Have the OPTIMOX-2, CAIRO-3, COIN, DREAM and other recent trials settled the question of maintenance versus
observation in advanced CRC?
• Yes • Deborah Schrag, MD, MPH• No• John L. Marshall, MD
Maintenance
• Why we do it– Optimox, should we optimiri
• Timing of change– Switch or reduce
• What drugs– 5fu or capecitabine– Bev? Erlotinib, other?
• What if front line is an EGFR regimen?• Do we build resistance vs start and stop?• Other diseases- lung, breast, heme, prostate….
3
Study Design and Drugs
Phase III Trial of CapeOx vs. FOLFOX4 plus Bevacizumab or Placebo in First-line MCRC
CapeOx + placebo (N=350)
FOLFOX4 + placebo (N=351)
CapeOx + bevacizumab (N=350)
FOLFOX4 + bevacizumab (N=350)
CapeOx (N=317)
FOLFOX4 (N=317)
Recruitment June 2003–May 2004 Recruitment Feb 2004–Feb 2005
Initial 2-arm open-label study (N=634)
• Publication of Bevacizumab Phase III data (Hurwitz H, et al. N Engl J Med 2004;350:2335-2352).• Original Protocol Amended to a 2x2 placebo controlled design.
Cassidy J. et al., Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-2012.
PFS XELOX Non-inferiority
Roche Medical Affairs. All rights reserved.
Phase III Trial of XELOX vs. FOLFOX4 plus Bevacizumab or Placebo in First-line mCRC
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N=1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumab N=1017; 813 events
Primary Objective Achieved Based on ITT
Cassidy et al. ESMO 2006. Oral Presentation
PFS Superiority of Bevacizumab + CT
Roche Medical Affairs. All rights reserved.
HR=0.83 [97.5% CI 0.72–0.95] (ITT)p=0.0023
FOLFOX+placebo/XELOX+placeboN=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumabN=699; 513 events
Primary Objective Achieved XELOX Subgroup FOLFOX Subgroup
HR=0.77 [97.5% CI 0.63–0.94] (ITT)p=0.0026
XELOX+placeboN=350; 270 events XELOX+bevacizumabN=350; 258 events
HR=0.89 [97.5% CI 0.73–1.08] (ITT)p=0.1871
FOLFOX+placeboN=351; 277 events FOLFOX+bevacizumabN=349; 255 events
Phase III Trial of XELOX vs. FOLFOX4 plus Bevacizumab or Placebo in First-line mCRC
Cassidy et al. ESMO 2006. Oral Presentation
Patients should remain ‘on treatment*’ to achieve the optimal clinical benefit with
Bevacizumab
Saltz, et al. ASCO 2007 (poster)*Preplanned analysis
0 5 10 15 20Months
PF
S e
stim
ate
FOLFOX4/XELOX + Bevacizumab
FOLFOX4/XELOX + placebo1.0
0.8
0.6
0.4
0.2
0
GENERAL: HR=0.83(PFS 9.4 vs 8.0 months, p=0.0023)
ON TREATMENT: HR=0.63 (PFS 10.4 vs 7.9 months, p<0.0001)
6 months
OPTIMOX Studies
OPTIMOX-1: Maintenance therapy
(N=620)
FOLFOX 4 until progression
FOLFOX 7 FOLFOX 7
sLV5FU2
OPTIMOX-2: Chemotherapy-free interval
(N=202)
mFOLFOX 7 mFOLFOX 7
sLV5FU2
mFOLFOX 7 mFOLFOX 7
Chemotherapy-free interval
Tournigand et al. J Clin Oncol. 2006;24:394.Maindrault-Goebel et al. ASCO, 2007. Abstract 4013.
Progression-free SurvivalProgression-free survival
0 10 20 30 40 50 60 70 80 90 1000.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 36 weeks
OPTIMOX2 median 29 weeks
weeks
Pro
ba
bili
ty
p=0.08
Overall SurvivalOverall Survival
0 10 20 30 40 500.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 26 months
OPTIMOX2 median 19 months
p=0.0549
months
Pro
ba
bili
ty
Maughan TS et al. Lancet. 2003;361:457-464.
