Transcript Document

Bevacizumab (BEV) plus chemotherapy (CT)
continued beyond first progression in patients with
metastatic colorectal cancer (mCRC) previously
treated with BEV + CT: Results of a randomised
phase III intergroup study – TML (ML18147)
D Arnold1, T Andre2, J Bennouna3, J Sastre4, P Österlund5, R Greil6
E Van Cutsem7, R von Moos8, I Reyes-Rivera9, B Bendahmane10, S Kubicka11
on behalf of the AIO, GERCOR, FFCD, UNICANCER GI, TTD, GEMCAD and AGMT groups
1Hamburg,
Germany; 2Paris, France; 3Nantes, France; 4Madrid, Spain
5Helsinki, Finland; 6Salzburg, Austria; 7Leuven, Belgium; 8Chur, Switzerland
9South San Francisco, USA; 10Basel, Switzerland; 11Reutlingen, Germany
Disclosure: Dirk Arnold
 Consultant / advisory board: F. Hoffmann-La Roche, Merck
Serono, Amgen
 Honoraria: F. Hoffmann-La Roche, Merck Serono, Amgen
 Research funding: F. Hoffmann-La Roche
Background
 Bevacizumab (BEV) in combination with fluoropyrimidine-
based chemotherapy (CT) is a standard of care for mCRC in
first-line and (BEV-naive) second-line settings
 VEGF is an early and persistent promoter of tumour
angiogenesis.1 Sustained VEGF inhibition achieves and
maintains tumour regression in preclinical studies2,3
 In non-randomised observational studies (BRiTE, ARIES) in
patients with mCRC, continuing anti-angiogenic therapy with
BEV + CT beyond first progressive disease (PD) correlates
with prolonged survival vs no continuation of BEV4,5
1. Ferrara et al. Nature Med 2003;9:669–76
2. Klement et al. J Clin Invest 2000;105:R15–24
3. Klement et al. Clin Cancer Res 2002;8:221–232
4. Grothey et al. J Clin Oncol 2008;26:5326–34
5. Cohn et al. J Clin Oncol 2010;28(15s):Abstr 3596
Aims and objectives
 The efficacy and safety of BEV continued after first PD has not
been investigated in a randomised clinical trial
 TML (ML18147) is the first randomised phase III study to
evaluate BEV continued with standard second-line CT in
patients with mCRC who progressed after BEV plus standard
first-line CT
Study design and patient characteristics
ML18147 study design (phase III)
BEV + standard
first-line CT (either
oxaliplatin or
irinotecan-based)
(n=820)
Standard second-line CT
(oxaliplatin or irinotecanbased) until PD
PD
Randomise 1:1
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
BEV (2.5 mg/kg/wk) +
standard second-line CT
(oxaliplatin or irinotecanbased) until PD
Primary endpoint
• Overall survival (OS) from randomisation
Secondary endpoints
included
• Progression-free survival (PFS)
• Best overall response rate
• Safety
Stratification factors
• First-line CT (oxaliplatin-based, irinotecan-based)
• First-line PFS (≤9 months, >9 months)
• Time from last BEV dose (≤42 days, >42 days)
• ECOG PS at baseline (0/1, 2)
Study conducted in 220 centres in Europe and Saudi Arabia
Statistical considerations
 Study initiated as AIO KRK 0504 then transferred to Roche
(after enrolment of 261 patients)
– Primary endpoint changed from PFS to OS
– Sample size increased from 572 to 810 patients
 Designed to detect 30% (HR 0.77) improvement in median OS
(90% power, 2-sided 5%)
– 613 events required for analysis
 OS curves estimated using Kaplan–Meier method, differences
assessed using unstratified log-rank tests
– Unstratified Cox regression model used to estimate HR for OS
– Stratified log-rank tests and Cox regression analyses used as
supportive analyses
Main eligibility criteria
Inclusion
 Patients ≥18 years with histologically confirmed diagnosis of mCRC
 Eastern Cooperative Oncology Group (ECOG) PS 0–2
 PD (≥1 measurable lesion according to RECIST v1 assessed by
investigator, documented by CT or MRI), ≤4 weeks prior to start of
study treatment
 Previously treated with BEV plus standard first-line CT, not candidates
for primary metastasectomy
Exclusion
 Diagnosis of PD >3 months after last BEV administration
