-Q, et al. Proc Amer Assoc Cancer Res 2004;45 (Abstract 2203); 6Warren RS, et al. J Clin Invest 1995;95:1789–97

VEGF = vascularendothelial growth factor

Anti-VEGF therapy regresses some existing tumour microvasculature

Reduction in tumour vessel blood flow after 1 day of anti-VEGF therapy

Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83*AG013736 (VEGF tyrosine kinase inhibitor)

Control Anti-VEGF therapy*

Abnormal vasculature normalised following VEGF inhibition*

Inai T, et al. Am J Pathol 2004;165:35–52 Rugo HS, et al. J Clin Oncol 2005;23:5474–83*AG013736 (VEGF tyrosine kinase inhibitor)

Normalisation of tumour vasculature improves delivery of chemotherapy

46% increase in intratumoral availability of irinotecan after pretreatment with an anti-VEGF antibody*

Wildiers H, et al. Br J Cancer 2003;88:1979–86

20

15

10

5

0 Placebo A4.6.1

Tu

mo

ur

irin

ote

can

co

nce

ntr

atio

n (

mg

/g)

10.93

15.98

*In a preclinical model

Withdrawal of anti-VEGF therapyresults in vessel regrowth

Continue anti-angiogenic therapy to avoid vessel regrowth

Mancuso MR, et al. J Clin Invest 2006;116:2610–21

CD31 Untreated AG-013736, 7d Withdrawal, 2d Withdrawal, 7d

RIP-Tag2

EARLY EFFECTS CONTINUED EFFECTS

1 Regression Normalisation2 Inhibition3

Linking the MoA of bevacizumab with clinical benefit in adjuvant CRC

Prevent growth of small, unresected

tumours

Improve delivery of chemotherapy

Suppress the ‘angiogenic switch’ in dormant cells

Eliminate residual cancer cells

following surgery

Improve DFS

QUASAR-2 (phase III): study design

Primary endpoint: DFS

Secondary endpoints include survival and tolerability

Recruitment

– started September 2006

– 306 patients enrolled (March 2007)

Bevacizumab (7.5mg/kg) + capecitabine every 3 weeks (bevacizumab 16 cycles and capecitabine 8 cycles over

24 weeks)

Capecitabine (8 cycles over 24 weeks)

Colon cancer (stage II/III)(n=2,240)

Phase III trial BO17920 (AVANT):study design

Randomised, open-label study

Primary endpoint: DFS at 3 years for stage III Secondary endpoints: OS and safety Accrual completed Q2 2007

Surgery for high-risk stage II + stage III colon

cancer(n=3,450)

FOLFOX4

FOLFOX4 + bevacizumab

(5mg/kg every 2 weeks)

CAPOX + bevacizumab

(7.5mg/kg every 3 weeks)

Bevacizumab alone(7.5mg/kg every

3 weeks)

Bevacizumab alone(7.5mg/kg every

3 weeks)

Observation

Duration of treatment phases 24 weeks 24 weeks

24 weeks 24 weeks

NSABP C-08: study design

Primary endpoint: DFS at 3 years

Secondary endpoints include survival and tolerability

Trial design

– 90% power for 25% reduction in risk of progression after 3 years

– 82% power for 25% reduction in risk of death after 7 years

Patient recruitment is complete, efficacy results expected for ASCO 2009

mFOLFOX6

mFOLFOX6 + bevacizumab 5mg/kg every

2 weeks

Dukes’ C colon cancer (n=2,714)

Bevacizumab 5mg/kg every

2 weeks

Observation

Trials of bevacizumab/capecitabinein the adjuvant setting

Trial n Cancer Treatment

E5202 (Cooperative)

3,610 Stage II colon FOLFOX ± bevacizumab (high risk) Observation (low risk)

NSABP C-08 (Cooperative)

2,714 Stage II/III colon FOLFOX ± bevacizumab

QUASAR-2 (Cooperative)

2,240 Stage II/III colon Capecitabine ± bevacizumab

XELOXA (Cooperative)

1,886 Stage III colon CAPOX vs bolus 5-FU (Mayo Clinic or Roswell Park regimen)

AVANT (Roche)

3,450 Stage II/III colon FOLFOX vs FOLFOX + bevacizumab vs XELOX + bevacizumab

Important adjuvant capecitabine/bevacizumab-based combination trials

2004 2005 2006 2007 2008 2009 2010 2011

XELOXA final safety

XELOXA 1° efficacy

XELOXA survival follow-up

QUASAR-2 1° efficacy

AVANT 1° efficacy

NSABP C-08 1° efficacy

Conclusions

Adjuvant capecitabine is as effective as bolus 5-FU/LV, with fewer grade 3/4 toxicities

Capecitabine in combination with oxaliplatin is a promising option in the adjuvant setting

There is a strong rationale for the use of bevacizumab in the adjuvant setting

Adjuvant bevacizumab and capecitabine clinical development programme is ongoing, results expected soon