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-RubioOn behalf of the Spanish Cooperative Group for the

Treatment of Digestive Tumors (TTD)

RationaleRationale• Optimal duration of treatment of mCRC is still under debate• While some physicians maintain treatment until

unacceptable toxicity and/or progression occurs, some others stop all or part of the drugs after patients have been treated for around 4-6 months

• Bevacizumab has a good long-term safety profile and cross-study comparisons suggest that its maximum benefit may be observed when it is maintained until disease progression

• This study was aimed to demonstrate that maintenance treatment with single agent bevacizumab after 6 cycles of induction chemotherapy plus bevacizumab could be a reasonable option, thus avoiding cumulative toxicity without reducing the efficacy of treatment

Study DesignStudy Design

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Statistical designStatistical design• Sample Size:

– Non-inferiority design, 10 months as median PFS – Non-inferiority limit (NIL) of 7.6 m and HR = 1.32– Alpha error = 0.025, one side– Power = 80%– Randomization 1:1– 470 patients; 235 per arm

• 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 ObjectivesStudy 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 CriteriaInclusion Criteria

• Age ≥ 18 years • Histologically confirmed mCRC 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

TreatmentTreatment

• XELOX-BEV – Oxaliplatin: 130 mg/m2, iv, d1 q3wk – Capecitabine: 1000 mg/m2 oral bid, d1-14 q3wk– Bevacizumab (BEV): 7.5 mg/kg, iv, d1 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

CONSORTCONSORT

Pt SelectedN=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 characteristicsPatient characteristicsXELOX-BEV

(N=239)s/a BEV (N=241)

Age median (range), years 63 (30-80)64 (33-

82)

Sex: Male/Female, % 64/36 64/36

ECOG PS 0/1/2 % 49/49/2 59/39/2

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 SurvivalProgression Free Survival

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

Patients at risk

Overall Survival Overall Survival

Patients at risk

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

Confirmed ORR (RECIST)Confirmed ORR (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 efficacySummary of efficacy

XELOX-BEV (N=239)

s/a BEV(N=241)

HR (95% CI)

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

PFS Non-inferiorityPFS Non-inferiorityresults results interpretationinterpretation

1

0.89 1.11 1.37

1.32

HR Protocol PFS

HR Macro PFS

XELOX-BEV better

s/a BEV better

Non-inferiority limit

SafetySafety

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 (%)

G 3-4 AEs

SAEs

AEs leading to death

Death within 60 days

Treatment-related AEs

G 3-4 Treatment-related AEs*G 3-4 Treatment-related AEs*

 

XELOX-BEV N=238

s/a BEV N=238

N % N %

Paresthesia 59 24.8 18 7.6

Diarrhea 26 10.9 33 13.9

Hand-foot syndrome 29 12.2 16 6.7

Fatigue 24 10.5 10 4.2

Hypertension 9 3.8 17 7.1

Protenuria 1 0.4 4 1.7

Thrombosis 2 0.8 3 1.3

GI perforation 2 0.8 1 0.4

Bleeding 1 0.4 1 0.4

*According to NCI-CTCAE v3.0

Includes grade 5

Treatment complianceTreatment compliance

XELOX-BEV

(N=238)

s/a BEV (N=238)

Total cycles administered induction + maintenance phases, median (range)

9(1-37)

10(1-53)

Induction phase cycles, median (range)

6

(1-6)

6

(1-6)

Maintenance phase cycles, median (range)

3

(0-31)

4

(0-47)

Oxaliplatin exposureOxaliplatin exposure

11,6

4,7

0

5

10

15

Xelox-Bev(Cycles = 1807)

s/a Bev(Cycles = 1229)

% Cycles Reduced or Suspended

800 770

0

100

200

300

400

500

600

700

800

900

Xelox-Bev(N = 238)

s/a Bev(N = 238)

Median Cumulative Dose (mg/m2)

Oxaliplatine Cumulative Doses

XELOX-BEV s/a BEV

0

1000

2000

3000

4000

Cu

mu

lati

ve

do

se

Treatment

XELOX-BEV s/a BEV

++

(mg

/m2

)

Oxaliplatin exposure

Mean (CI 95%)

Median

XELOX-BEV893 (833 - 951)

800

s/a BEV649 (621 - 678)

770

Treatment

Cu

mu

lati

ve d

ose

(m

g/m

2 )

Bevacizumab exposureBevacizumab exposure

2,8 2,8

0

1

1

2

2

3

3

4

Xelox-Bev(Cycles = 2521)

s/a Bev(Cycles = 2730)

67,574,1

0

10

20

30

40

50

60

70

80

90

100

Xelox-Bev(N = 238)

s/a Bev(N = 238)

% Cycles Reduced or Suspended

Median Cumulative Dose (mg/Kg)