 First-line patients with PFS in first-line of <3 months
 Patients receiving <3 consecutive months of BEV in first-line
Demographic and baseline characteristics:
Randomised patients
CT
(n=411)
BEV + CT
(n=409)
Male, %
63
65
Age, median years
63
63
ECOG performance status, %
0
1
2
43
52
5
44
51
5
First-line PFS, %
≤9 months
>9 months
56
44
54
46
First-line CT, %
Irinotecan-based
Oxaliplatin-based
58
42
59
41
Characteristic
Patients were accrued between February 2006 and June 2010
Demographic and baseline characteristics:
Randomised patients (cont’d)
CT
(n=411)
BEV + CT
(n=409)
Duration from last BEV dose to
randomisation, %
≤42 days
>42 days
77
23
77
23
Patient populationa, %
AIO
ML18147
32
68
32
68
Liver metastasis only, %
No
Yes
71
29
73
27
No. of organs with metastasis, %
1
>1
39
61
36
64
Characteristic
aPatient
population refers to sequential enrolment of patients in original AIO study and
subsequent enrolment in ML18147 when study was transferred to Roche
Second-line chemotherapy during study:
Randomised patients
CT
(n=407)
BEV + CT
(n=407)
43
42
FOLFIRI
14
16
LV5FU2 + CPT11 (Douillard regimen1)
7
7
XELIRI
12
12
Other regimens
10
7
Oxaliplatin-based CT
57
58
FOLFOX4 / mFOLFOX4
18
19
FOLFOX6
13
16
FUFOX
9
6
XELOX
11
14
Other regimens
6
4
Second-line CT regimen, %
Irinotecan-based CT
1. Douillard et al. Lancet 2000;355:1041–7
Primary endpoint:
overall survival
OS: ITT population
CT (n=410)
BEV + CT (n=409)
1.0
OS estimate
0.8
0.6
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
0.4
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p=0.0211 (log-rank test)
0.2
9.8 mo
0
0
No. at risk
CT
BEV + CT
410
409
6
293
328
11.2 mo
12
18
24
30
162
188
Time (months)
51
24
7
64
29
13
36
42
48
3
4
2
1
0
0
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Subsequent anti-cancer therapies: Safety
population
CT
(n=409)
BEV + CT
(n=401)
67.7
68.6
BEV
12.2
11.5
Anti-EGFR
41.3
39.2
Other
50.4
54.9
Subsequent therapy, %
Patients who received ≥1
subsequent anti-cancer therapy
Subsequent anti-cancer therapies
EGFR: epidermal growth factor receptor
Subgroup analysis of OS: ITT population
Category
All
Patient
populationa
Gender
Age
ECOG performance status
First-line PFS
First-line CT
Time from last BEV
Liver metastasis only
No. of organs
with metastasis
Subgroup
n
HR
(95% CI)
All
819
0.81
(0.69–0.94)
AIO
ML18147
Female
260
559
294
0.86
0.78
0.99
(0.67–1.11)
(0.64–0.94)
(0.77–1.28)
Male
525
0.73
(0.60–0.88)
<65 years
458
0.79
(0.65–0.98)
≥65 years
361
0.83
(0.66–1.04)
0
357
0.74
(0.59–0.94)
≥1
458
0.87
(0.71–1.06)
≤9 months
449
0.89
(0.73–1.09)
>9 months
369
0.73
(0.58–0.92)
Oxaliplatin-based
343
0.79
(0.62–1.00)
Irinotecan-based
476
0.82
(0.67–1.00)
≤42 days
630
0.82
(0.69–0.97)
>42 days
189
0.76
(0.55–1.06)
No
592
0.81
(0.67–0.97)
Yes
226
0.79
(0.59–1.05)
1
307
0.83
(0.64–1.08)
>1
511
0.77
(0.64–0.94)
HR
aPatient
0
1
2
population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when
study was transferred to Roche. All patients listed under AIO were included in primary analysis
Secondary endpoints:
PFS and best overall response
PFS: ITT population
CT (n=410)
BEV + CT (n=409)
1.0
PFS estimate
0.8
0.6
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78)
p<0.0001 (log-rank test)
0.4
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
p<0.0001 (log-rank test)
0.2
0
4.1 mo
0
No. at risk
CT
BEV + CT
5.7 mo
6
12
18
24
30
36
42
0
2
0
2
0
0
Time (months)
410
409
119
189
20
45
6
12
4
5
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose
of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Best overall response: Measurable disease
population
Outcome
CT
(n=406)
BEV + CT
(n=404)
Respondersa, n (%)
16 (3.9)
22 (5.4)
p-value (unstratified)
0.3113
p-value (stratified)
0.4315
Complete response, n (%)
2 (<1)
1 (<1)
Partial response, n (%)
