role of vascular endothelial growth factor (vegf) in crpc
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CALGB 90401: A randomized double-blind placebo controlled phase III trial comparing docetaxel, prednisone and placebo with docetaxel, prednisone and bevacizumab in men with metastatic castrate resistant prostate cancer (mCRPC). - PowerPoint PPT PresentationTRANSCRIPT
CALGB 90401: A randomized double-blind placebo controlled phase III trial comparing docetaxel,
prednisone and placebo with docetaxel, prednisone and bevacizumab in men with metastatic castrate resistant
prostate cancer (mCRPC).
Wm. Kevin Kelly, Susan Halabi, Michael Carducci, Daniel George, John F. Mahoney, Walter M. Stadler, Michael
Morris, Philip Kantoff, Paul Monk, Eric J. Small
for the Cancer and Leukemia Group B (CALGB) and Eastern Cooperative Oncology Group (ECOG)
Role of Vascular Endothelial Growth Factor (VEGF) in CRPC
Lower baseline urinary VEGF levels are associated with improved survival (P = 0.024). (Bok, R. A. et al. Cancer Res 2001;61:2533-2536)
Multivariate model of plasma VEGF levels predicting survival time among 197 CRPC patients(George DJ, et al. Clin Cancer Res. 2001 7:1932-6)
Factor HR P
VEGF
(>260 vs ≤260)
2.42 .006
Measurable disease
( Y vs N)
2.01 <.001
Alkakine phosphatase
(>170 vs ≤170)
1.60 .030
Baseline PSA
(>150 vs ≤150)
1.48 .050
Cancer and Leukemia Group B:Phase II Studies in CRPC
Authors N Objective
Response
50% PSA
Decline
TTP-
PSA(Months)
Median Survival
(Months)
Savarese et al.1
EstramustineDocetaxel
47 50% 68% 7 20
Oh et al.2
EstramustineDocetaxelCarboplatin
40 55% 68% 9 18
Picus et al.3
EstramustineDocetaxelBevacizumab
77 59% 75% 8 24
1J Clin Oncol. 2001 May 1;19(9):2509-16 2Cancer. 2003 Dec 15;98(12):2592-83Picus et al. Cancer in press
CALGB 90401
• Primary Objective– To determine if the addition of bevacizumab to
docetaxel and prednisone increases overall survival compared to docetaxel and prednisone alone in patients with CRPC.
• Secondary Objectives– To compare the PFS of these two regimens in patients
with CRPC.– To compare the proportion of patients who experience
50% post-therapy PSA decline from baseline.– To compare proportion of patients who have grade 3 or
higher toxicities
CALGB 90401: Eligibility Criteria
• Progressive adenocarcinoma of the prostate by consensus criteria • No prior cytotoxic chemotherapy or anti- angiogenic agents • Four or more weeks since major surgery or radiation therapy• Eight or more weeks from radio-isotope therapy• ECOG performance status of 0-2• Signed Informed Consent
• Patient with HTN were to be well controlled (< 160/90)• No significant history of bleeding within 6 months of registration• No GI perforation or arterial thrombotic event within 12 months
of registration
Required initial laboratory values:
– Absolute neutrophil count: ≥ 1500/ µL– Platelet count ≥ 100,000/ µL – Creatinine ≤ 1.5 x ULN– Bilirubin* ≤ 1.5 x ULN– AST ≤ 1.5 x ULN– PSA ≥ 5 ng/ml (non-measurable ds.)– UPC ratio < 1.0– Serum Testosterone ≤ 50 ng/dl
*Patient with Gilbert’s Disease, ≤ 2.5 x ULN is allowed
CALGB 90401: Eligibility Criteria
CALGB 90401: Stratification Factors
1. Predicted 24 month survival probability using the nomogram developed by Halabi et al*.
• Group 1: < 10%• Group 2: 10-29.9% • Group 3: ≥ 30%
2. Age• < 65 years• ≥ 65 years
3. Prior history of arterial events (cardiac ischemia/infarction, cerebral ischemia, peripheral arterial ischemia or CNS hemorrhage.
