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Background

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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Background

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  1. 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

  2. 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

  3. 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)

  4. 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

  5. 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

  6. Study design PFS1 PFS2 capecitabine + bevacizumab observation Re-introduction CAPOX-B SD or better after 6 cycles CAPOX- B PD PD R

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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)

  12. 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

  13. Baseline characteristics stratification parameters

  14. Baseline characteristics other * Covariates of which the differences are statistically significant

  15. 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

  16. 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

  17. PFS1 • adjusted HR 0.41, p <0.001

  18. Treatment until PFS1

  19. 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

  20. Primary endpoint PFS2 • adjusted HR 0.77, p 0.007

  21. Treatment until PFS2

  22. Treatment until PFS2

  23. 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

  24. Treatment until 2nd progression other than CAPOX-B

  25. TT2PD • adjustedHR 0.63, p <0.001

  26. Overall Survival • adjusted HR 0.80, p 0.035 • preliminary survival analysis

  27. Toxicity (grade 3-4) during observation/maintenance

  28. Drugs administered during metastatic disease

  29. 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

  30. 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

  31. 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

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