14 (3)
21 (5)
Stable disease, n (%)
204 (50)
253 (63)
Disease control rate, n (%)
220 (54)
275 (68)
p-valueb
<0.0001
PD, n (%)
142 (35)
87 (22)
Missingc, n (%)
44 (11)
42 (10)
aPatients
with a best overall response of confirmed complete or partial response
analysis was not prespecified
cIncludes ‘not-evaluable’ or ‘no tumour assessment’ following baseline visit
bThis
Safety
Treatment duration: Safety population
CT (n=409)
BEV + CT (n=401)
0
Duration from randomisation (ie first study drug) until discontinuation of all study drugs
was 3.2 months for CT and 4.2 months for BEV + CT
Overview of adverse events: Safety population
CT
(n=409)
BEV + CT
(n=401)
Any AE
99
98
Serious AEs
34
32
Grade 3–5 AEs
58
64
Grade 5 AEsa
3
3
Discontinued any treatment due
to AEs
9
16
Discontinued CT due to AE
9
13
N/A
2
Patients, %
Discontinued BEV only due to AE
aPD
leading to death captured for some patients as grade 5 AE; these events were excluded from this summary
AE: adverse event
Grade 3–5 adverse events (incidence ≥2%)
in any arm: Safety population
Adverse event, %
Neutropenia
Leukopenia
Diarrhoea
Vomiting
Nausea
Abdominal pain
Subileus
Asthenia
Fatigue
Mucosal inflammation
Dyspnoea
Pulmonary embolism
Polyneuropathy
Neuropathy peripheral
Hypokalaemia
Decreased appetite
CT
(n=409)
13
3
8
3
3
3
<1
4
2
1
3
2
2
2
2
2
BEV + CT
(n=401)
16
4
10
4
3
4
2
6
4
3
2
3
3
1
2
1
Adverse events of special interest to BEV:
Safety population
CT
(n=409)
BEV + CT
(n=401)
All grades
Grade 3–5
All grades
Grade 3–5
21
6
41
12
Hypertension
7
1
12
2
Proteinuria
1
–
5
<1
Bleeding/haemorrhage
9
<1
26
2
Abscesses and fistulae
–
–
1
<1
GI perforation
<1
<1
3
2
Congestive heart failure
<1
<1
<1
–
VTE
4
3
6
5
ATE
1
<1
<1
<1
Wound-healing
complications
<1
<1
1
<1
RPLS
–
–
–
–
Patients, %
AEs of special interest to BEV
ATE: arterial thromboembolic events; GI: gastrointestinal; RPLS: reverse posterior leukoencephalopathy
syndrome; VTE: venous thromboembolic events
Summary and Conclusions
Summary
 BEV + standard second-line CT, crossed over from BEV + standard first-
line CT, significantly prolongs OS and PFS
– OS
• Median: BEV + CT 11.2 months, CT 9.8 months
• HR: 0.81 (95% CI: 0.69–0.94), p=0.0062a
– PFS
• Median: BEV + CT 5.7 months, CT 4.1 months
• HR: 0.68 (95% CI: 0.59–0.78), p≤0.0001a
 Findings from subgroup analyses for OS generally consistent with
overall population
– Treatment effect according to gender appeared to be different; however,
treatment-gender interaction test was not statistically significant
 Differences in best overall response rate not statistically significant;
low response rate in both treatment groups
 AEs not increased when continuing BEV beyond PD; AE profile
consistent with previous findings
aUnstratified
log-rank test
Conclusions
 First randomised clinical trial that prospectively investigated the
impact of continued VEGF inhibition with BEV beyond first
progression
 Study confirms that continuing BEV beyond first progression
while modifying CT is beneficial for patients with mCRC and
leads to a significant improvement in OS and PFS
 This provides a new second-line treatment option for patients
who have been treated with BEV + standard CT in first line while
maintaining an acceptable safety profile
 Findings indicate a potential new model for treatment
approaches through multiple lines and this is currently being
investigated in other tumour types
Acknowledgements
 Patients and their families
 Investigators, study coordinators and nurses
 ML18147 study team at Roche
ML18147 study investigators
Austria: Andel J, Balcke P, Benedicic B, Eisterer W, Fridrick M, Greil R, Jagdt B, Keil F, Kretschmer A, Krippl P, Oexle H, Pecherstorfer M,
Samonigg H, Schmid M, Thaler J, Tinchon C, Weiss H; Belgium: 
Arts J, De Man M, Demolin G, Janssens J, Polus M, Van Cutsem E.
