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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).

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slide1

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)

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

background
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 ClinOncol 2009

2Adams et al. Lancet Oncol 2011

3Labianca et al. Ann Oncol2011

4Saltz et al. J ClinOncol 2008

study rationale
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
CAIRO3 treatment

Pre-study induction treatment with 6 cycles of 3-weekly CAPOX- B

Capecitabine 1000 mg/m2b.i.d. orally day 1 – 14

Oxaliplatin 130 mg/m2i.v. day 1

Bevacizumab 7.5 mg/kg i.v. day 1

Maintenance treatment

Capecitabine 625 mg/m2b.i.d. orally continuously

Bevacizumab 7.5 mg/kg i.v. day 1, 3-weekly

cairo3 main inclusion criteria
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
Study design

PFS1

PFS2

capecitabine +

bevacizumab

observation

Re-introduction

CAPOX-B

SD or better

after 6 cycles

CAPOX- B

PD

PD

R

definition of pfs1
Definition of PFS1

PFS1

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

Re-introduction

CAPOX-B

PD

PD

R

  • PFS1: time from randomization until first progression after observation or maintenance treatment
definition of pfs2 primary endpoint
Definition of PFS2primary endpoint

PFS1

PFS2

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

Re-introduction

CAPOX-B

PD

PD

R

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
definition of tt2pd
Definition of TT2PD

PFS1

TT2PD

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

any treatment

incl. CAPOX-B

PD

PD

R

  • TT2PD = time to second progression of disease, time from randomization to progression upon any treatment including CAPOX-B, given after PFS1
statistical design
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
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
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
slide13

Baseline characteristics

stratification parameters

slide14

Baseline characteristics

other

* Covariates of which the differences are statistically significant

cairo3 study profile
CAIRO3 study profile

558 patients enrolled

279 patients

maintenance

279 patients

observation

148 patients

(53%)

- ongoing maint.

- no treatment

- other treatment

67 patients

(24%)

- ongoing obs.

- no treatment

- other treatment

212 patients

(76%)

re-introduction

CAPOX-B

131 patients

(47%)

re-introduction

CAPOX-B

results pfs1
Results: PFS1

PFS1

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

Re-introduction

CAPOX-B

PD

PD

R

  • PFS1: time from randomization until first progression
slide17

PFS1

  • adjusted HR 0.41, p <0.001
results pfs2 primary endpoint
Results: PFS2primary endpoint

PFS1

PFS2

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

Re-introduction

CAPOX-B

PD

PD

R

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
slide20

Primary endpoint PFS2

  • adjusted HR 0.77, p 0.007
results tt2pd
Results: TT2PD

PFS1

TT2PD

capecitabine +

bevacizumab

observation

SD or better

after 6 cycles

CAPOX- B

any treatment

incl. CAPOX-B

PD

PD

R

  • TT2PD = time to second progression of disease, time from randomization to progression upon any treatment given after PFS1
slide25

TT2PD

  • adjustedHR 0.63, p <0.001
slide26

Overall Survival

  • adjusted HR 0.80, p 0.035
  • preliminary survival analysis
slide27

Toxicity (grade 3-4)

during observation/maintenance

slide28

Drugs administered

during metastatic disease

conclusions i
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
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 acknowledgements
DCCG CAIRO3 study - acknowledgements

Investigators:

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.OttenAmsterdam; J.Douma, Arnhem; P.Nieboer,Assen; F.Valster, Bergen op Zoom; P. van den Berg Blaricum; O.Loosveld, A.TenTijeBreda; D.Kehrer, Capelle a/d IJssel; M.Bos, Delft; Z.Erjavec,Delfzijl; H.Sinnige, Den Bosch; H.SleeboomDen 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.vanBochove, 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