Miriam Koopman, L Simkens, A ten Tije, G Creemers, O Loosveld, F de Jongh, F Erdkamp, Z Erjavec, A van der Torren, J van der Hoeven, P Nieboer, J Braun, R Jansen, J Haasjes, A Cats, J Wals, L Mol, O Dalesio, H van Tinteren, C Punt

Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in

metastatic colorectal cancer

Phase 3 CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG)

Background

• The value of chemotherapy-free intervals has been tested in the OPTIMOX2, COIN and GISCAD studies, and is still a matter of debate1-3

• The optimal duration of chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) is unknown

• The benefit of bevacizumab added to chemotherapy in the NO16966 study (FOLFOX/CAPOX +/- bevacizumab) may have been compromised due to the low percentage of patients that received treatment until disease progression4

• Drug holidays are preferred by many patients 1Chibaudel et al. J Clin Oncol 20092Adams et al. Lancet Oncol 20113Labianca et al. Ann Oncol 20114Saltz et al. J Clin Oncol 2008

Study rationale

CAIRO3 study was designed to investigate the efficacy of

observation

versus

maintenance treatment with capecitabine + bevacizumab

after induction treatment with 6 cycles of capecitabine, oxaliplatin + bevacizumab (CAPOX-B)

CAIRO3 treatment

Pre-study induction treatment with 6 cycles of 3-weekly CAPOX- B• Capecitabine 1000 mg/m2 b.i.d. orally day 1 – 14• Oxaliplatin 130 mg/m2 i.v. day 1• Bevacizumab 7.5 mg/kg i.v. day 1

Maintenance treatment• Capecitabine 625 mg/m2 b.i.d. orally continuously• Bevacizumab 7.5 mg/kg i.v. day 1, 3-weekly

CAIRO3 main inclusion criteria

• Histological proof of metastatic CRC

• Age 18 years, WHO PS 0-1

• Stable disease or better after first-line treatment with 6 cycles of CAPOX- B

• Eligible for further treatment with CAPOX- B

• No intention of radical resection of metastases

• Adequate organ functions

• Written informed consent

Study design

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

PD PDRe-introduction

CAPOX-B

PFS1 PFS2

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

Re-introductionCAPOX-BPD

PFS1

PD

• PFS1: time from randomization until first progression after observation or maintenance treatment

Definition of PFS1

Definition of PFS2primary endpoint

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

PD

PFS2

Primary endpoint: PFS2 • time from randomization to progression upon re-introduction of CAPOX- B• PFS2 is considered to be equal to PFS1 for patients in whom CAPOX- B is not

reintroduced after PFS1 for any reason

PD

PFS1

Re-introductionCAPOX-B

Definition of TT2PD

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

PD

TT2PD

PD

PFS1

any treatmentincl. CAPOX-B

• TT2PD = time to second progression of disease, time from randomization to progression upon any treatment including CAPOX-B, given after PFS1

Statistical design

• Endpoints were calculated from time of randomization upon progression/death (i.e. not including 6 x CAPOX-B induction)

• Sample size was calculated to detect a hazard ratio of 0.78 which translates into an increase of PFS2 from 9 to 11.5 months

• 525 events were required, providing 80% power to detect a decrease of 22% in the hazard of progression (α=0.05, 2-tailed test)

• Stratified as well as adjusted HR's with corresponding p-values will be shown using stratified cox proportional hazard models adjusting for covariates with imbalances at baseline

Duration and evaluation of treatment

• Treatment was to be continued until progression, unless:– unacceptable toxicity– patient refusal – continuation not considered in the interest of the patient

• Evaluation of tumor response and toxicity every 9 weeks (RECIST, NCI-CTC criteria, 3.0)

Accrual and follow-up

• 74 Dutch hospitals

• 558 patients were randomized between May 2007 and June 2012

• Cut-off data 19-04-2013 (updated from abstract)

• Median duration of follow-up is 40 months

Observationn = 279

Maintenance n = 279

Prior adjuvant treatment (yes/no) 19/81% 18/82%

Serum LDH (normal/abnormal) 44/56% 44/56%

Response to induction treatment (CR+PR/SD) 66/34% 66/34%

WHO performance status (0/1) 62/38% 62/38%

Institution

Baseline characteristicsstratification parameters

Observationn = 279

Maintenance n = 279

Age (median, range) 64 (31-81) 63 (26-81)

Gender (male / female) 64/36% 66/34%

Number of metastatic sites (1 / >1) 46/54% 48/52%

Interval between primary diagnosis and randomization in the study (mean in months) *

