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….
Phase III Trial of CapeOx vs. FOLFOX4 plus
Bevacizumab or Placebo in First-line MCRC
Study Design and Drugs
Recruitment June 2003–May 2004
Recruitment Feb 2004–Feb 2005
CapeOx (N=317)
CapeOx + placebo
(N=350)
CapeOx + bevacizumab
(N=350)
FOLFOX4 (N=317)
FOLFOX4 + placebo
(N=351)
FOLFOX4 + bevacizumab
(N=350)
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.
3
Phase III Trial of XELOX vs. FOLFOX4 plus
Bevacizumab or Placebo in First-line mCRC
PFS XELOX Non-inferiority
Primary Objective Achieved Based on ITT
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab
XELOX/XELOX+placebo/XELOX+bevacizumab
Cassidy et al. ESMO 2006. Oral Presentation
N=1017; 826 events
N=1017; 813 events
Roche Medical Affairs. All rights reserved.
Phase III Trial of XELOX vs. FOLFOX4 plus
Bevacizumab or Placebo in First-line mCRC
PFS Superiority of Bevacizumab + CT
Primary Objective
Achieved
HR=0.83 [97.5% CI 0.72–0.95] (ITT)
p=0.0023
XELOX Subgroup
FOLFOX Subgroup
HR=0.77 [97.5% CI 0.63–0.94] (ITT)
p=0.0026
HR=0.89 [97.5% CI 0.73–1.08] (ITT)
p=0.1871
FOLFOX+placebo/XELOX+placebo
N=701; 547 events
FOLFOX+bevacizumab/XELOX+
bevacizumab
N=699; 513 events
Cassidy et al. ESMO 2006. Oral Presentation
XELOX+placebo
N=350; 270 events
XELOX+bevacizumab
N=350; 258 events
FOLFOX+placebo
N=351; 277 events
FOLFOX+bevacizumab
N=349; 255 events
Roche Medical Affairs. All rights reserved.
Patients should remain ‘on treatment*’ to
achieve the optimal clinical benefit with
Bevacizumab
6 months
1.0
FOLFOX4/XELOX + Bevacizumab
FOLFOX4/XELOX + placebo
PFS estimate
0.8
0.6
ON TREATMENT: HR=0.63
(PFS 10.4 vs 7.9 months, p<0.0001)
0.4
GENERAL: HR=0.83
(PFS 9.4 vs 8.0 months, p=0.0023)
0.2
0
0
*Preplanned analysis
5
10
Months
15
20
Saltz, et al. ASCO 2007 (poster)
OPTIMOX Studies
FOLFOX 4 until progression
OPTIMOX-1:
Maintenance therapy
(N=620)
FOLFOX 7
FOLFOX 7
sLV5FU2
mFOLFOX 7
OPTIMOX-2:
Chemotherapy-free interval
(N=202)
mFOLFOX 7
sLV5FU2
mFOLFOX 7
mFOLFOX 7
Chemotherapyfree interval
Tournigand et al. J Clin Oncol. 2006;24:394.
Maindrault-Goebel et al. ASCO, 2007. Abstract 4013.
Progression-free Survival
P rogression-free surv iv al
1 .0
O P T IMO X 1 m e d ian 3 6 we e ks
0 .8
P r o b a b ility
O P T IMO X 2 m e d ian 2 9 we e ks
0 .6
p =0 .0 8
0 .4
0 .2
0 .0
0
10
20
30
40
50
weeks
60
70
80
90
100
Overall Survival
O v erall S urv iv al
1 .0
O P T IMO X 1 m e d ian 2 6 m o nths
0 .8
P r o b a b ility
O P T IMO X 2 m e d ian 1 9 m o nths
0 .6
p =0 .0 5 4 9
0 .4
0 .2
0 .0
0
10
20
30
m o n th s
40
50
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
100
PFS HR1.20 (0.96-1.49)
favor continuous
75
50
OS (%)
PFS (%)
100
75
50
25
25
0
0
0
12
24
36
Months From Randomization
48
Intermittent
Continuous
0
12
24
36
Months From Randomization
48
No. at Risk
Intermittent
178 (162)
14 (6)
6 (0)
2 (0)
1
178 (94)
76 (41)
24 (12)
5 (0)
3
176 (152)
19 (15)
1 (1)
0 (0)
0
176 (94)
74 (49)
17 (12)
2 (0)
2
Continuous
Maughan TS et al. Lancet. 2003;361:457-464.
