A multinational, randomized phase III

study of bevacizumab with FOLFOX4 or

XELOX vs. FOLFOX4 alone as adjuvant

treatment for colon cancer: Results and

subgroup analyses from the AVANT trial

André T, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S,

Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera

F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F,

Shmueli E, Bajetta E, Makrutzki M, Shang A, de Gramont A,

Hoff PM, on behalf of the AVANT Investigators

Disclosure – Thierry André

Honoraria/consulting:

Roche

Sanofi-Aventis

For work unrelated to the AVANT study

Rationale for Adjuvant Bevacizumab

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

Using anti-VEGF therapy such as bevacizumab when micrometastases are dormant and potentially reliant on VEGF may prevent the ‘angiogenic switch’1,2

Specifically in colorectal cancer, increased VEGF expression correlates with invasiveness, vascular density, metastasis and recurrence2–5

Clinical studies show that treatment with bevacizumab increases PFS and/or OS in metastatic disease5,6

1. Folkman J. N Engl J Med 19952. Carmeliet P. Nature 2000

3. Takahashi Y. Cancer Res 19954. Warren RS. J Clin Invest 1995

5. Hurwitz H. N Eng J Med 20046. Saltz L. J Clin Oncol 2008VEGF = vascular endothelial growth factor

NSABP C-08 Study Design

Duration of treatment 24 weeks 24 weeks

Primary endpoint: disease-free survival

mFOLFOX6

mFOLFOX6 + Bev(5mg/kg q 2 weeks)

Observation

Bev mono(5mg/kg q 2 weeks)

Stage II/III colon cancer

(n=2700)

R

Wolmark N. ASCO 2009Allegra C. J Clin Oncol 2010

XELOX + bevacizumab

FOLFOX4+ bevacizumab

Bevacizumab monotherapy

Bevacizumab monotherapy

Observation

Follow-up

Follow-up

Follow-upFOLFOX4

Surgery for high-risk stage II

or stage III

colon cancer (N=3451)

Bev 5 mg/kg q2w

Bev 7.5 mg/kg q3w

Bev 7.5 mg/kg q3w

AVANT Study Design

Bev 7.5 mg/kg q3w

24 weeks24 weeks 24 weeks24 weeks

Analysis Plan

Primary endpoint:

DFS in stage III patients*

– STEP 1Test global hypothesis:DFS (FOLFOX4) = DFS (FOLFOX4 + Bev) = DFS (XELOX + Bev)If p≤0.05 proceed to

– STEP 2Compare FOLFOX4 + Bev vs. FOLFOX4 and XELOX + Bev vs. FOLFOX4

Secondary endpoints:

OS in stage III patients

Safety

Non-inferiority DFS and OS: FOLFOX4 + Bev vs. XELOX + Bev (if co-primary objectives met)

*non-stratified log-rank test (two-sided, at overall 5% -level), power at least 80%

Study Conduct

Conducted worldwide:

– 330 centres

– 34 countries

– 8 regions (stratified)

3451 patients randomized:

– between 20 December 2004 and 08 June 2007

– 2867 patients with Stage III disease

Data cut-off date: 30 June 2010 (3-year minimum follow-up)

Median duration of follow-up was 48 months (range 0–66)

Patient Demographics (ITT Stage III)FOLFOX4(N=955)

FOLFOX4 + Bev(N=960)

XELOX + Bev(N=952)

Male, % 55 51 55

Median age, years 59 58 59

Race, % White / Asian 83 / 15 85 / 12 84 / 13

ECOG PS 0, % 87 86 87

Primary tumour T4, % 19 17 19

Nodal status, % N1 / N2 61 / 39 61 / 39 60 / 40

No. of lymph nodes, % <12 / ≥12 28 / 72 27 / 73 29 / 71

Median duration of follow-up, months* 48.3 48.3 48.4

*Calculated for alive patients as no. of months from randomization to last date patients known to be alive*Calculated for alive patients as no. of months from randomization to last date patients known to be alive

AEs of Special Interest for Bevacizumab(All Patients)

Grade 3–5, %FOLFOX4(N=1126)

FOLFOX4 + Bev(N=1145)

XELOX + Bev(N=1135)

