Targeting VEGF for the Treatment of Colorectal Cancer Herbert Hurwitz Duke University Medical Center...
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Transcript of Targeting VEGF for the Treatment of Colorectal Cancer Herbert Hurwitz Duke University Medical Center...
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.