PFS HR1.20 (0.96-1.49) favor continuous
Continuous vs. Intermittent Therapy: MRC Trial
• Median off-treatment duration with intermittent therapy was 4.3 months– Significantly fewer adverse events
• Overall survival was similar in both groups
Intermittent Continuous
100
75
50
25
0O
S (%
)
178 (94)
176 (94)
76 (41)
74 (49)
24 (12)
17 (12) 2 (0)
5 (0) 3
2
PFS
(%)
100
75
50
25
00
Months From Randomization 12 24 36 48
No. at RiskIntermittent
Continuous 178 (162)
176 (152)
14 (6)
19 (15)
6 (0)
1 (1)
2 (0)
0 (0)
1
0
0 12 24 36 48Months From Randomization
CR, PR, SDCR, PR, SD
Previously Untreated
mCRC
Previously Untreated
mCRC
RANDOM I ZAT I ON
RANDOM I ZAT I ON
FOLFIRI x 2
months
FOLFIRI x 2
months
FOLFIRI x 2
months
FOLFIRI x 2
months
EVALUATE
EVALUATE
Progression – Off Trial
Continuous vs. Intermittent Therapy: GISCAD Trial
11
Break x 2 months then
FOLFIRI x 2 months
Break x 2 months then
FOLFIRI x 2 months
FOLFIRI x 4 months
FOLFIRI x 4 months
Labianca R et al. Ann Oncol. 2011;22:1236-1242.
146
147
75
70
25
27
10
9
146
147
95
101
39
43
10
13
No. at RiskContinuous
Intermittent
Months 0
Patie
nts,
%0 6 12 18
Months
100
80
60
40
20
0
Patie
nts,
%
6 12 18 24 30 36
130
124
60
68
19
29
Labianca R et al. Ann Oncol. 2011;22:1236-1242.
Overall Survival Progression-Free Survival
100
80
60
40
20
0
Continuous armIntermittent arm
Events145143
Totals146147
Continuous armIntermittent arm
Events145143
Totals146147
Continuous vs. Intermittent Therapy: GISCAD Trial
CR, PR, SDCR, PR, SD
Patients with newly
diagnosedmCRC
N = 480
Patients with newly
diagnosedmCRC
N = 480
RANDOM I ZAT I ON
RANDOM I ZAT I ON
CapecitabineOxaliplatin
Bevacizumab6 cycles, q3
weeks
CapecitabineOxaliplatin
Bevacizumab6 cycles, q3
weeks
CapecitabineOxaliplatin
Bevacizumab6 cycles, q3
weeks
CapecitabineOxaliplatin
Bevacizumab6 cycles, q3
weeks
EVALUATE
EVALUATE
Maintenance Bevacizumab: MACRO Trial
13Diaz-Rubio E et al. Oncologist. 2012;17:15-25.
CapecitabineOxaliplatin
Bevacizumabuntil
Progression
CapecitabineOxaliplatin
Bevacizumabuntil
Progression
Bevacizumab until
Progression
Bevacizumab until
Progression
MACRO: Overall Survival (ITT)
XELOX-Bev Bev
No. of Patients 239 241
Event 175 (73%) 174 (72%)
Censored 64 (27%) 67 (28%)
Median (95% CI) 23.2 (19.79, 26.01)
19.99 (17.98,23.25)
Time (months)
XELOX-BevBev
No. at Risk
241 239
Su
rviv
al P
rob
abil
ity
0.0
0.25
0.50
0.75
1.00
0
02
39
1913
33
2623
30
3940
27
5460
24
7785
21
101120
18
132146
15
159170
12
193191
9
210208
6
226227
3
86
36
BevXELOX-Bev
Diaz-Rubio E et al. Oncologist. 2012;17:15-25.
