Targeting VEGF for the Treatment of Colorectal Cancer

Herbert Hurwitz

Duke University Medical Center Durham, North Carolina, USA

Phase III trial of IFL ± BV in MCRC study design

IFL

bolus 5-FU 500mg/m2

leucovorin 20mg/m2

irinotecan 125mg/m2

given 4/6 weeks

Option of BV at PD

Option of BV at PD

No BV at PD

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

5-FU/LV

bolus 5-FU 500mg/m2

leucovorin 500mg/m2

given 6/8 weeks

Bevacizumab

5mg/kg every 2 weeks

Previously untreatedmetastatic

CRC

PD

PD

PD

Bolus IFL + placebo(n=412)

Bolus IFL + bevacizumab

(n=403)

5-FU/LV + bevacizumab

(n=110)

SurvivalP

rob

abil

ity

of

surv

ival

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + placebo

IFL + bevacizumab

Median survival (months)IFL + placebo: 15.6 vsIFL + bevacizumab: 20.3HR: 0.66, p=0.00004

HR = hazard ratio Source: Hurwitz H et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colon cancer. N Eng J Med 2004;350(23):2335-42. Copyright © 2004 Massachusetts Medical Society. All

rights reserved.

Bevacizumab plus chemotherapy in1st Line CRC

Study Group

AVF2107g Bevacizumab/IFL vs

placebo/IFL

AVF2192g Bevacizumab/5-FU vs

placebo/5-FU

AVF0780g Bevacizumab/5-FU vs

placebo/5-FU

AVF2107g Bevacizumab/Arm 3 5-FU vs IFL/

5-FU

0.2 0.40.6 1 2 3 4 5 6

PatientsLower Upper (n) CL HR CL

813 0.55 0.67 0.82

209 0.58 0.80 1.11

71 0.25 0.52 1.08

210 0.53 0.74 1.03

CL = confidence limit

HR

Adverse Events

*p<0.01 vs placeboNB: not adjusted for different time on therapy

IFL + placebo(n=397)

IFL + bevacizumab(n=393)

Any grade 3/4 event 74.0 84.9*

Event leading to studydiscontinuation 7.1 8.4

Event leading to death 2.8 2.6

60-day mortality 4.9 3.0

Patients (%)

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

IFL-related Adverse Events

NB: not adjusted for different time on therapy

Patients (%)

IFL + placebo (n=397)

IFL + bevacizumab (n=393)

Diarrhea Grade 3 Grade 4

23.7

1.0

28.8

3.6

Leukopenia Grade 3 Grade 4

23.2

7.8

25.0 12.0

Vomiting Grade 3 Grade 4

9.8 0.5

7.4 0.3

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

2nd Line FOLFOX-4 ± BV (E3200) study design

FOLFOX4

Oxaliplatin 85mg/m2 i.v. over 120 minutes, day 1

LV 200mg/m2 i.v. over 120 minutes, days 1 and 2

5-FU 400mg/m2 i.v. bolus followed by

5-FU 600mg/m2 i.v. over 22 hours, days 1 and 2

Bevacizumab

10mg/kg every 2 weeks

FOLFOX4 + placebo

FOLFOX4 + bevacizumab

Bevacizumab alone

Giantonio B, et al. Proc Am Clin Oncol GI Symposium 2004 (Abstract 241)PS = performance statusRT = radiotherapy

Previously treatedmetastatic CRC

Stratification factors:

PS: 0 vs 1, 2Prior RT

E3200: overall survivalProbability

1.0

0.8

0.6

0.4

0.2

0

Overall survival (months)0 3 6 9 12 15 18 21 24 27 30 33 36

AliveDead MedianTotalA: FOLFOX4 + bevacizumab 289 246 43 12.9B: FOLFOX4 290 257 33 10.8C: Bevacizumab 243 216 27 10.2

HR=0.76

A vs B: p=0.0018

B vs C: p=0.95

HR = hazard ratioSource: With permission. Giantonio BJ et al. Presentation. ASCO 2005. Abstract 2

10.2 12.9

10.8

E3200: grade 3/4 toxicityFOLFOX4 +

bevacizumab

(n=287)

FOLFOX4

(n=284)

Bevacizumab

(n=234) p-value

Grade 3 Grade 4 Grade 3 Grade 4Grade

3Grade 4 A vs B

Hypertension (%) 5 1 2 <1 7 0 0.018

Bleeding (%) 3 <1 <1 0 2 0 0.011

Neuropathy (%) 16 <1 9 <1 <1 <1 0.016

Vomiting (%) 9 1 3 <1 5 0 0.010

Proteinuria (%) 1 0 0 0 <1 0 0.25

Source: With permission. Giantonio BJ et al. Presentation. ASCO 2005. Abstract 2

TREE-1 and TREE-2

First-line metastatic CRC (n=223)

FOLFOX + BV(5mg/kg every 2

weeks)

CAPEOX + BV(7.5mg/kg every 3

weeks)

bFOL + BV (5mg/kg every 2

weeks)

PD

PD

PD

Endpoints: grade 3/4 toxicity, response rate and time to progression

TREE1 = same design w/o BV (n=150)bFOL = bolus 5-fluorouracil/oxaliplatin/leucovorin

