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