• Yes• No
*Halabi et al JCO.2:1232-7, 2003
CALGB 90410: Treatment SchemaR
AN
DO
MIZ
E (
1:1)
RA
ND
OM
IZE
(1:
1)
Arm 2Dexamethasone 8 mg po x 3 doses Docetaxel 75 mg/m2 on day 1 q 21 daysPrednisone 10 mg po dailyPlacebo1 IV on day 1 q 21 days
Arm 1Dexamethasone 8 mg po x 3 dosesDocetaxel 75 mg/m2 on day 1 q 21 daysPrednisone 10 mg po dailyBevacizumab1 15 mg/kg IV on day 1 q 21 days
•ASA 325 mg encouraged in all patients that can tolerate 1In the event of intolerable toxicity to Docetaxel the Bevacizumab\placebo may be continued alone until POD
CALGB 90410: Study Evaluation
Baseline Frequency
•Physical exam
•Toxicity assessment
•Routine chemistry, CBC, Urine protein\creatinine ratio
•Prostate specific antigen (PSA)
•Testosterone
•Chest x-ray
•Bone Scan
•CT or MRI of abdomen\pelvis
q cycle
q cycle
q cycle
*q cycle
*Every 3 cycles
*Every 3 cycles
*Every 3 cycles
*Every 3 months until evidence of progression or relapse for a maximum of 5 years from the time of registration
• Primary endpoint: Overall Survival (OS)
• Secondary endpoint: –50% decline in PSA1
–Progression Free Survival (PFS)1
–Toxicity
• 1050 men randomized
• 86% power to detect a hazard ratio (HR) of 1.26 (assume an increase in median OS from 19 mo. in DP to 24 mo. with DP+B)
–Final analysis was based on 748 deaths
• Primary analysis an intent-to-treat approach using the stratified
log-rank statistic adjusting for the stratification factors
• Trial was monitored for efficacy and safety by the CALGB DSMB1PSAWG Criteria, J.Clin.Oncol. 22:537-556, 2004
CALGB 90401:Trial Design and Data Analysis
Baseline Clinical Characteristics(N =1050)
May 2005 – December 2007
Arm 1DP + BN=524
Arm 2DP
N=526
RaceWhite 88% 87%
Age<6565+ years
34%66%
33%67%
Prior history of arterial eventsYesNo
7%93%
8%92%
24-Month Predicted Survival Probability<10%10%-29.9%30%+
18%34%47%
18%35%47%
ECOG PS 0, 12
96%4%
95%5%
Measurable Disease 48% 52%
Percent on opioid pain medication 35% 35%
Median Number of Treatment Cycles
0 2 4 6 8 10
ARM 1: DB + B
ARM 2: DP
Overall
Bev or Placebo Docetaxel
Range
(0-40)(0-40)
(0-40)(0-40)
(0-38)(0-37)
0 6 12 18 24 30 36 42
Time(months)
0.0
0.2
0.4
0.6
0.8
1.0
Ove
rall
Sur
viva
l (pr
obab
ility
)
Placebo+DoceBev+Doce, log-rank p=0.181
Kaplan-Meier Overall Survival Curves by Treatment Arm
526 480 390 305 199 100 44 22524 484 417 327 217 117 52 23
Placebo+DoceBev+Doce
Number of Patients at Risk
Median DP = 21.5 (20.0-23.0)Median DPB=22.6 (21.1-24.5) HR= 0.91 (0.78-1.05)
0 6 12 18 24 30 36 42
Time(months)
0.0
0.2
0.4
0.6
0.8
1.0
PF
S (
pro
babili
ty)
Placebo+DoceBev+Doce, log-rank p<0.0001
Kaplan-Meier PFS Curves by Treatment Arm
526 303 134 75 34 8 4 0524 381 194 97 44 15 5 1
Placebo+DoceBev+Doce
Number of Patients at Risk
Median DP = 7.5 (6.7-8.0)Median DPB=9.9 (9.1-10.6) HR= 0.77 (0.68-0.88)
Secondary Endpoints: Objective Response and 50% Decline in PSA
Clinical Endpoint
Arm 1DP+B
(N=524)
Arm 2 DP
(N=526)
p-value
≥50% decline in PSA(95% CI)
69.5% (65.2-73.5)
57.9% (53.3-62.3)
0.0002
Objective Response(95% CI) (# with measurable disease)
53.2%(46.8-59.6)
(248)
42.1% (36.2-48.2)
(273)
0.0113
DP + B better DP better
Variable
PS0 1
