j. tabernero e. aranda , a. gomez, b. massutí , j. sastre, a. abad,

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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, M. Valladares, F. Rivera, Mª J. Safont, E. Diaz-Rubio On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)

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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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Page 1: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 2: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 3: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

Study Design

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Page 4: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 5: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 6: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 7: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 8: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 9: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 10: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

Progression Free Survival ITT

LNI: 1.32

Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)

Patients at risk

Page 11: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

Overall Survival ITT

Patients at risk

Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)

Page 12: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 13: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 14: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 15: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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%

Page 16: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 17: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 18: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 19: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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.

Page 20: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

BACK-UP

Page 21: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 22: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 23: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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)

Page 24: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 25: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 26: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 27: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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

Page 28: J. Tabernero E.  Aranda , A. Gomez, B.  Massutí , J. Sastre, A. Abad,

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%