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 Clin Oncol 2009
2Adams et al. Lancet Oncol 2011
3Labianca et al. Ann Oncol 2011
4Saltz et al. J Clin Oncol 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/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

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 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

7. 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

8. Definition of PFS2 primary endpointPD
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

9. 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

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 (updated from abstract)
Median duration of follow-up is 40 months

13. 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

14. 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

15. 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

16. 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

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

18. 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)

19. Results: PFS2 primary endpointPD
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

20. Primary endpoint PFS2 Median PFS2 Observation 10.5 m [95%CI: 9.3-12.3]
Maintenance
11.8 m
[95%CI: ]
Stratified HR
0.81
[95%CI: ]
p value
0.028
adjusted HR 0.77, p 0.007

21. 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%)

22. 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%)

23. 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

24. 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%)

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

26. Overall Survival Median OS Observation 18.2 m [95%CI: 16.3-20.8]
Maintenance
21.7 m
[95%CI: ]
Stratified HR
0.87
[95%CI: ]
p value
0.156
adjusted HR 0.80, p 0.035
preliminary survival analysis

27. 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%

28. 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%)

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.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
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