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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, - PowerPoint PPT Presentation
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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. TaberneroE. 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)
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
Study Design
ProgressionRCapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
Bevacizumabuntil progression
N=480
N=239
N=241
CapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
CapecitabineOxaliplatin
Bevacizumabuntil progression
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)
Study Objectives• Primary endpoint
– 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
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
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
CONSORTPt Selected
N=483
Pt RandomizedN=480
XELOX-BEVN=239
s/a BEVN=241
XELOX-BEVN=238
s/a BEVN=238
ITT
Safety
• 2 Incl / Excl criteria• 1 Other
• 1 Incl / Excl criteria
• 3 Incl / Excl criteria
Patient characteristicsXELOX-BEV
(N=239)s/a BEV (N=241)
Age median, years (range) 63 (30-80) 64 (33-82)
Sex: Male/Female, % 64/36 64/36ECOG PS 0/1/2 % 49/49/2 59/39/2Site of primary tumor rectum/colon/both % 31/57/12 23/67/10
Metastases confined to liver % 39 35Previous Adjuvant CT / RDT % 13/8 17/8Nº of organs affected 2 (1-5) 3 (1-12)Surgery of primary tumor % 69 75
Progression Free Survival ITT
LNI: 1.32
Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)
Patients at risk
Overall Survival ITT
Patients at risk
Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)
Confirmed Objective Best Tumor Response (RECIST)
Series10
10
20
30
40
50
60Patients%
Xelox-Bev(N=239)
s/a Bev(N=241)
46 % 49 %Odds ratio (95% CI)= 0.89 (0.62-1.27)
Summary of efficacyXELOX-BEV (N=239)
s/a BEV(N=241) HR (CI 95%)
PFS medianEvents %
10.4 (9.3-11.9)67%
9.7 (8.5-10.6)72%
1.11 (0.89–1.37)
OS medianEvents %
23.4 (20.0-26.0)55%
21.7 (18.3-25.1)54%
1.04 (0.81–1.32)
Confirmed OR % 46% 49% 0.89 (0.62-
1.27)**Odds Ratio
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)2 (0.8)3 (1.2)
Time to surgery median (months) range
6.8(3.5-30-0)
8.7(3.8-17.6)
Chemotherapy: 2nd lines
53 54
29 30
14 15
0
10
20
30
40
50
60
2nd Lines 3rd Lines 4th Lines ormore
XELOX_BEV s/a BEV
Patients%
Safety
XELOX-Bev(N=238)
128 (53.8)
34 (14.2)
4 (1.7)
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
Safety: Treatment-related NCI Grade 3-4* AEs
XELOX-BEV N=238 s/a BEV N=238
N % N %NEUROPATHY SENSORY 59 24.8 18 7.6DIARRHEA 26 10.9 33 13.9HAND FOOT SKIN REACTION 29 12.2 16 6.7FATIGUE 24 10.5 10 4.2HYPERTENSION 9 3.8 17 7.1PROTEINURIA 1 0.4 4 1.7THROMBOSIS 2 0.8 3 1.3PERFORATION, GI 2 0.8 1 0.4BLEEDING 1 0.4 1 0.4OBSTRUCTION/GI . . 1 0.4CARDIAC ISCHEMIA . . 1 0.4
* Include grade 5
Treatment complianceXELOX-
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)
6(1-6)
Maintenance phase cycles, median (range)
3(0-31)
4(0-47)
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.