19 14

Stage of disease (I-III / IV) * 33/67% 23/76%

Baseline characteristicsother

* Covariates of which the differences are statistically significant

CAIRO3 study profile

558 patients enrolled

279 patientsobservation

279 patientsmaintenance

212 patients(76%)

re-introductionCAPOX-B

131 patients(47%)

re-introductionCAPOX-B

67 patients(24%)

- ongoing obs.- no treatment- other treatment

148 patients(53%)

- ongoing maint.- no treatment- other treatment

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

Re-introductionCAPOX-BPD

PFS1

PD

• PFS1: time from randomization until first progression

Results: PFS1

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

Observation n=279

Maintenance n=279

Observation/maintenance ongoing 13 (5%) 20 (7%)

Treatment discontinuation 266 (95%) 256 (92%)

No follow up 0 3 (1%)

Reasons for discontinuation n=266 n=256

disease progression/death 264 (95%) 214 (77%)

toxicity 0 25 (10%)

refusal 0 5 (2%)

other 2 (1%) 12 (5%)

Median number of cycles (range)

Capecitabine - 9 (1-85)

Bevacizumab - 10 (1-88)

Treatment until PFS1

Results: PFS2primary endpoint

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

PD

PFS2

PD

PFS1

Re-introductionCAPOX-B

Primary endpoint: PFS2 • time from randomization to progression upon re-introduction of CAPOX- B• PFS2 is considered to be equal to PFS1 for patients in whom CAPOX- B is not

reintroduced after PFS1 for any reason

Time (mths)

PF

S2

Pro

ba

bili

ty

0 6 12 18 24 30 36

0.0

0.2

0.4

0.6

0.8

1.0

279 207 111 42 16 11 4 Observation

279 207 130 66 38 23 12 Maintenance

Observation

Maintenance

median PFS2 - Observation : 10.5 (95% CI: 9.3 - 12.3 )

median PFS2 - Maintenance : 11.8 (95% CI: 10.2 - 13.3 )

ITT, events/n ( 246 / 279 - 243 / 279 )

HR= 0.81 ( 95% CI: 0.67 - 0.98 )

stratified log-rank p-value 0.028

Primary endpoint PFS2

Median PFS2

Observation 10.5 m [95%CI: 9.3-12.3]

Maintenance 11.8 m [95%CI: 10.2-13.3]

Stratified HR 0.81 [95%CI: 0.67-0.98]

p value 0.028

adjusted HR 0.77, p 0.007

Observationn=279

Maintenancen=279

Observation/maintenance ongoing 13 (5%) 20 (7%)

No re-introduction CAPOX-B 54 (19%) 125 (45%)

Re-introduction CAPOX-B 212 (76%) 131 (47%)

No follow-up 0 3 (1%)

Reasons for discontinuation CAPOX-B n=212 n=131

Ongoing CAPOX- B 13 (6%) 8 (6%)

Disease progression/death 137 (65%) 97 (74%)

Toxicity 30 (14%) 18 (14%)

Patient refusal 11 (5%) 1 (1%)

Other 21 (10%) 7 (5%)

Treatment until PFS2

Observationn=279

Maintenancen=279

Observation/maintenance ongoing 13 (5%) 20 (7%)

No re-introduction CAPOX-B 54 (19%) 125 (45%)

Re-introduction CAPOX-B 212 (76%) 131 (47%)

No follow-up 0 3 (1%)

Reasons CAPOX-B was not re-introduced n=54 n=125

Persisting neurotoxicity 3 (6%) 15 (12%)

Other toxicities - 26 (21%)

Poor clinical condition 15 (28%) 19 (15%)

Patient refusal 8 (15%) 13 (10%)

Other 28 (52%) 52 (42%)

Treatment until PFS2

Results: TT2PD

SD or better after 6 cycles CAPOX- B

observation

R

capecitabine + bevacizumab

PD

TT2PD

PD

PFS1

any treatmentincl. CAPOX-B

• TT2PD = time to second progression of disease, time from randomization to progression upon any treatment given after PFS1

Observationn=279

Maintenancen=279

Observation/maintenance ongoing 13 (5%) 20 (7%)

No re-introduction CAPOX-B 54 (19%) 125 (45%)

Re-introduction CAPOX-B 212 (76%) 131 (47%)

No follow-up 0 3 (1%)

Treatment other than re-introduction CAPOX-B after PFS1

n=54 n=125

No treatment 29 (54%) 46 (37%)

Irinotecan 18 (33%) 53 (42%)

