1. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC) the MACRO trial
J. Tabernero
E. Aranda, A. Gomez, B. Massutí, J. Sastre, A. Abad,
M. Valladares, F. Rivera, Mª J. Safont, E. Diaz-Rubio
On behalf of the Spanish Cooperative Group for the
Treatment of Digestive Tumors (TTD)

2. Disclosures for J. Tabernero
Advisory Board member and lecturer for:
Sanofi-Aventis and Roche;
Merck-Serono; Amgen; Imclone; MSD; Bayer; Onyx; BMS; Boehringer; Celgene; Johnson & Johnson; Novartis; Pfizer

3. Study Design R N=239 Progression N=480 N=241 Capecitabine Oxaliplatin
Bevacizumab
x6 cycles q3w
until progression
N=480
N=239
N=241
sample size refres to IIT population. Check demographics etc to see if all are PP

4. Statistical analysis Sample Size: 470 patients; 235 per arm
Non-inferiority design
Assuming 10 months as median PFS
Non-inferiority limit of 7.6 m (HR=1.32)
Alpha error = 0.025, one side
Power = 80%
Randomization 1:1
Efficacy analysis populations:
ITT population: All randomized patients
Safety population: All patients with, at least, one dose of treatment
Statistical Analysis:
Kaplan-Meier curves
Cox model hazard ratio (if proportional assumptions are met)

5. Study Objectives Primary endpoint Secondary endpoints
Progression free survival* (PFS)
Secondary endpoints
Overall survival (OS)
Objective tumor response by RECIST
Time to response (TTR)
Response duration
Number of treatment cycles
Safety
* Time from randomization to progression or death

6. Inclusion Criteria Age ≥ 18 years
Histologically confirmed metastatic colorectal adenocarcinoma
Measurable disease (RECIST)
ECOG ≤ 2
No previous exposure to bevacizumab
No previous chemotherapy for metastatic or advanced colorectal cancer
No adjuvant chemotherapy within 6 months before randomization
No clinically significant cardiovascular disease

7. Treatment XELOX-BEV Bevacizumab (BEV): 7.5 mg/kg, iv, d1 q3wk
Oxaliplatin: 130 mg/m2, iv, d1 q3wk
Capecitabine: 1000 mg/m2 oral bid, d1-14 q3wk
Administered until progression of disease, severe toxicity or consent withdrawal
s/a BEV
6 cycles XELOX-BEV q3wk
BEV 7.5 mg/kg, iv, d1 q3wk until progression of disease, severe toxicity or consent withdrawal

8. CONSORT ITT Safety Pt Selected N=483 Pt Randomized N=480 XELOX-BEV
s/a BEV
N=241
N=238
ITT
Safety
2 Incl / Excl criteria
1 Other
1 Incl / Excl criteria
3 Incl / Excl criteria

9. Patient characteristics
XELOX-BEV (N=239)
s/a BEV (N=241)
Age median, years (range)
63 (30-80)
64 (33-82)
Sex: Male/Female, %
64/36
ECOG PS 0/1/2 %
49/49/2
59/39/2
Site of primary tumor
rectum/colon/both %
31/57/12
23/67/10
Metastases confined to liver % 39 35
Previous Adjuvant CT / RDT %
13/8
17/8
Nº of organs affected
2 (1-5)
3 (1-12)
Surgery of primary tumor % 69 75

10. Progression Free Survival ITT
LNI: 1.32
Follow-up median months (range) (0-40) (0-38)
Patients at risk

11. Overall Survival ITT
Patients at risk
Follow-up median months (range) (0-40) (0-38)

12. Confirmed Objective Best Tumor Response (RECIST)
Patients %
Xelox-Bev (N=239)
s/a Bev (N=241)
46 %
49 %
Odds ratio (95% CI)= 0.89 ( )

13. Summary of efficacy XELOX-BEV (N=239) s/a BEV (N=241) HR (CI 95%)
PFS median
Events %
10.4 ( )
67%
9.7 ( )
72%
1.11 (0.89–1.37)
OS median
23.4 ( )
55%
21.7 ( )
54%
1.04 (0.81–1.32)
Confirmed OR %
46%
49%
0.89 ( )*
Moreover this post hoc change raises some multiplicity concerns too. With 3 arms there is a multiplicity of hypothesis test leading to a alpha risk inflation. To be confirmatory, the trial must control this inflation by using a signification level adjustment (Bonferroni, etc.). In the reported analysis, no such a method was performed.
So given the post hos change of hypothesis and the multiplicity concern these results are only exploratory, not confirmatory.
The present conclusion is a little bit stronger given these restrictions.
For the calculation of the sample size, the underlying incidence (in the control group) is missing.
The sample size calculation presented here is for 2 groups, I guess that in the protocol a sample size calculation for 3 arms was performed initially
Is this trial registered into a clinical trial register (if yes what are the change in the protocol compared with the description put in the register)
In the abstract the trial was described as a phase II/III trial, here it’s a phase III only
The methodology of this trial seems like meta analysis or others?
One more point may be that the number of patients enrolled is not so large which may make people challenge the results.
*Odds Ratio

14. Surgery XELOX-BEV (N=239) s/a BEV (N=241) Salvage surgery N (%)
28 (11.7)
23 (9.5)
R0 N (%)
21 (8.8)
14 (5.8)
Site:
Liver N (%)
Lung N (%)
Other N (%)
25 (10.5)
2 (0.8)
1 (0.4)
18 (7.5)
3 (1.2)
Time to surgery median (months) range
6.8
( )
8.7
( )

