Future directions for Avastin®

in colorectal cancer (CRC) Fairooz Kabbinavar

David Geffen School of Medicine at UCLALos Angeles, USA

Optimising Avastin in metastatic CRC:ongoing clinical trial programme

The current clinical trial programme will generate additional data with Avastin in combination with FOLFIRI, XELIRI, FOLFOX and XELOX in metastatic CRC

Ongoing trials will provide further guidance regarding

• the true benefit of combining Avastin with oxaliplatin-containing therapy

• how best to use Avastin with oxaliplatin-containing regimens given the cumulative neurotoxicity of oxaliplatin

DREAM studymFOLFOX7 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

CONcePT: first-line metastatic CRC phase IV optimisation

Primary endpoint: time to treatment failure

mFOLFOX7 + AvastinCONTINUOUS

oxaliplatin‘treat-to-failure’

± intravenous

Ca/Mg

mFOLFOX = modified FOLFOX

mFOLFOX7 + AvastinINTERMITTENT

oxaliplatinPatients with metastatic

CRC (n=532)

2x2 randomised, multicentre study

CONcePT: intermittent oxaliplatin

Stage 1: Avastin 5mg/kg CI 5-FU/LV x8 cycles, months 1–4 Oxaliplatin 85mg/m2

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

Stage 3: Avastin 5mg/kg CI 5-FU/LV x8 cycles, months 9–12 Oxaliplatin 85mg/m2

*Cumulative doseCI = continuous infusion

x8 cycles, months 5–8

Oxaliplatin 680mg/m2*

Oxaliplatin 1,360mg/m2*

OASIS - Oxaliplatin Avastin Sequence to Investigate Survival: study design

Patients with

metastatic CRC

(n=800)

FOLFOX6 + Avastin(cycles 1–

8)

FOLFOX6 + Avastin(cycles 1–

8)

PD

PD

Primary endpoint: first progression-free survival

Secondary endpoints: duration of tumour control, overall survival and neurotoxicity

Trial has 80% power to detect increase in progression-free survival from 10.5 to 14 months

FOLFIRI +

Avastin

5-FU/LV +

Avastin

FOLFOX6 re-

introduction

FOLFIRI FOLFOX6 re-

introduction

PD

PD

First line Second/third line*

*Avastin may be used second/third line

PD

Ongoing and planned trials of Avastin in CRC

Trial n Treatment

NO16966 1,920 XELOX or FOLFOX ± Avastin

CALGB/SWOG 2,289 mFOLFOX6 or FOLFIRI + Avastin, cetuximab or Avastin + cetuximab

AVIRI 202 FOLFIRI + Avastin

ACCORD 13 (MEXICO) 144 XELIRI/FOLFIRI + Avastin

ML18524 300 Xeloda + Avastin vs metronomic Xeloda + Avastin vs XELIRI + Avastin

Avastin in the (neo)adjuvant setting

Rationale for Avastin in the adjuvant setting

The role of angiogenesis and VEGF in colorectal tumour growth is well established

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

Preclinical studies show that treatment with Avastin leads to regression of human tumour xenografts,1–3 and a reduction in the number and size of liver metastases in nude mice.4 Therefore, Avastin may have a greater impact in earlier disease stages

1Gerber HP, et al. Cancer Res 2000;60:6253–582Wildiers H, et al. Br J Cancer 2003;88:1979–86

3Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45:508 (Abstract 2203)

4Warren RS, et al. J Clin Invest 1995;95:1789–97

Adjuvant anti-VEGF therapy may prevent the angiogenic switch

Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25

Stages at which angiogenesis plays a role in tumour progression

Premalignantstage

Malignanttumour

Tumourgrowth

Vascularinvasion

Dormantmicrometastasis

(Avasculartumour)

(Angiogenicswitch)

(Vascularisedtumour)

(Tumour cellintravasation)

(Seeding indistant organs)

A4.6.1 Control MAb

Warren RS, et al. J Clin Invest 1995;95:1789–97

A4.6.1 therapy and growth inhibition of colorectal liver metastases in an animal

model

Tum

our

volu

me (

mm

3)

Time (days)

ControlControl MAb (200µg)Anti-VEGF MAb (10µg)Anti-VEGF MAb (50µg)Anti-VEGF MAb (100µg)Anti-VEGF MAb (200µg)

1,600

1,200

800

400

00 7 14 21

Randomised, phase III trial of adjuvant Avastin plus FOLFOX (AVANT): study design

Randomised, open-label study

Primary endpoint: disease-free survivalSecondary endpoints: overall survival and safety

Surgery for high risk stage II + stage III

colon cancer(n=3,450)

FOLFOX4

FOLFOX4 + Avastin(5mg/kg every

2 weeks)

XELOX + Avastin(7.5mg/kg every

3 weeks)