BACK-UP
PFS Non-inferiorityresults interpretation
1
0.89 1.11 1,37
1,32
HR Protocol PFS
HR Macro PFS
XELOX-BEV better
s/a BEV better
LNI
Objective Best Tumor Response (RECIST)
Patients%
OR Confirmed OR0
10203040506070
XELOX-BEV N=239 s/a BEV N=241
62.3 58.9
Odds ratio (95% CI)= 1.15 (0.80-1.67)
46.0 49.0
Odds ratio (95% CI)= 0.89 (0.62-1.27)
Objective Best Tumor Response (RECIST)
0
10
20
30
40
50
60
70
XELOX-BEV N=239 s/a BEV N=241Not confirmed 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 5.4
XELOX-BEV N=239
s/a BEV N=241
N (%)
N (%)
Odds Ratio (CI95%)
OR Total 149 (62.3%)
142 (58.9%)
1.15 (0.80 - 1.67)
OR Confirmed 110 (4.0%)
118 (49.0%)
0.89 (0.62 - 1.27)
Safety: NCI Grade 3-4* AEsXELOX-BEV N=238 s/a BEV N=238
N % N %DIARRHEA 26 10.9 35 14.7OBSTRUCTION/GI 9 3.8 13 5.5PERFORATION, GI 4 1.7 2 0.8NEUROPATHY SENSORY 59 24.8 18 7.6HAND FOOT SKIN REACTION 29 12.2 16 6.7FATIGUE 31 13,0 12 5HYPERTENSION 11 4.6 18 7.6CARDIAC ISCHEMIA 2 0.8 1 0.4THROMBOSIS 2 0.8 4 1.7PROTEINURIA 1 0.4 4 1.7BLEEDING 3 1.3 2 0.8
* Include grade 5
Safety: NCI Grade 3-4 AEsXELOX-BEV N=238 s/a BEV N238
NCI Grade 3 NCI Grade 4* NCI Grade 3 NCI Grade 4*
N % N % N % N %NEUROPATHY SENSORY 59 24.8 . . 18 7.6 . .DIARRHEA 26 10.9 . . 34 14.3 1 0.4HAND FOOT SKIN REACTION 29 12.2 . . 16 6.7 . .FATIGUE 30 12.6 1 0.4 12 5.0 . .HYPERTENSION 11 4.6 . . 18 7.6 . .OBSTRUCTION/GI 7 2.9 2 0.8 8 3.4 5 2.1THROMBOSIS 1 0.4 1 0.4 4 1.7 . .PERFORATION, GI 2 0.8 2 0.8 . . 2 0.8PROTEINURIA 1 0.4 . . 4 1.7 . .BLEEDING 2 0.8 1 0.4 2 0.8 . .CARDIAC ISCHEMIA 2 0.8 . . 1 0.4 . .
* Include grade 5
Safety: Treatment-related NCI Grade 3-4 AEs
XELOX-BEV N=238 s/a BEV N=238
NCI Grade 3NCI Grade
4 NCI Grade 3 NCI Grade 4
N % N % N % N %NEUROPATHY SENSORY 59 24.8 . . 18 7.6 . .DIARRHEA 26 10.9 . . 32 13.5 1 0.4HAND FOOT SKIN REACTION 29 12.2 . . 16 6.7 . .FATIGUE 23 9.7 1 0.4 10 4.2 . .HYPERTENSION 9 3.8 . . 17 7.1 . .PROTEINURIA 1 0.4 . . 4 1.7 . .THROMBOSIS 1 0.4 1 0.4 3 1.3 . .PERFORATION, GI . . 2 0.8 . . 1 0.4BLEEDING 1 0.4 . . 1 0.4 . .OBSTRUCTION/GI . . . . . . 1 0.4CARDIAC ISCHEMIA . . . . 1 0.4 . .
* Include grade 5
Treatment-related AEs leading to death
XELOX-BEV N=238
s/a BEV N=238
N % N %PERFORATION, GI 2 0.8 2 0.8UNEXPECTED SUDDEN DEATH 1 0.4 1 0.4DIARRHEA . . 1 0.4CARDIOPULMONARY ARREST . . 1 0.4OBSTRUCTION/GI . . 1 0.4GASTROINTESTINAL/OTHER 1 0.4 2 0.8Total 4 1.7 8 (*) 3.4
* Seven deaths cycles 1-6; one death cycle 42
Treatment Cycles
1-6 cycles 7-12 cycles
13-18 cycles
>18 cycles
05
10152025303540
38
28
16 18
3235
17 16
XELOX_BEV s/a BEV
Patients%