15. Chemotherapy: 2nd lines
Patients %

16. Treatment-related AEs
Safety
XELOX-Bev (N=238)
128 (53.8)
34 (14.2)
4 (1.7)
s/a Bev (N=238)
114 (47.9)
48 (19.0)
8 (3.4)
6 (2.5)
n (%)
AEs G3-4
SAEs
AEs leading to death
Death 60 days
Treatment-related AEs

17. Safety: Treatment-related NCI Grade 3-4* AEs
XELOX-BEV N=238
s/a BEV N=238 N %
NEUROPATHY SENSORY 59
24.8 18
7.6
DIARRHEA 26
10.9 33
13.9
HAND FOOT SKIN REACTION 29
12.2 16
6.7
FATIGUE 24
10.5 10
4.2
HYPERTENSION 9
3.8 17
7.1
PROTEINURIA 1
0.4 4
1.7
THROMBOSIS 2
0.8 3
1.3
PERFORATION, GI
BLEEDING
OBSTRUCTION/GI .
CARDIAC ISCHEMIA
* Include grade 5

18. Treatment compliance XELOX-BEV (N=238) s/a BEV (N=238)
Total cycles administered treatment + maintenance, median (range) 9
(1-37) 10
(1-53)
Treatment phase cycles, median (range) 6
(1-6)
Maintenance phase cycles, median (range) 3
(0-31) 4
(0-47)

19. Conclusions
This data indicate that a priori specified non-inferiority cannot be still confirmed, but we can reliably exclude a detriment of larger than 3 weeks in PFS.
This study suggests that maintenance therapy with single agent BEV may be an appropriate option following induction XELOX-BEV in pts with mCRC.
Further studies evaluating single agent BEV after standard chemotherapy in mCRC are warranted.

20. BACK-UP

21. PFS Non-inferiority results interpretation1
0.89
1.11
1,37
1,32
HR Protocol PFS
HR Macro PFS
XELOX-BEV better
s/a BEV better
LNI

22. Objective Best Tumor Response (RECIST)
Patients %
62.3
58.9
Odds ratio (95% CI)= 1.15 ( )
46.0
49.0
Odds ratio (95% CI)= 0.89 ( )

23. Objective Best Tumor Response (RECIST)
XELOX-BEV N=239
s/a BEV N=241 N
(%)
Odds Ratio (CI95%)
OR Total
149
(62.3%)
142
(58.9%)
1.15
( )
OR Confirmed
110
(4.0%)
118
(49.0%)
0.89
( )
Not confirmed
Complete
Partial
Stable
Progression
Patients %
Total
(Confirmed)
5.4
(3.3)
4.6
(4.6)
56.9
(42.7)
54.4
(44.4)
25.9
27.4
7.5

24. Safety: NCI Grade 3-4* AEs
XELOX-BEV N=238
s/a BEV N=238 N %
DIARRHEA 26
10.9 35
14.7
OBSTRUCTION/GI 9
3.8 13
5.5
PERFORATION, GI 4
1.7 2
0.8
NEUROPATHY SENSORY 59
24.8 18
7.6
HAND FOOT SKIN REACTION 29
12.2 16
6.7
FATIGUE 31
13,0 12 5
HYPERTENSION 11
4.6
CARDIAC ISCHEMIA 1
0.4
THROMBOSIS
PROTEINURIA
BLEEDING 3
1.3
* Include grade 5

25. Safety: NCI Grade 3-4 AEs XELOX-BEV N=238 s/a BEV N238%
NEUROPATHY SENSORY 59
24.8 . 18
7.6
DIARRHEA 26
10.9 34
14.3 1
0.4
HAND FOOT SKIN REACTION 29
12.2 16
6.7
FATIGUE 30
12.6 12
5.0
HYPERTENSION 11
4.6
OBSTRUCTION/GI 7
2.9 2
0.8 8
3.4 5
2.1
THROMBOSIS 4
1.7
PERFORATION, GI
PROTEINURIA
BLEEDING
CARDIAC ISCHEMIA
* Include grade 5

26. Safety: Treatment-related NCI Grade 3-4 AEs
XELOX-BEV N=238
s/a BEV N=238
NCI Grade 3
NCI Grade 4 N % % 
NEUROPATHY SENSORY 59
24.8 . 18
7.6
DIARRHEA 26
10.9 32
13.5 1
0.4
HAND FOOT SKIN REACTION 29
12.2 16
6.7
FATIGUE 23
9.7 10
4.2
HYPERTENSION 9
3.8 17
7.1
PROTEINURIA 4
1.7
THROMBOSIS 3
1.3
PERFORATION, GI 2
0.8
BLEEDING
OBSTRUCTION/GI
CARDIAC ISCHEMIA
* Include grade 5

27. Treatment-related AEs leading to death
XELOX-BEV N=238
s/a BEV N=238 N %
PERFORATION, GI 2
0.8
UNEXPECTED SUDDEN DEATH 1
0.4
DIARRHEA .
CARDIOPULMONARY ARREST
OBSTRUCTION/GI
GASTROINTESTINAL/OTHER
Total 4
1.7
8 (*)
3.4
* Seven deaths cycles 1-6; one death cycle 42

28. Treatment Cycles
Patients %