56.9%

37.5%

42.9%

32.0%

63.4%

46.9%

0

10

20

30

40

50

60

70

% of patients

mFOLFOX6–

TREE-1 vs TREE-2Response Rate

* Not all responses confirmed.Hochster et al. ASCO, 2005. Abstract 3515. Updated from poster presentation.

mFOLFOX6+bevacizumab

bFOL–

bFOL+bevacizumab

CapeOx–

CapeOx+bevacizumab

TREE-2Grade 3/4 Toxicities

% of Patients

Adverse Event

mFOLFOX6 + Bevacizumab

(n=71)

bFOL +Bevacizumab

(n=70)

CapeOx +Bevacizumab

(n=72)

Vomiting 3 13 10

Dehydration 6 13 8

Diarrhea 13 27 20

Neutropenia 45 17 10

Febrile neutropenia 3 1 0

Hand-foot syndrome 0 0 10

Neurotoxicity (gr. 3) 14 11 15

Hypertension 9 7 14

Bleeding 4 4 1

Thrombosis (arterial) 0 0 4

Proteinuria 1 1 1

Any grade 3/4 85 73 75

Hochster et al. ASCO, 2005. Abstract 3515. Updated from poster presentation.

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 hyp ertension 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

Possible BV-related Toxicity

NB: not adjusted for different time on therapy*p<0.05 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

GI Perforations in MCRC

No. of PatientsNo. of Patients With GI Perforation (%)

AVF2192g

5-FU/LV + placebo 104 0 (0)

5-FU/LV + bevacizumab 100 2 (2)

AVF2107g

IFL + placebo 396 1 (0.3)

IFL + bevacizumab 392 6 (1.5)

5-FU/LV + bevacizumab 109 4 (3.7)

E3200

Bevacizumab 234 3 (1.3)

FOLFOX4 + placebo 284 0 (0)

FOLFOX4 + bevacizumab 287 3 (1.0)Bevacizumab PI: (bevacizumab) PI; Giantonio et al. ASCO, 2005. Abstract 2. Updated from oral presentation; Kabbinavar et al. J Clin Oncol. 2005;23:3697.

Surgical wound healing complications

The longest interval between last dose of therapy and dehiscence was 56 days Avastin PI February 2004

Therapy

Patients with surgery after treatment (n)

Number of complications (%)

IFL + placebo 25 1 (4%)

IFL + bevacizumab 39 6 (15%)

Therapy

Patients with surgery < 60d

(n) Complications (%)

IFL + placebo 155 1 (0.6%)

IFL + bevacizumab 150 3 (2.0%)

Bleeding complications during full dose anti- coagulation: IFL +/- BV

*Median duration of warfarin therapy with bevacizumab = 181 vs 218 days

Therapy Patients anti-

coagulated* (n) Number of

complications (%)

IFL + placebo 30 2 (6.6%)

IFL + bevacizumab 53 2 (3.8%)

Bevacizumab PI February 2004

Arterial Thromboembolic Events inTrials of Bevacizumab + Chemotherapy

% of Patients

Chemotherapy Alone

(n=782)

Bevacizumab + Chemotherapy

(n=963)

ATEs (overall)* 1.9 4.4

Cerebrovascular 0.5 1.9

Cardiovascular 1.0 2.1

Fatal 0.4 0.7

Rate/ 100pt*yrs 3.1 5.5 (p=0.76)

Hazard Ratio 1.99 (p=0.03)

*From an exploratory analysis pooling data from 5 randomized, controlled clinical trials of bevacizumab in combination with chemotherapy vs chemotherapy alone (N=1745).

ATEs included cerebral infarction, myocardial infarction, transient ischemic attacks, and angina In multivariate analysis, only age >65 y and prior history of ATE were risk factors for developing ATEs Skillings et al. ASCO, 2005. Abstract 3019. Updated from poster presentation. Bevacizumab PI Bevacizumab therapy should be permanently discontinued in patients who experience a severe ATE

Arterial Thromboembolic Events (ATE) by Risk Group: Pooled Analysis

No. of Patients/n (%) Hazard Ratio†

Baseline Risk Factor

Chemotherapy + Placebo

Chemotherapy + Bevacizumab PFS OS

All patients 13/782 (1.7) 37/963 (3.8) 0.54 0.66

None 5/490 (1.0) 11/602 (1.8) 0.53 0.73

Age ≥65 y* 7/279 (2.5) 24/339 (7.1) 0.57 0.61

History of ATEs* 2/59 (3.4) 14/89 (15.7) 0.61 0.38

Age ≥65y + history of ATEs 1/46 (2.2) 12/67 (17.9) 0.55 0.59

*These groups are not mutually exclusive; †Patients from AVF2107g only.

Skillings et al. ASCO, 2005. Abstract 3019. Updated from poster presentation.

Conclusions

The addition of bevacizumab to 5FU based chemotherapy improves survival, progression-free survival, and response rate for both 1st and 2nd line colorectal cancer

Chemotherapy side effects are not increased

HTN is common but is readily manageable

Important but uncommon side effects include: arterial thromboembolic events, GI perforation, altered wound healing, proteinura, bleeding.