Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV...
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Transcript of Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV...
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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-RubioOn behalf of the Spanish Cooperative Group for the
Treatment of Digestive Tumors (TTD)
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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
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Study DesignStudy Design
ProgressionRCapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
Bevacizumabuntil progression
N=480
N=239
N=241
CapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
CapecitabineOxaliplatin
Bevacizumabuntil progression
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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)
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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
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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
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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
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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
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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
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Progression Free SurvivalProgression Free Survival
Follow-up 21.1 (0-40) 20.4 (0-38)median (range), months
Patients at risk
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Overall Survival Overall Survival
Patients at risk
Follow-up 21.1 (0-40) 20.4 (0-38) median (range), months
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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)
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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
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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
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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
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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
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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)
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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)
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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 )
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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)
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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)
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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)
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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%
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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)
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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
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BACK-UP
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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)
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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
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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
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Treatment CyclesPatients
%
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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)
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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)
+
+
+