Avastin alone(7.5mg/kg every

3 weeks)

Avastin alone(7.5mg/kg every

3 weeks)

Observation

Duration of treatment phases: 24 weeks 24 weeks

XELOX = Xeloda® + oxaliplatin

AVANT: eligibility criteria

Histologically confirmed colon carcinoma

Tumour classification according to AJCC/UICC stage III stage II (high-risk population)

Potentially curative tumour resection within 28–56 days prior to starting treatment

ECOG performance status 1

AJCC = American Joint Commission on CancerUICC = International Union Against CancerECOG = Eastern Cooperative Oncology Group

AVANT: study description

Primary endpoint: disease-free survival at 3 years for stage III

Statistical assumption: 80% power to demonstrate a 23% reduction in the hazard ratio (72.2% vs 77.8%)

2,880 stage III (960 per arm)

570 stage II for exploratory analysis

Recruitment period: 23 months, first patient included 21 December, 2004 Multicentre: ~350 centres planned in 36 countries

First results expected in 2008

Study currently on hold for interim safety analysis

Other trials in the adjuvant setting

Trial n Cancer Treatment

NSABP C-08 2,700 Colon FOLFOX ± Avastin

E5202 3,282 Colon FOLFOX ± Avastin

QUASAR2 3,510 Colon Xeloda + Avastin vs Xeloda

AVF3105s TBD Rectal Avastin, 5-FU and radiotherapy

NSABP = The National Surgical Adjuvant Breast and Bowel ProjectXELIRI = Xeloda + irinotecan

Avastin in the neoadjuvant setting

The anti-angiogenic action of Avastin in preventing tumour growth and metastasis, and potential synergistic activity with radiotherapy, provides a strong rationale for use earlier in the treatment of CRC

Avastin in the neoadjuvant setting may help reduce the size of the tumour, making it resectable

Available data indicate that neoadjuvant therapy with Avastin is feasible1

Several trials of Avastin in this setting are planned

Willett CG, et al. Nat Med 2004;10:145–7

Neoadjuvant Avastin in patients with rectal cancer: phase I trial design

Avastin 5mg/kg

Avastin 5mg/kg +

5-FU + radiotherapy

Patients with primary and non-metastatic rectal

cancer

Surgery

2 weeks 3 x 2-week cycles

Willett CG, et al. Nat Med 2004;10:145–7

Assessment

Neoadjuvant Avastin in patients with rectal cancer: outcomes after Avastin

treatment

12 days after Avastin administration• tumour regression of >30% in one patient• no change in tumour size in five patients

Computed tomography (CT) scans (n=5) showed• 40–44% decrease in tumour blood perfusion (n=4/5; p<0.05)• 16–39% decrease in tumour blood volume (n=4/5; p<0.05)• 25–59% reduction in tumour microvessel density (n=5/5;

p<0.05)

All patients underwent subsequent surgery without peri- or post-operative complications

Willett CG, et al. Nat Med 2004;10:145–7

Changes in tumour vasculature following a single Avastin dose in patients with rectal

cancerB

lood fl

ow

(mL/

min

/10

0g t

issu

e)

100

90

80

70

60

50

40

30Pretreatment Day 12

PS (

mL/

min

/10

0g t

issu

e)

17

16

15

14

13

12

11

10

9

1

3

4

5

6

Pretreatment Day 12

Patient

Willett CG, et al. Nat Med 2004;10:145–7PS = permeability-surface area

Changes in tumour vasculature following a single Avastin dose in patients with rectal

cancer (cont’d)

Willett CG, et al. Nat Med 2004;10:145–7

Num

ber

of

vess

els

per

field

20

16

12

8

4

0

Patient

1 3 4 5 6

IFP (

mm

Hg)

22.5

18

13.5

9

4.5

0

Pretreatment Day 12

Patient

3 4 5 6

IFP = interstitial fluid pressure

Trials of Avastin in theneoadjuvant setting

Trial Country/group n Cancer Treatment

MO19051 Belgium/EORTC 108 Locally advanced

rectal cancer

Avastin, radiotherapy, Xeloda ± oxaliplatin

ML18641 The Netherlands

60 Rectal cancer Avastin and radiochemotherapy (Xeloda)

ML18522 Italy 80 Locally advanced

rectal cancer

Avastin and radiochemotherapy (Xeloda)

MO18725 France 80 CRC liver metastases

FOLFOX ± Avastin

EORTC = European Organisation for Research and Treatment of Cancer

Avastin plus targeted therapies

Rationale for combining anti-VEGF and anti-HER1/EGFR

agents

Both HER1/EGFR and VEGF are overexpressed in many tumours1

VEGF has been implicated in resistance to anti-HER1/EGFR therapy

Treatment with two agents targeting two different critical pathways may be more effective than a single one2

