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

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