Capecitabine exposureCapecitabine exposure

8,2

12,4

0

3

5

8

10

13

15

Xelox-Bev(Cycles = 2521)

s/a Bev(Cycles = 2730)

212.796

153.425

0

50.000

100.000

150.000

200.000

250.000

Xelox-Bev(N = 238)

s/a Bev(N = 238)

% Cycles Reduced or Suspended

Median Cumulative Dose (mg/m2)

Surgery Surgery

XELOX-BEV

(N=239)

s/a BEV (N=241)

Salvage surgery N (%) 28 (11.7) 23 (9.5)

R0 surgery 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 (range), months

6.8

(3.5-30-0)

8.7

(3.8-17.6)

Treatment upon progressionTreatment upon progression

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%

ConclusionsConclusions

• This data indicate that a priori specified non-inferiority cannot still be confirmed, but we can reliably exclude a detriment of larger than 3 weeks in median PFS

• This study suggests that maintenance therapy with single agent bevacizumab may be an appropriate treatment option following induction XELOX-bevacizumab in patients with mCRC

• Other studies evaluating maintenance treatment with bevacizumab after standard chemotherapy in mCRC are under recruitment/evaluation (DREAM, CAIRO-3, AIO-ML21768)

AcknowledgmentsAcknowledgments

E. Aranda (H. Reina Sofía)B. Massutí (H. General Universitario de Alicante)J. Sastre (H. Universitario Clínico San Carlos)A. Abad (ICO. H. Germans Trias i Pujol )M. Valladares (C. H. Universitario)F. Rivera (H. Marqués de Valdecilla)Mª J. Safont (H. General Universitario de

Valencia)P. Martínez de Prado (H. de Basurto)M. Gallén (H. del Mar)E. González (H. Virgen de las Nieves)M. Benavides (H. Universitario Carlos Haya)E. Marcuello (H. Santa Creu i Sant Pau)C. Fernández-Martos(Instituto Valenciano de

Oncología)F. Losa (H. General de L'Hospitalet)P. Escudero (H. C. Universitario Lozano Blesa)A. Cervantes (H. Clínico de Valencia)A. Arrivi (F. H. Son Llatzer)R. Dueñas (H. Ciudad de Jaén)A. Lacasta (H. de Donostia)M. Llanos (H. Universitario de Canarias)A. López-Ladrón (H. Nuestra Señora de Valme)A. Anton (H. Miguel Servet)J. Tabernero (H. Universitari Vall d’Hebrón)

J. Remón (H. de Mataró)C. Martín (H. del Espíritu Santo)J. Mª. Vicent (H. de Sagunto)H. Manzano (H. Son Dureta) J. Alfaro (C. Sanitari de Terrasa)Mª. J. Gómez (H. Puerta del Mar)T. García (H. Morales Meseguer)A. Velasco (H. Universitario de la Princesa)J. L. García López (H. Ramón y Cajal)D. Almenar (H. Dr. Peset)R. Vera (H. de Navarra)E. Jiménez (H. Jerez de la Frontera)A. Carrato (H. General Universitario de Elche)J. L. García Puche (H. Clínico San Cecilio)J. García-Foncillas (C. Universitaria de Navarra)V. Alberola (H. Arnau de Vilanova)M. Constenla (Complejo Hospitalario)A. Etxeberría (Instituto Oncológico)P. Bueso (H. de Barbastro)T. Checa (I. de Oncología Corachán)L. del Río (H. Virgen de los Lirios)A. Ruiz (H. de Fuenlabrada)C. Alonso (H. General de Albacete)

The physicians listed below cared for the patients in this study.The authors thank them for their cooperation and support:

TTD Data Center: I Ruiz de Mena and S. RodríguezStatistics and Data Management: Pivotal (N. Martin and J.J. García)Monitoring: Dynamic Solutions: A. Ríos and A. Sotés Sponsors: Roche: B. Bendahmane and G. Garcia Sanofi Aventis:O. Diez and X. Marfà

BACK-UP

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 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 CyclesPatients

%

Bevacizumab Bevacizumab Cumulative Doses

XELOX-BEV s/a BEV

0

100

200

300

400

Cu

mu

lati

ve d

ose

(mg

/kg

)

Treatment

XELOX-BEV s/a BEV

++

N Median + Mean (CI 95%)

XELOX-BEV 328 800 + 893 (833 - 951)

s/a BEV 328 770 + 649 (621 - 678)

Capecitabine Cumulative Doses

XELOX-BEV s/a BEV

0

250000

500000

750000

1000000

Cu

mu

lati

ve

do

se

(mg

/m2

)

Treatment

+

+

Capecitabine

Mean (CI 95%)

Median (N)

XELOX-BEV250.993 (227.983 – 274.004)

212.796 (328)

s/a BEV133.131 (126.043 – 140.249)

153.425 (328)

+

+

+