HGB<=12.8>12.8
ALK<=118>118
LDH<=205>205
PSA<=85>85
TEST<=20>20
TotalN = 1050
ARM 1 DP +B
26.716.7
19.3 26.7
27.9 19.7
26.0 19.4
26.6 20.1
22.6 22.8
22.6
Median Survival (months)
Arm 2DP23.817.2
17.0 26.7
26.6 16.3
26.5 16.3
24.5 18.4
19.9 23.4
21.5
HR
0.8320.996
0.8151.045
1.0140.793
1.0190.802
0.8960.892
0.7891.074
0.906
p-value
0.0810.971
0.040.145
0.9020.02
0.870.029
0.3230.267
0.0160.549
0.181
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
Forest Plot of Overall Survival in Select Subgroups
DP + B better DP better
Variable
PS0 1
HGB<=12.8>12.8
ALK<=118>118
LDH<=205>205
PSA<=85>85
TEST<=20>20
TotalN = 1050
ARM 1 DP +B
26.716.7
19.3 26.7
27.9 19.7
26.0 19.4
26.6 20.1
22.6 22.8
22.6
Median Survival (months)
Arm 2DP23.817.2
17.0 26.7
26.6 16.3
26.5 16.3
24.5 18.4
19.9 23.4
21.5
HR
0.8320.996
0.8151.045
1.0140.793
1.0190.802
0.8960.892
0.7891.074
0.906
p-value
0.0810.971
0.040.145
0.9020.02
0.870.029
0.3230.267
0.0160.549
0.181
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
Forest Plot of Overall Survival in Select Subgroups
Significant Grade ≥ 3 Adverse Events
ARM 1
DP +B
ARM 2
DP
Neutrophils 30% 24%
Fatigue 18% 10%
Leukocytes 17% 13%
Febrile Neutropenia 7% 4%
Hypertension 7% 1%
Hemorrhage, GI 6% 2%
GI, Perforation 4% 0%
Mucositis\stomatitis 3% 0%
Pneumonitis 2% 0%
Thrombosis\embolism 4% 7%
Adverse Events Summary
Arm Grade 3
# (%)
Grade 4
# (%)
*Grade 5
# (%)
Maximum Hematologic AE DP + B
DP
11%
12%
24%
17%
0%
0%
Maximum non-Hematologic AE
DP + B
DP
53%
35%
11%
10%
3.8%
1.1%
Maximum Overall AE DP + B
DP
41%
31%
30%
23%
3.8%
1.1%
* Infection major cause of treatment related deaths
Conclusions
• The addition of bevacizumab to docetaxel/prednisone did not significantly prolong survival in men with metastatic CRPC, although a trend towards improved survival was observed (22.6 vs 21.5 m, p = 0.18).
• The addition of bevacizumab to docetaxel/prednisone DID have a significant impact on:PFS 9.9 mo. vs. 7.5 mo. p < 0.0001 Objective RR 53.2% vs. 42.1% p= 0.0113PSA decline ≥ 50% 69.5% vs. 57.9% p= 0.0002
Conclusions
• OS with docetaxel/prednisone is longer than previously reported (21.5 mos vs 19.2 mos in TAX327) and may be due to:
•Stage migration
•A good risk population (47% of pts had a 24 mo predicted survival of > 30%)
• Discrepancy between OS and other markers of clinical benefit such as PFS and RR may be due to:
•Impact of longer-than-expected survival in the control group on power calculations
•Impact of subsequent therapy on OS•True disconnect between PFS/RR and OS
Discordance between OS and PFS\overall response
• The addition of bevacizumab to docetaxel/prednisone
resulted in more severe toxicities.
• The role of anti-angiogenic therapeutics in metastatic
CRPC remains to be defined.
• Exploratory analysis of patient subsets that may have a
clinical benefit from bevacizumab are underway.
Conclusions
Acknowledgements
• Patients and families that participated in the
study
• All colleagues and investigators that contributed
to the success of CALGB 90401.
• Cancer and Leukemia Group B central office and
statistical staff– Eleanor Leung, Ellen Kaplan, Jennifer Williams, John
Taylor
Thank You