Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in...
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Bevacizumab continuation versus no continuation after first-line
chemo-bevacizumab therapy in patients with metastatic colorectal cancer:
a randomized phase III non-inferiority trial
Koeberle D, Betticher D, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu R, Schacher S, Hess V, Herrmann R
Swiss Group for Clinical Cancer Reseach
Background
• Chemotherapy plus Bevacizumab (BEV) is a standard option for first-line treatment in patients with metastatic colorectal cancer
• In many countries duration of first line chemotherapy in the absence of disease progression or severe toxicity is usually limited to 4-6 months
• After stopping first-line chemotherapy plus BEV the value of BEV monotherapy as maintenance strategy until disease progression is unknown
Study design
First-line chemo-therapy + BEVfor 4-6 months
No PDNo PD
Randomization1: 1
BEV continuation(7.5 mg/kg q 3 w)
until PD
No antitumor treatment(no BEV) until PDStratification factors:
• Best response during first-line chemotherapy + BEV (CR/PR vs SD)• Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks)• Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs Fluoropyrimidine mono)• Disease burden (metastases in one organ vs multiple organs)• Center
Study conducted in 26 sites in Switzerland (accrual period 2007-2012)
Main eligibility criteria
• Patients ≥ 18 years with pathologically confirmed diagnosis of colorectal adenocarcinoma
• First-line chemotherapy for metastatic disease with oral or intravenous fluoropyrimidine alone, or in combination with irinotecan or oxaliplatin
• Chemotherapy must have been given in combination with standard dose of BEV for at least 16, but no longer than 24 weeks as part of the first-line treatment
• Last administration of BEV within 4 weeks before randomization
• Stable disease (SD), partial response (PR) or complete response (CR) after end of chemotherapy/BEV first-line treatment (tumor assessment within 21 days before randomization)
Endpoints
Primary endpoint:
• Time to progression (TTP)– Measured by CT-scans q 6 weeks from randomization until PD
Secondary endpoints:
• Progression free survival (PFS)• Time to second-line treatment • Overall survival (OS) • Adverse events related to BEV • Treatment costs
Statistical considerations• Non-inferiority study
– Assumption: TTP of ≤ 22 weeks for BEV continuation TTP of ≥16 weeks for no BEV
– Hypothesis: BEV vs. no BEV Hazard Ratio (HR) HR ≥ 16/22 = 0.727
• 219 events required for a significance level of 10%, a power of 85% to detect a HR=1, one interim analysis
• Analysis based on 262 evaluable patients (131 in each arm)
Patient characteristicsCharacteristic (% patients) BEV (n=131) No BEV (n=131)
Age (range) 63 (40-83) 65 (23-85)
Sex: male / female 72 / 28 73 / 27
WHO performance status: 0 / 1 74 / 26 69 / 31
Adjuvant Chemotherapy 28 28
Clinically significant comorbidities 58 50
Response first-line: CR+PR / SD 62 / 38 59 / 41
First-line duration: 16-20 / 21-24 weeks 64 / 36 69 / 31
First-line chemotherapy: Irinotecan + fluoropyrimidine Oxaliplatin + fluoropyrimidine Fluoropyrimidine mono
3162 7
3263 5
RESULTS
Based on a median follow-up time of 30.1 months(Range in living patients 2.7 - 54.9)
TTP (from randomization)
/
/ / / /
/ /
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0 6 12 18 24 30 36 42 48
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
port
ion
with
out
prog
ress
ion
BEV
no BEV
No. at riskBEV 131 40 14 8 6 5 3 2 1no BEV 131 22 10 7 5 1 1 1 0
BEV no BEV
No. of events 124 123
Median(95%CI)
4.1 months(3.1-5.4)
2.9 months(2.8-3.8)
HR 95% CI
0.74 (0.57-0.95)
Non-inferiority p = 0.47
TTP subgroup analysis
0.5 0.727 1.0 1.5
BEV better no BEV better
all
age < 60
age > 60
female
male
WHO 0
WHO 1
FL CR/PR
FL SD
FL dur 16-20
FL dur 21-24
FL iri + fluo
FL oxa + fluo
FL fluo mono
1 organ
>1 organs
Hazard Ratio (95% CI)
FL = First-line
PFS (from start of first-line therapy)
/
/
/ / / /
/
/ / / / / /
0 6 12 18 24 30 36 42 48 54
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
port
ion
with
out
prog
ress
ion/
deat
h BEV
no BEV
No. at riskBEV 131 122 40 13 6 6 5 3 2 1no BEV 131 116 18 8 7 4 1 1 0 0
BEV no BEV
No. of events 125 124
Median(95%CI)
9.5 months(8.6.-10.2)
8.5 months(8-8.9)
HR 95% CI
0.75 (0.58-0.96)
Difference p = 0.021
Time to second-line treatment (from randomization)
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0 6 12 18 24 30 36 42 48
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
port
ion
with
out
seco
nd-li
ne t
reat
men
tBEV
no BEV
No. at riskBEV 131 60 23 16 9 7 4 2 1no BEV 131 46 17 11 8 4 3 1 0
BEV no BEV
No. of events 112 112
Median(95%CI)
5.9 months(4.8-7.5)
4.8 months(4.1-5.5)
HR 95% CI
0.81(0.62-1.05)
Difference p = 0.104
Overall Survival (from start of first-line therapy)
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0 6 12 18 24 30 36 42 48 54 60
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
port
ion
surv
ivin
g
BEV
no BEV
No. at riskBEV 131 130 115 86 52 33 22 10 3 1 0no BEV 131 131 107 76 44 25 13 6 1 1 1
BEV no BEV
No. of events 84 84
Median(95%CI)
25.1 months(22-28.9)
22.8 months (20.3-26.1)
HR 95% CI
0.83(0.61-1.12)
Difference p = 0.218
Adverse events
BEVN=131
No BEVN=131
CTCAE grade
Patients (%) 1-2 3-4 5 1-2 3-4 5
Hemorrhage 5 - - 1 - -
Hypertension 15 6 - 3 1 -
Proteinuria 15 - - 1 - -
Thrombosis - 2 - - - -
GI-Perforation - - - - - -
Cost analysis
Included resource use Base case 1) Low (-30%) High (+30%)
BEV continuation USD 5.58/mg
BEV administration USD 372
Control visit to oncologist USD 165 115 215
In-patients USD 1600/day 1120/day 2080/day
CT-scan USD 663
MRI USD 735
1) Swiss prices and Swiss health system
Not included costs: Laboratory tests, out-patient AE treatments, other out-patient treatments/care
Cost analysis
BEV NO BEV
Cost analysis
To
tal c
ost
s U
SD
Summary
• Non-inferiority could not be demonstrated
• The difference in median TTP between BEV continuation versus no treatment after randomization is 5 weeks
• Overall survival in both arms is not significantly different
• Utility of BEV continuation needs to be balanced
with significantly higher treatment costs
Acknowledgements
• Patients
• Investigators, study coordinators and nurses at SAKK coordination center and study sites
Swiss Association of Social Health Insurance Companies
Swiss Group for Clinical Cancer Research