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 64/36

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

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)Patients

%

Xelox-Bev(N=239)

s/a Bev(N=241)

46 %49 %

Odds ratio (95% CI)= 0.89 (0.62-1.27)

Summary of efficacy

XELOX-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 7.6

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 2 0.8 1 0.4

BLEEDING 1 0.4 1 0.4

OBSTRUCTION/GI . . 1 0.4

CARDIAC ISCHEMIA . . 1 0.4

* Include grade 5

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)

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%

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)

Not 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=239s/a BEV N=241

 

 N (%)

N (%)

Odds Ratio (CI95%)

OR Total149

(62.3%)142

(58.9%)1.15

(0.80 - 1.67)

OR Confirmed110

(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 14.7

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 18 7.6

CARDIAC ISCHEMIA 2 0.8 1 0.4

THROMBOSIS 2 0.8 4 1.7

PROTEINURIA 1 0.4 4 1.7

BLEEDING 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 0.4

HAND 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 2.1

THROMBOSIS 1 0.4 1 0.4 4 1.7 . .

PERFORATION, GI 2 0.8 2 0.8 . . 2 0.8

PROTEINURIA 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 0.4

HAND 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 0.4

BLEEDING 1 0.4 . . 1 0.4 . .

OBSTRUCTION/GI . . . . . . 1 0.4

CARDIAC 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 0.8

UNEXPECTED SUDDEN DEATH 1 0.4 1 0.4

DIARRHEA . . 1 0.4

CARDIOPULMONARY ARREST . . 1 0.4

OBSTRUCTION/GI . . 1 0.4

GASTROINTESTINAL/OTHER 1 0.4 2 0.8

Total 4 1.7 8 (*) 3.4

* Seven deaths cycles 1-6; one death cycle 42

Treatment CyclesPatients

%