Continuous vs. Intermittent Therapy:
GISCAD Trial
Previously
Untreated
mCRC
R
A
N
D
O
M
I
Z
A
T
I
O
N
FOLFIRI
x2
months
FOLFIRI
x2
months
E
V
A
L
U
A
T
E
Break x 2
months then
FOLFIRI
x 2 months
CR, PR, SD
FOLFIRI
x 4 months
Progression – Off Trial
Labianca R et al. Ann Oncol. 2011;22:1236-1242.
11
Continuous vs. Intermittent Therapy:
GISCAD Trial
Progression-Free Survival
Overall Survival
Events
Continuous arm
145
Intermittent arm 143
Totals
146
147
Events
Continuous arm 145
Intermittent arm 143
80
80
Patients, %
100
Patients, %
100
60
40
No. at Risk
Continuous
60
40
20
20
0
0
0
6
12
18
24
Months
30
36
Totals
146
147
0
6
12
18
Months
146
130
95
60
39
19
10
146
75
25
10
Intermittent 147
124
101
68
43
29
13
147
70
27
9
Labianca R et al. Ann Oncol. 2011;22:1236-1242.
Maintenance Bevacizumab:
MACRO Trial
Patients with
newly
diagnosed
mCRC
N = 480
R
A
N
D
O
M
I
Z
A
T
I
O
N
Capecitabine
Oxaliplatin
Bevacizumab
6 cycles, q3
weeks
Capecitabine
Oxaliplatin
Bevacizumab
6 cycles, q3
weeks
E
V
A
L
U
A
T
E
CR, PR, SD
Capecitabine
Oxaliplatin
Bevacizumab
until
Progression
Bevacizumab
until
Progression
13
Diaz-Rubio E et al. Oncologist. 2012;17:15-25.
MACRO: Overall Survival (ITT)
Bev
239
241
Event
175 (73%)
174 (72%)
Censored
64 (27%)
67 (28%)
23.2 (19.79,
26.01)
19.99
(17.98,23.25)
No. of Patients
1.00
Survival Probability
XELOX-Bev
0.75
Median (95% CI)
HR: 1.05 (0.851, 1.295)
0.50
XELOX-Bev
Bev
0.25
0.0
0
3
6
9
239
241
227
226
208
210
191
193
12
15
18
21
24
27
30
33
36
39
170
159
146
132
120
101
85
77
60
54
40
39
23
26
13
19
6
8
2
0
No. at Risk
XELOX-Bev
Bev
Time (months)
Diaz-Rubio E et al. Oncologist. 2012;17:15-25.
OPTIMOX3 – DREAM protocol
INDUCTION (N=700)
R
E
G
I
S
T
R
A
T
I
O
N
mFOLFOX7 +
bevacizumaba
XELOX2 +
bevacizumabb
FOLFIRI +
bevacizumabc
4 Jan 2007 – 13 Oct 2011
aOxaliplatin
No
PD
MAINTENANCE (N=446)
R
A
N
D
O
M
I
S
A
T
I
O
N
Bevacizumab
(7.5 mg/kg q3w)
+ erlotinib
(150 mg/d)
until PD
n=222
Bevacizumab
(7.5 mg/kg q3w)
until PD
n=224
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 cycles
100 mg/m² d1 (6 cycles), capecitabine 1.25–1.5 g/m² bid d1–d8, bev 5 mg/kg d1 q2w, 6–12 cycles
c 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
bOxaliplatin
Maintenance PFS
(from randomization)
100
Bevacizumab
Bevacizumab
+ erlotinib
224
222
Events
177 (79%)
150 (68%)
Censored
47 (21%)
72 (32%)
4.57 [4.1–5.5]
5.75 [4.5–6.2]
No. of patients
Maintenance PFS (%)
80
Median [95% CI]
HR [95% CI]
60
0.73 [0.59–0.91]
p-value
0.0050
40
Bevacizumab
Bevacizumab + erlotinib
20
0
0
2
No. at risk:
Bevacizumab
224
172
Bevacizumab + erlotinib
222
176
4
6
Time (months)
8
10
12
110
67
40
26
15
116
73
53
37
28
PFS from registration
