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, Spain5Helsinki, 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
4. Grothey et al. J Clin Oncol 2008;26:5326–345. Cohn et al. J Clin Oncol 2010;28(15s):Abstr 3596
1. Ferrara et al. Nature Med 2003;9:669–762. Klement et al. J Clin Invest 2000;105:R15–243. Klement et al. Clin Cancer Res 2002;8:221–232
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
BEV + standard first-line CT (either
oxaliplatin oririnotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT (oxaliplatin or irinotecan-
based) until PD
BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-
based) until PD
PD
ML18147 study design (phase III)
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Study conducted in 220 centres in Europe and Saudi Arabia
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)
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
CharacteristicCT
(n=411)BEV + CT(n=409)
Male, % 63 65
Age, median years 63 63
ECOG performance status, %012
43525
44515
First-line PFS, %≤9 months>9 months
5644
5446
First-line CT, %Irinotecan-basedOxaliplatin-based
5842
5941
Demographic and baseline characteristics: Randomised patients
Patients were accrued between February 2006 and June 2010
Demographic and baseline characteristics: Randomised patients (cont’d)
aPatient population refers to sequential enrolment of patients in original AIO study and subsequent enrolment in ML18147 when study was transferred to Roche
Characteristic CT
(n=411) BEV + CT
(n=409)
Duration from last BEV dose to randomisation, %
≤42 days >42 days
7723
7723
Patient populationa, %AIOML18147
3268
3268
Liver metastasis only, %NoYes
7129
7327
No. of organs with metastasis, %1>1
3961
3664
Second-line chemotherapy during study: Randomised patients
Second-line CT regimen, % CT
(n=407) BEV + CT
(n=407)
Irinotecan-based CT 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
1. Douillard et al. Lancet 2000;355:1041–7
Primary endpoint:overall survival
OS: ITT populationO
S e
stim
ate
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
No. at riskCT 410 293 162 51 24 7 3 2
0BEV + CT 409 328 188 64 29 13 4 1
0
CT (n=410)BEV + CT (n=409)
9.8 mo 11.2 mo
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p=0.0211 (log-rank test)
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)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
Subsequent anti-cancer therapies: Safety population
Subsequent therapy, %CT
(n=409)BEV + CT(n=401)
Patients who received ≥1 subsequent anti-cancer therapy
67.7 68.6
Subsequent anti-cancer therapies
BEV 12.2 11.5
Anti-EGFR 41.3 39.2
Other 50.4 54.9
EGFR: epidermal growth factor receptor
Subgroup analysis of OS: ITT population
aPatient 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
Category Subgroup n HR (95% CI)
All All 819 0.81 (0.69–0.94)
Patient populationa AIO 260 0.86 (0.67–1.11)
ML18147 559 0.78 (0.64–0.94)
Gender Female 294 0.99 (0.77–1.28)
Male 525 0.73 (0.60–0.88)
Age <65 years 458 0.79 (0.65–0.98)
≥65 years 361 0.83 (0.66–1.04)
ECOG performance status 0 357 0.74 (0.59–0.94)
≥1 458 0.87 (0.71–1.06)
First-line PFS ≤9 months 449 0.89 (0.73–1.09)
>9 months 369 0.73 (0.58–0.92)
First-line CT Oxaliplatin-based 343 0.79 (0.62–1.00)
Irinotecan-based 476 0.82 (0.67–1.00)
Time from last BEV ≤42 days 630 0.82 (0.69–0.97)
>42 days 189 0.76 (0.55–1.06)
Liver metastasis only No 592 0.81 (0.67–0.97)
Yes 226 0.79 (0.59–1.05)
No. of organswith metastasis
1 307 0.83 (0.64–1.08)
>1 511 0.77 (0.64–0.94)
HR 0 1 2
Secondary endpoints: PFS and best overall response
PFS: ITT populationP
FS
est
imat
e
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2
0
CT (n=410)BEV + CT (n=409)
4.1 mo 5.7 mo
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
p<0.0001 (log-rank test)
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
aPatients with a best overall response of confirmed complete or partial responsebThis analysis was not prespecifiedcIncludes ‘not-evaluable’ or ‘no tumour assessment’ following baseline visit
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)
Safety
Treatment duration: Safety population
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
0
CT (n=409)
BEV + CT (n=401)
Overview of adverse events: Safety population
aPD leading to death captured for some patients as grade 5 AE; these events were excluded from this summaryAE: adverse event
Patients, % 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
Discontinued BEV only due to AE
N/A 2
Grade 3–5 adverse events (incidence ≥2%) in any arm: Safety population
Adverse event, %CT
(n=409)BEV + CT(n=401)
Neutropenia 13 16Leukopenia 3 4Diarrhoea 8 10Vomiting 3 4Nausea 3 3Abdominal pain 3 4Subileus <1 2Asthenia 4 6Fatigue 2 4Mucosal inflammation 1 3Dyspnoea 3 2Pulmonary embolism 2 3Polyneuropathy 2 3Neuropathy peripheral 2 1Hypokalaemia 2 2Decreased appetite 2 1
Adverse events of special interest to BEV: Safety population
Patients, %
CT(n=409)
BEV + CT(n=401)
All grades Grade 3–5 All grades Grade 3–5
AEs of special interest to BEV 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 – – – –ATE: arterial thromboembolic events; GI: gastrointestinal; RPLS: reverse posterior leukoencephalopathy syndrome; VTE: venous thromboembolic events
Summary and Conclusions
Summary
aUnstratified log-rank test
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
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