All 9 23 18

Bleeding / haemorrhage 0.5 1.2 0.4

Hypertension 1.1 10.6 10.1

Proteinuria 0.1 0.9 1.1

Fistula / abscess 0.4 1.4 0.8

GI perforation 0.1 0.7 0.2

Congestive heart failure 0.3 0.3 0.1

Wound-healing complication 0.4 0.3 0.4

Venous thromboembolism 5.4 8.0 4.6

Arterial thromboembolism 1.0 1.5 1.3

60-day mortality rate 0.2 0.4 0.5

AE onset between time of very first drug intake and 183 days after very last drug intakeAE onset between time of very first drug intake and 183 days after very last drug intake

AEs of Special Interest for Bevacizumab(All Patients)

Grade 3–5, %FOLFOX4(N=1126)

FOLFOX4 + Bev(N=1145)

XELOX + Bev(N=1135)

All 9 23 18

Bleeding / haemorrhage 0.5 1.2 0.4

Hypertension 1.1 10.6 10.1

Proteinuria 0.1 0.9 1.1

Fistula / abscess 0.4 1.4 0.8

GI perforation 0.1 0.7 0.2

Congestive heart failure 0.3 0.3 0.1

Wound-healing complication 0.4 0.3 0.4

Venous thromboembolism 5.4 8.0 4.6

Arterial thromboembolism 1.0 1.5 1.3

60-day mortality rate 0.2 0.4 0.5

AE onset between time of very first drug intake and 183 days after very last drug intakeAE onset between time of very first drug intake and 183 days after very last drug intake

Summary of Results For DFS (ITT Stage III)

FOLFOX4(N=955)

FOLFOX4 + Bev(N=960)

XELOX + Bev(N=952)

Lost to follow-up, n (%) 62 (7) 52 (5) 52 (6)

Patients with event, n (%) 237 (25) 280 (29) 253 (27)

P-value for global hypothesis p=0.2024

3-year DFS rate, % 76 73 75

DFS (ITT Stage III) Data Cut-off Date: 30 June 2010 (3-Year Minimum Follow-Up)

FOLFOX4(N=955)

FOLFOX4 + Bev(N=960)

XELOX + Bev(N=952)

HR(95% CI)

1.17(0.98, 1.39)

1.07(0.90, 1.28)

955960952

890921900

823868865

779791784

740728722

708695688

451436415

FOLFOX4FOLFOX4 + BevXELOX + Bev

Number at risk

609586580

282280268

FOLFOX4

FOLFOX4 + Bev

XELOX + Bev

Event-free rate

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 18 30 36 42 480 12 24

Time (months)

54 60 66 72

121123110

010

323328

000

DFS: Cumulative Hazard Ratio (ITT Stage III)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1

Time from randomization (years)

1.5 2 2.5 3

0.63 0.61

1.001.02

1.121.15

1.11 1.13 1.131.08

FOLFOX4 + Bev

XELOX + Bev

Hazard ratio

Site of Recurrence (ITT Stage III)

FOLFOX4(N=955)

FOLFOX4 + Bev(N=960)

XELOX + Bev(N=952)

Pts with tumour recurrence, %* 23 26 23

Local recurrence 4 4 5

Regional lymph nodes 2 2 2

Distant lymph nodes 4 3 3

Liver 9 9 7

Lung 5 7 6

Other 6 9 7

1 involved site, % 17 20 19

>1 involved site, % 6 6 5

*And without evidence of disease at randomization; percentages based on N*And without evidence of disease at randomization; percentages based on N

Interim OS (ITT Stage III)Median duration of follow-up 48 months (range 0–66)

FOLFOX4(N=955)

FOLFOX4 + Bev(N=960)

XELOX + Bev(N=952)

EventsHR(95% CI)

115 (12%) 151 (16%)1.31

(1.03, 1.67)

145 (15%)1.27

(0.99, 1.62)

955960952

914942920

899925908

884900894

863869861

844835840

573573546

FOLFOX4FOLFOX4 + BevXELOX + Bev

Number at risk

776763765

461449445

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 18 30 36 42 480 12 24

Time (months)

54 60 66 72

288269290

010

637064

000

Event-free rate FOLFOX4

FOLFOX4 + Bev

XELOX + Bev

Time from Recurrence / New Occurrence to Death (ITT Stage III patients)

FOLFOX4 + BevN=259

XELOX + BevN=228

HR(95% CI)

1.23( 0.95, 1.60)

1.10(0.84, 1.44)

222259228

178209193

135158158

111104110

656579

343947

748

FOLFOX4FOLFOX4 + BevXELOX + Bev

Number at risk

161626

212

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 18 30 36 42 480 12 24Time (months)