Anti-EGFR 0 10 (8%)

5FU-bevacizumab 4 (7%) 11 (9%)

Other 3 (6%) 5 (4%)

Treatment until 2nd progressionother than CAPOX-B

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 < 0.00001

adjusted 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 0.156

adjusted HR 0.80, p 0.035

preliminary survival analysis

Observationn = 279

Maintenancen = 279

Hypertension 18% 24%

Hematological toxicity NeutropeniaTrombocytopenia

00

2%1%

Diarrhea 1% 3%

Vomiting 1% 0.4%

Nausea 0 2%

Hand-foot syndrome 0 22%

Neurotoxicity 5% 10%

GI perforation 0 1%

Venous thromboembolic events 2% 3%

Fatigue 2% 4%

Toxicity (grade 3-4)during observation/maintenance

Observation

n=279Maintenance

n=279

4 drugs

capecitabine, oxaliplatin, bevacizumab, irinotecan

138 (49%) 136 (49%)

5 drugs

capecitabine, oxaliplatin, bevacizumab, irinotecan, anti-EGFR

34 (12%) 32 (11%)

Drugs administered during metastatic disease

Conclusions - I• Maintenance treatment with capecitabine plus

bevacizumab after 6 cycles CAPOX-B is feasible, and significantly prolongs PFS1 and PFS2

• The number of patients that was eligible for re-introduction of CAPOX-B is lower than expected

• When any treatment after PFS1 is considered, maintenance treatment also significantly prolongs the time to second progression (TT2PD)

• There is a non-significant benefit in median OS for maintenance treatment, which is significant in the adjusted analysis

Conclusions - II

• The percentage of patients that received 4 or 5 effective drugs during their metastatic disease is comparable in both treatment arms

• Therefore, time on treatment appears to be an additional relevant factor for overall survival in this study

• Our data support the use of maintenance treatment with capecitabine plus bevacizumab until progression or unacceptable toxicity after induction treatment of 6 cycles with CAPOX-B

DCCG CAIRO3 study - acknowledgementsInvestigators: C. Smorenburg, Alkmaar; R.Hoekstra, Almelo; C.Rodenburg, Amersfoort; G.Timmers, Amstelveen; A.Cats, M.Geenen, W. van Leeuwen, D.Richel, C.Punt, O.Leeksma, J.Otten Amsterdam; J.Douma, Arnhem; P.Nieboer,Assen; F.Valster, Bergen op Zoom; P. van den Berg Blaricum; O.Loosveld, A.Ten Tije Breda; D.Kehrer, Capelle a/d IJssel; M.Bos, Delft; Z.Erjavec,Delfzijl; H.Sinnige, Den Bosch; H.Sleeboom Den Haag; J.Berends, Den Helder; A.Imholz, Deventer; S.Hovenga, Drachten; E.Balk, Ede; G.Creemers, M.Dercksen, Eindhoven; M.Legdeur, Enschede; A.Smals, Geldrop; M. van Hennik, Gorinchem; A.van der Torren, Gouda; G.Hospers, R.de Jong, Groningen; M.Temizkan, Harderwijk; J.Wals, Heerlen; V.Derleyn, Helmond; E. Siemerink, Hengelo;J.Schrama, Hoofddorp; J.Haasjes, Hoogeveen; M.Polee, Leeuwarden;E. Batman, A.Gelderblom, J. van der Hoeven Leiden; R.Jansen, Maastricht; M.Los, Nieuwegein; C.Punt, C.Mandigers, Nijmegen; A.Vos, Oss; M.den Boer, Roermond; F.de Jongh, Rotterdam; J.Braun, Schiedam; F.Erdkamp, Sittard; G.Veldhuis, Sneek; C.Kruijtzer, Tiel; H.Roerdink, J. van Riel, Tilburg; S.van der Vegt, E.Voest, Utrecht; G.Vreugdenhil, Veldhoven; M.Werter, Venlo; P.Schiphorst, Winterswijk; A.van Bochove, Zaandam; H.Seinen, Zevenaar; A.Honkoop, Zwolle Statisticians: H, van Tinteren, O.Dalesio, Amsterdam Central Datamanagement: L.Mol, F.van Leeuwen, IKNL Nijmegen Independent Data Monitoring Committee: E. de Vries, E. vd Wall, J. Nortier, M. Buyse, K. Roest Supported by: Dutch Cancer Foundation, and unrestricted scientific grants from Roche, Sanofi-Aventis

Contact: email-address: M.Koopman-6@umcutrecht.nl