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 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 2009 2Adams et al. Lancet Oncol 2011 3Labianca et al. Ann Oncol 2011 4Saltz 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 R observation PD PD SD or better after 6 cycles CAPOX- B PFS1 PFS2 observation PD PD R SD or better after 6 cycles CAPOX- B Re-introduction CAPOX-B capecitabine + bevacizumab

Definition of PFS1 R PD observation PD Re-introduction CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab PFS1: time from randomization until first progression after observation or maintenance treatment

Definition of PFS2 primary endpoint PD PFS2 PFS1 observation PD R Re-introduction CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab 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 R PD observation PD any treatment incl. CAPOX-B PFS1 observation PD R any treatment incl. CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab 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

Baseline characteristics stratification parameters Observation n = 279 Maintenance Prior adjuvant treatment (yes/no) 19/81% 18/82% Serum LDH (normal/abnormal) 44/56% Response to induction treatment (CR+PR/SD) 66/34% WHO performance status (0/1) 62/38% Institution

Baseline characteristics other Observation n = 279 Maintenance 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% * Covariates of which the differences are statistically significant

CAIRO3 study profile 558 patients enrolled 279 patients observation maintenance 212 patients (76%) re-introduction CAPOX-B 67 patients (24%) - ongoing obs. - no treatment - other treatment 131 patients (47%) re-introduction CAPOX-B 148 patients (53%) - ongoing maint. - no treatment - other treatment

Results: PFS1 R PD observation PD Re-introduction CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab PFS1: time from randomization until first progression

PFS1 Median PFS1 Observation 4.1 m [95%CI: 3.9-4.4] Maintenance 8.5 m Stratified HR 0.44 [95%CI: 0.36-0.53] p value < 0.00001 adjusted HR 0.41, p <0.001

Treatment until PFS1 Observation n=279 Maintenance Observation/maintenance ongoing 13 (5%) 20 (7%) Treatment discontinuation 266 (95%) 256 (92%) No follow up 3 (1%) Reasons for discontinuation n=266 n=256 disease progression/death 264 (95%) 214 (77%) toxicity 25 (10%) refusal 5 (2%) other 2 (1%) 12 (5%) Median number of cycles (range) Capecitabine - 9 (1-85) Bevacizumab 10 (1-88)

Results: PFS2 primary endpoint PD PFS2 PFS1 observation PD R Re-introduction CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab 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

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

Treatment until PFS2 Observation n=279 Maintenance 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 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 Observation n=279 Maintenance 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 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%)

Results: TT2PD R PD observation PD any treatment incl. CAPOX-B PFS1 observation PD R any treatment incl. CAPOX-B SD or better after 6 cycles CAPOX- B capecitabine + bevacizumab TT2PD = time to second progression of disease, time from randomization to progression upon any treatment given after PFS1

Treatment until 2nd progression other than CAPOX-B Observation n=279 Maintenance 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 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 10 (8%) 5FU-bevacizumab 4 (7%) 11 (9%) Other 3 (6%) 5 (4%)

TT2PD Median TT2PD Observation 15.0 m [95%CI:13.6-16.4] Maintenance Stratified HR 0.67 [95%CI: 0.55-0.81] p value < 0.00001 adjusted HR 0.63, p <0.001

Overall Survival Median 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

during observation/maintenance Toxicity (grade 3-4) during observation/maintenance Observation n = 279 Maintenance Hypertension 18% 24% Hematological toxicity Neutropenia Trombocytopenia 2% 1% Diarrhea 3% Vomiting 0.4% Nausea Hand-foot syndrome 22% Neurotoxicity 5% 10% GI perforation Venous thromboembolic events Fatigue 4%

during metastatic disease Drugs administered during metastatic disease Observation n=279 Maintenance 4 drugs capecitabine, oxaliplatin, bevacizumab, irinotecan 138 (49%) 136 (49%) 5 drugs bevacizumab, irinotecan, anti-EGFR 34 (12%) 32 (11%)

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 - 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.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