54 60 66 72

000

000

000

000

FOLFOX4

FOLFOX4 + Bev

XELOX + Bev

Event-free rate

Recurrence/new occurrence Recurrence/new occurrence

Subgroup analysis

Hazard Ratio for DFS by Subgroup(ITT Stage III): FOLFOX4 + Bev vs FOLFOX4

All

Age category (years)

Category

T stage

1681

1915

204

1366345

1.17

1.17

1.23

1.270.95

EstimateN

234 1.19

Gender 898 1.321017 1.07

Race category* 2541604

2.181.09

No. of lymph nodes analyzed 5301379

1.261.13

N stage 1175740

1.370.99

Subgroup

All

<70

T3T4

≥70

Other

Hazard ratio

0.2 0.4 0.6 1 2 3 4 5 6 10 20

Favours FOLFOX4+Bev Favours FOLFOX4Favours FOLFOX4+Bev Favours FOLFOX4

FemaleMale

Asian

White

<12≥12

N1N2

*Other races contain very small number of patients (n=55) and therefore not displayed*Other races contain very small number of patients (n=55) and therefore not displayed

Hazard Ratio for DFS by Subgroup(ITT Stage III): XELOX + Bev vs FOLFOX4

All

Age category (years)

Category

T stage

EstimateN

Gender

Race category*

No. of lymph nodes analyzed

N stage 1157750

1.140.99

1907 1.07

1652 1.04255 1.28

197 0.84

1349 1.07361 1.11

8571050

1.111.04

2621586

1.521.04

5441359

1.061.08

Subgroup

All

<70

T3T4

≥70

Other

Hazard ratio

0.2 0.4 0.6 1 2 3 4 5 6 10 20

Favours XELOX+Bev Favours FOLFOX4Favours XELOX+Bev Favours FOLFOX4

FemaleMale

Asian

White

<12≥12

N1N2

*Other races contain very small number of patients (n=55) and therefore not displayed*Other races contain very small number of patients (n=55) and therefore not displayed

DFS by N Stage (ITT Stage III)

585370590370572380

550340562359545355

528295541327533332

506273501290495289

487253464264462260

475233451244448240

305146279157267148

FOLFOX4 III N1FOLFOX4 III N2FOLFOX4 + Bev III N1FOLFOX4 + Bev III N2XELOX + Bev III N1XELOX + Bev III N2

Number at risk

411198379207376204

19092

18199

17791

784375487436

000100

221020131711

000000

N2

N1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.70.8

0.9

1.0

6 18 30 36 42 480 12 24

Time (months)

54 60 66 72

Event-free rate

FOLFOX4 (N1)

FOLFOX4 (N2)

FOLFOX4 + Bev (N1)

FOLFOX4 + Bev (N2)

XELOX + Bev (N1)

XELOX + Bev (N2)

60%

40%

Summary and Conclusions

Addition of bevacizumab to FOLFOX4 or XELOX did not prolong DFS in adjuvant treatment of stage III colon cancer

– chemotherapy alone arm was favoured numerically

Bevacizumab treatment effect was not constant over time

– transient favourable effect can be seen within 1 year, which is in-line with NSABP C-08

– although transient favourable effect is more dominant in N2 subgroup, overall treatment effect is lost

Further subgroup analysis results for DFS were consistent with those seen in overall stage III colon cancer population

Immature OS data suggest a potential detriment. Follow up will continue until at least June 2012, for 5 years minimum follow up for analysis of OS

Biomarker programme might help us to understand results seen with bevacizumab in the adjuvant setting

Food for Thought

Why is an active therapy in advanced disease not active in the adjuvant setting?

Is it something different?

Is bevacizumab induction of tumour cell dormancy possible?

Is induction of pro-survival pathway and tumour resistance a possibility?

Does bevacizumab show any transient favourable effect in relation to action on undetectable macro-metastases?

1. Goss PE. Nat Rev Cancer 2010 2. Almog N. Cancer Lett 2010

3. Naumov GN. Clin Exp Metastasis 20094. Ebos JM. Clin Cancer Res 2009

1. Goss PE. Nat Rev Cancer 2010 2. Almog N. Cancer Lett 2010

3. Naumov GN. Clin Exp Metastasis 20094. Ebos JM. Clin Cancer Res 2009

Acknowledgments

Thanks to the following:

Patients and their families

Investigators, study coordinators and nurses at 330 centres in 34 countries

AVANT study team at Genentech, Roche & Chugai

Thank you for your attention