Preclinical studies have shown that anti-VEGF and anti-HER1/EGFR therapies have at least additive effects3

Clinical trials in various indications (RCC,4 NSCLC,5 HNSCC6) have shown that the combination of Avastin® and TarcevaTM is active

1Viloria-Petit A, et al. Cancer Res 2001;61:5090–101; 2Herbst RS, et al. Eur J Cancer Suppl 2003;1:S293; 3Ciardiello F, et

al. Clin Cancer Res 2000;6:3739–47; 4Spigel DR, et al. J Clin Oncol 2005;23(June 1 Suppl.):387s (Abstract 4540);

5Sandler AB, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 2000; 6Vokes EE, et al. J Clin Oncol 2005;23(June

1 Suppl.):501s (Abstract 5504)

HER = human epidermal growth factor receptorEGFR = epidermal growth factor receptorVEGF = vascular endothelial growth factor RCC = renal cell cancerNSCLC = non-small cell lung cancerHNSCC = head and neck squamous cell carcinoma

Experimental evidence for combined EGFR and VEGF inhibition

Jung YD, et al. Eur J Cancer 2002;38:1133–40

Ciardiello F, et al. Clin Cancer Res 2000;6:3739–47

GEO colon cancer xenograft

TMK-1 gastric cancer xenograft

DC101: Anti-VEGF receptor MAbC225: Anti-EGFR MAb

0.75

0.50

0.25

0Tu

mou

r w

eig

ht

(kg

)

Control DC101 C225 DC101/C225

ControlVEGF-ASMAbC225

CombinationControl-AS

2

1

0

Tum

ou

r volu

me (

cm3)

0 20 40 60 80 100

Days

MAb = monoclonal antibody

Clinical data to support dual VEGF and EGFR inhibition

1Cunningham D, et al. N Engl J Med 2004;351:337–452Saltz LB, et al. J Clin Oncol 2005;23(June 1 Suppl.):248s (Abstract 3508)

Inter-trial analysis shows that Avastin plus cetuximab improves response rate and time to progression in previously treated metastatic CRC patients

Cetuximab/ irinotecan

(historical)1

Cetuximab/ irinotecan/ Avastin2

p value

Response rate (%) 23 37 0.03

Time to progression (months) 4.0 7.9 <0.01

Cetuximab alone (historical)1

Cetuximab/ Avastin2

p value

Response rate (%) 11 20 0.05

Time to progression (months) 1.5 5.6 <0.01

Trial

Phase n Cancer Treatment Primary endpoint(s) Notes

PACCE (Amgen)

III ~1,000 First-line metastatic CRC

FOLFOX or FOLFIRI + Avastin vs FOLFOX or FOLFIRI + Avastin + panitumumab

PFS Ongoing

US intergroup

III ~2,500 First-line metastatic CRC

Chemotherapy + Avastin vs chemotherapy + cetuximab vs chemotherapy + Avastin + cetuximab

PFS Ongoing

CAIRO-2 III 750 Metastatic CRC

Avastin + XELOX vs Avastin + XELOX + cetuximab

PFS Planned

Avastin with otheranti-HER1/EGFR agents in CRC

FOLFOX = 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatinFOLFIRI = 5-FU/LV + irinotecanXELOX = Xeloda® + oxaliplatinPFS = progression-free survival

Combinations with biological agents: summary

Several agents targeting the VEGF pathway or EGFR have received regulatory approval or are in the late stages of clinical development for the treatment of various cancer types

Evidence suggests that combined blockade of the two pathways may provide better efficacy than blocking either pathway alone

Avastin in multiple lines of treatment

First line

Avastin +

IFL / FOLFIRI(XELIRI)

Avastin +

5-FU/LV(Xeloda)

Avastin +

FOLFOX(XELOX)

5-FU/LV = 5-fluorouracil/leucovorin; IFL/FOLFIRI = irinotecan, 5-FU/LV; FOLFOX = 5-FU/LV + oxaliplatin; XELOX = Xeloda + oxaliplatin; XELIRI = Xeloda + irinotecan

Second line FOLFOX ±Avastin

FOLFIRI /FOLFOX ±

Avastin

FOLFIRI ±Avastin

Cetuximab ±irinotecan

Cetuximab ±irinotecan

Cetuximab +irinotecan

5-FU/LV ? Cetuximab

Clinical trial

Conclusions

Avastin is being evaluated in combination with all active chemotherapy regimens, such as FOLFIRI, XELIRI, FOLFOX and XELOX, to further optimise the treatment for metastatic CRC

The potential of Avastin as an effective option in the (neo)adjuvant setting is being evaluated in phase III clinical trials

Ongoing trials are examining the efficacy and safety of combining first-line Avastin with EGFR-targeted therapies in patients with metastatic CRC