Czech Republic: Benczikova B, Melichar B, Prausova J, Vitek P. Denmark: Andersen FZ, Jensen BB, Keldsen N, Østerlind K, Vistisen K.
Estonia: Elme A, Magi A, Ojamaa K. Finland: Osterlund P, Ristamäki R, Salminen T. France: André T, Ben Abdelghani M, Bennouna J,
Borg C, Bouche O, Bouhier-Leporrier K, Breysacher G, Chone L, Clavero Fabri M-C,Deplanque G, Desseigne F, Dourthe L-M, Ezenfis J,
Faroux R, François E, Garnier C, Gaspard M-H, Hebbar M, Illory JF, Kaminsky M-C, Lecomte T, Legoux J-L, Levache B, Lobry C, Lotz J-P,
Mabro M, Manet-Lacombe S, Manfredi S, Matysiak Budnik T, Miglianico L, Mineur L, Moullet I, Naman H, Nouyrigat P, Oziel-Taieb S,
Perrier H, Pezet D, Philip J, Pottier V, Porneuf M, Ramdani M, Re D, Rinaldi Y, Spaeth D, Taieb J, Terrebonne E, Texereau P, Thirot
Bidault A, Tournigand C, Tubiana-Mathieu N, Vantelon J-M, Viret F, Ychou M. Germany: Arnold D, Bangerter M, Bertram ME, Bohnsteen
B, Brinkmann L, Caca K, Constantin C,Cordes H-J, Dietrich G, Eggert J, Engel E, Fahlke J, Fensterer H, Florschütz A, Folprecht G,
Forstbauer H, Freier W, Freund M, Frickhofen N, Gäbele E, Geißler M, Gieseler F, Göhler T, Graeven U, Groschek M, Grundeis M, Hacker
U, Hagen V, Hebart HF, Hegewisch-Becker S, Heike M, Herrmann T, Hildebrandt B, Höffkes H-G, Hübner G, Hübner J, Kettner E, Kneba
M, Kohnke JW, Kojouharoff G, König C, Kretzschmar A, Kröning H, Kubicka S, Kürner K, Lammert F, Lerchenmüller C, Lück A, Meiler J,
Mergenthaler H-G, Müller L, Müller-Naendrup C, Nusch A, Papke J, Porschen R, Rädle J, Reddemann C, Ridwelski K, Riera-Knorrenschild
J, Rudi J, Schlichting C, Schmalenberger A, Schimanski C-C, Schlegel F, Schmidt P, Schmiegel W, Schmitz S, Schulze-Bergkamen H,
Schwaner I, Schwarzer A, Schwerdtfeger M, Selbach J, Sieber M, Siebler J, Staib P, Stauch M, Steffens C-C, Stübs P, Tischendorf J,
Trarbach T, Tummes D, Valdix A-R, Vogel A, Von Wichert GPL, Walther M, Welslau W, Wilhelm G, Wobster H, Wolf T, Zeigenhagen N,
Zomorodbaksch B. Netherlands: Batman E, Bloemendal HJ, Kehrer DFS. Norway: Guren T, Indrebø G, Kersten C, Soerbye H. Portugal:
Fragoso M, Fragoso R, Mellidez JC, Sa A. Saudi Arabia: Aljobran A, Darwish T. Spain: Alonso-Orduna V, Aparicio J, Aranda E, Bosch C,
Galan-Brotons A, Busquier Hernandez I, Camara JC, Campos Cervera JM, Carlos Garcia Giron C, Del Prado PM, Donnay O, Escudero P,
Falco E, Gallego Plazas J, Garcia Alfonso P, Gonzalez Flores E, Gravalos C, Guardeno R, Juárez A, Lopez Ladron A, Losa Gaspa F,
MªVicent Vergé J, Marcuello Gaspar E, Massuti Sureda B, Molina J, Montero IC, Muñoa AL, Naranjo MB, Oruezabal Moreno MJ, Pachón
Olmos V, Pericay C, Reina Zoilo JJ, Rivera F, Ruiz Casado A, Safont MJ, Salud Salvia A, Sastre Valera J, Tobena M, Toral JC, Valenti V,
Valladares Ayerbes M, Vera R, Vieitez de Prado JM. Sweden: Berglund A, Fernebro E. Switzerland: Hess-Umbricht V, Pless M, Popescu
R, Von Moos R, Winterhalder R