(randomised population)
100
Bevacizumab
Bevacizumab +
erlotinib
224
222
Events
177 (79%)
150 (68%)
Censored
47 (21%)
72 (32%)
9.23 [8.5–10.1]
10.22 [9.6–11.1]
No. of patients
Maintenance PFS (%)
80
Median [95% CI]
0.73 [0.59–0.91]
HR [95% CI]
60
p-value
0.0045
40
Bevacizumab
Bevacizumab + erlotinib
20
0
0
2
No. at risk
Bevacizumab
224
224
Bevacizumab + erlotinib
222
222
4
6
216
185
218
193
8
10
Time (months)
12
14
16
18
123
76
42
30
20
15
136
90
58
39
27
19
Overall survival
(all patients, from registration)
100
Overall survival (%)
80
60
40
Median overall survival 25.4 months [95% CI 22.96–28.19]
(n=700)
20
0
0
No. at risk:
700
4
8
12
Time (months)
16
20
24
660
580
469
384
313
231
Study design
PFS1
PFS2
observation
SD or better
after 6 cycles
CAPOX- B
PD
R
capecitabine +
bevacizumab
Re-introduction
CAPOX-B
PD
PFS1
1.0
median PFS1 - Observation : 4.1 (95% CI: 3.9 - 4.4 )
median PFS1 - Maintenance : 8.5 (95% CI: 6.9 - 10.2 )
Median PFS1
0.8
ITT, events/n
( 256 / 279 - 266 4.1
/ 279 m
)
Observation
Maintenance
8.5 m
PFS1 Probability
HR= 0.44 ( 95% CI: 0.36 - 0.53 )
stratified log-rank
Stratified
HR p-value
0.440
0.6
p value
[95%CI: 3.9-4.4]
[95%CI: 6.9-10.2]
[95%CI: 0.36-0.53]
< 0.00001
Maintenance
adjusted HR 0.41, p <0.001
0.4
0.2
Observation
0.0
279
85
18
9
6
6
3 Observation
279
172
89
44
29
15
9 Maintenance
0
6
12
18
Time (mths)
24
30
36
TT2PD
1.0
median TT2PD - Observation : 15.0 (95% CI: 13.6 - 16.4 )
median TT2PD - Maintenance : 19.8 (95% CI: 18.0 - 21.9
)
Median
0.8
TT2PD
ITT, events/n ( 223 / 279 - 251 / 279 )
Observation
15.0 m [95%CI:13.6-16.4]
TT2PD Probability
HR= 0.67 ( 95% CI: 0.55 - 0.81 )
Maintenance
19.8
stratified log-rank p-value
0 m [95%CI: 18.0-21.9]
0.6
Stratified HR
Maintenance
p value
0.67
[95%CI: 0.55-0.81]
< 0.00001
adjusted HR 0.63, p <0.001
0.4
Observation
0.2
0.0
279
247
174
97
52
36
13 Observation
279
251
187
134
87
52
31 Maintenance
0
6
12
18
Time (mths)
24
30
36
Overall Survival
1.0
median OS - Observation : 18.2 (95% CI: 16.3 - 20.8
)
Median
OS
median OS - Maintenance : 21.7 (95% CI: 19.4 - 24.0 )
Observation
0.8
18.2 m [95%CI: 16.3-20.8]
ITT, events/n ( 204 / 279 - 217 / 279 )
Maintenance
21.7
HR=
0.87 ( 95% CI: 0.71 - 1.06
)
m [95%CI: 19.4-24.0]
OS Probability
stratified log-rank p-value 0.156
Stratified
Maintenance
0.6
HR
p value
0.87
[95%CI: 0.71-1.06]
0.156 HR 0.80, p 0.035
adjusted
Observation
preliminary survival analysis
0.4
0.2
0.0
279
248
184
122
78
53
28 Observation
279
252
192
143
95
58
33 Maintenance
0
6
12
18
Time (mths)
24
30
36
Work to be done
• Agree to establish cape and bev as the
standard arm
• Now we must do the studies
– EGFR/VEGF
– Immune therapies
– Regorafanib, others