HR: 1.05 (0.851, 1.295)
OPTIMOX3 – DREAM protocol
mFOLFOX7 + bevacizumaba
XELOX2 +bevacizumabb
FOLFIRI +bevacizumabc
aOxaliplatin 100 mg/m² d1 (6 cycles), 5-FU 2.4 g/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 6–12 cyclesbOxaliplatin 100 mg/m² d1 (6 cycles), capecitabine 1.25–1.5 g/m² bid d1–d8, bev 5 mg/kg d1 q2w, 6–12 cyclesc Irinotecan 180 mg/m² d1, 5-FU 2.4 mg/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 12 cycles
Bevacizumab (7.5 mg/kg q3w)
+ erlotinib (150 mg/d)until PD
RANDOMISATION
NoPD
n=222
n=2244 Jan 2007 – 13 Oct 2011
INDUCTION (N=700) MAINTENANCE (N=446)
Bevacizumab (7.5 mg/kg q3w)
until PD
REGISTRATION
Maintenance PFS(from randomization)
BevacizumabBevacizumab
+ erlotinib
No. of patients 224 222
Events 177 (79%) 150 (68%)
Censored 47 (21%) 72 (32%)
Median [95% CI] 4.57 [4.1–5.5] 5.75 [4.5–6.2]
HR [95% CI] 0.73 [0.59–0.91]
p-value 0.0050
Ma
inte
na
nce
PF
S (
%)
0
20
40
60
80
100
Time (months)
2 60 4 8 10 12
BevacizumabBevacizumab + erlotinib
No. at risk:Bevacizumab
Bevacizumab + erlotinib224
222
172
176
110
116
67
73
40
53
26
37
15
28
PFS from registration(randomised population)
BevacizumabBevacizumab +
erlotinib
No. of patients 224 222
Events 177 (79%) 150 (68%)
Censored 47 (21%) 72 (32%)
Median [95% CI] 9.23 [8.5–10.1] 10.22 [9.6–11.1]
HR [95% CI] 0.73 [0.59–0.91]
p-value 0.0045
Ma
inte
na
nce
PF
S (
%)
0
20
40
60
80
100
Time (months)
2 60 4 8 10 12
BevacizumabBevacizumab + erlotinib
No. at riskBevacizumab
Bevacizumab + erlotinib224
222
224
222
216
218
185
193
76
90
42
58
20
27
15
19
14 16 18
30
39
123
136
Overall survival(all patients, from registration)
Ove
rall
surv
iva
l (%
)
Time (months)
4 80 12
Median overall survival 25.4 months [95% CI 22.96–28.19] (n=700)
No. at risk:700 660 580 469 384 231
16 20 24
313
0
20
40
60
80
100
Study design
SD or better after 6 cycles CAPOX- B
observation
R
capecitabine + bevacizumab
PD PDRe-introduction
CAPOX-B
PFS1 PFS2
Time (mths)
PF
S1
Pro
ba
bili
ty
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 85 18 9 6 6 3 Observation
279 172 89 44 29 15 9 Maintenance
Observation
Maintenance
median PFS1 - Observation : 4.1 (95% CI: 3.9 - 4.4 )
median PFS1 - Maintenance : 8.5 (95% CI: 6.9 - 10.2 )
ITT, events/n ( 256 / 279 - 266 / 279 )
HR= 0.44 ( 95% CI: 0.36 - 0.53 )
stratified log-rank p-value 0
Median PFS1
Observation 4.1 m [95%CI: 3.9-4.4]
Maintenance 8.5 m [95%CI: 6.9-10.2]
Stratified HR 0.44 [95%CI: 0.36-0.53]
p value < 0.00001
PFS1
adjusted HR 0.41, p <0.001
Time (mths)
TT
2P
D P
rob
ab
ility
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 247 174 97 52 36 13 Observation
279 251 187 134 87 52 31 Maintenance
Observation
Maintenance
median TT2PD - Observation : 15.0 (95% CI: 13.6 - 16.4 )
median TT2PD - Maintenance : 19.8 (95% CI: 18.0 - 21.9 )
ITT, events/n ( 223 / 279 - 251 / 279 )
HR= 0.67 ( 95% CI: 0.55 - 0.81 )
stratified log-rank p-value 0
TT2PD
Median TT2PD
Observation 15.0 m [95%CI:13.6-16.4]
Maintenance 19.8 m [95%CI: 18.0-21.9]
Stratified HR 0.67 [95%CI: 0.55-0.81]
p value < 0.00001adjusted HR 0.63, p <0.001
Time (mths)
OS
Pro
ba
bili
ty
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 248 184 122 78 53 28 Observation
279 252 192 143 95 58 33 Maintenance
Observation
Maintenance
median OS - Observation : 18.2 (95% CI: 16.3 - 20.8 )
median OS - Maintenance : 21.7 (95% CI: 19.4 - 24.0 )
ITT, events/n ( 204 / 279 - 217 / 279 )
HR= 0.87 ( 95% CI: 0.71 - 1.06 )
stratified log-rank p-value 0.156
Overall SurvivalMedian OS
Observation 18.2 m [95%CI: 16.3-20.8]
Maintenance 21.7 m [95%CI: 19.4-24.0]
Stratified HR 0.87 [95%CI: 0.71-1.06]
p value 0.156adjusted HR 0.80, p 0.035
preliminary survival analysis
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