Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX)

David Cunningham,1 Istvan Lang,2 Eugenio Marcuello,3 Vito Lorusso,4 Janja Ocvirk,5 Dong Bok Shin,6 Derek Jonker,7 Stuart Osborne,8 Niko Andre,9 Daniel Waterkamp,8 Mark P. Saunders10

1Royal Marsden Hospital, London and Surrey, United Kingdom; 2National Institute of Oncology, Budapest, Hungary; 3Hospital de Sant Pau de Barcelona, Barcelona, Spain; 4National Cancer Institute "Giovanni Paolo II" Bari, Italy; 5Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia; 6Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea; 7Department of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada; 8F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9Roche Pharma

AG, Grenzach-Wyhlen, Germany; 10Christie Hospital, Withington, Manchester, United Kingdom

Disclosures

• David Cunningham

– Research funding from F. Hoffmann-La Roche Ltd., Merck

KGaA, Novartis, Celgene, Amgen, and AstraZeneca

Background and rationale

• Although the median age of patients diagnosed with mCRC is 69 years, older patients are in general undertreated and the optimal treatment approach still needs to be evaluated1,2

• Bevacizumab (BEV) is a standard of care in mCRC3-5 and prior analyses have suggested that elderly patients benefit from the addition of BEV to chemotherapy6-8

• AVEX is the first phase III trial to prospectively evaluate the use of a biologic in an elderly patient population with mCRC

1Howlader N, et al. http://seer.cancer.gov/csr/1975_2009_pops09; 2Golfinopoulos V, et al. Cancer Treat Rev. 2006;32:1–8; 3Hurwitz H, et al. N Engl J Med. 2004;350:2335–42; 4Giantonio BJ, et al. J Clin Oncol. 2007;25:1539–44; 5Bennouna J, et al. Lancet Oncol. 2013;14:29–37; 6Cassidy J, et al. J Cancer Res Clin Oncol. 2010;136:737–43; 7Kozloff MF, et al. Oncology. 2010;78:329–39; 8Price TJ, et al. Ann Oncol. 2012;23:1531–6.

Study design

Previously untreated mCRC, age 70 years

N=280

Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d

Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d

+Bevacizumab 7.5 mg/kg

day 1, q21dRandomize

1:1

Stratification factors:– ECOG PS (0–1 vs 2)– Geographic region

• Key inclusion criteria– ECOG PS 0–2– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion– Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin

• Key exclusion criteria– Prior chemotherapy for mCRC or prior adjuvant anti-VEGF treatment– Clinically significant cardiovascular disease– Current or recent use of aspirin (>325 mg/day) or other NSAID – Use of full-dose anticoagulants or thrombolytic agents

Statistical considerations

• Primary endpoint: PFS

• Secondary endpoints: ORR, time to response, duration of response, OS, safety

• Designed to detect a 31% reduction in the risk of progression (HR 0.69)

– 232 events required to achieve 80% power for a 2-sided test at the 5% level

• PFS/OS curves estimated using Kaplan-Meier method, differences assessed using unstratified log-rank tests

– Stratified Cox regression model used to estimate HR

HR = hazard ratio; PFS = progression-free survival; ORR = overall response rate; OS = overall survival

Select baseline patient characteristics Cape + BEV

(n=140)Cape

(n=140)

Sex, % Female 40.0 40.0

Median age, years (range) 76 (70–87) 77 (70–87)

<75 years, % 39.3 32.9

≥75 years, % 60.7 67.1

ECOG performance status, % 0 50.0 42.9

1 41.4 47.9

2 7.1 7.9

Prior adjuvant therapy, % Yes 32.1 18.6

Site of metastatic disease, % Liver 62.9 67.9

Lung 35.7 40.7

Other 35.0 22.9

Liver only 37.1 38.6

Surgical resection, % Yes 73.6 63.6

Location of primary disease, % Colon only 57.9 54.3

Rectum 31.4 25.0

Colon and rectum 10.7 19.3

ITT population. Cape = capecitabine; ECOG PS = Eastern Cooperative Group performance status.

Progression-free survivalP

FS

est

imat

e

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Number at risk

Cape + BEV

Cape

140 121 99 80 68 55 41 28 23 16 13 9 8 3 2 2 2 2 1 0 0

140 109 82 56 38 25 13 9 6 4 4 2 1 1 1 1 1 1 1 1 0

Time (months)

Cape + BEV (n=140)

Cape (n=140)

5.1 mo 9.1 mo

HR=0.53 (95% CI: 0.41–0.69)P<0.001

ITT population. 113 PFS events in the Cape + BEV arm; 127 PFS events in the Cape arm. CI = confidence interval; PFS = progression-free survival

Category Subgroup N HR (95% CI)

All All 280 0.53 (0.41–0.69)

Sex Female 112 0.47 (0.30–0.72)

Male 168 0.57 (0.41–0.80)

Age <75 years 101 0.52 (0.32–0.83)

≥75 years 179 0.52 (0.37–0.72)

Baseline ECOG performance status

0 130 0.61 (0.41–0.89)

>0 147 0.50 (0.34–0.72)

Prior adjuvant therapy No 206 0.51 (0.37–0.69)

Yes 71 0.59 (0.33–1.04)

Liver metastases only No 162 0.53 (0.38–0.75)

Yes 106 0.54 (0.35–0.83)

Surgical resection No 86 0.27 (0.16–0.48)

Yes 192 0.62 (0.45–0.85)

Location of primary disease Colon only 157 0.67 (0.47–0.94)

Rectum and colon 42 0.22 (0.08–0.56)

Rectum only 79 0.41 (0.24–0.69)

Subgroup analysis of PFS

HR 0 1 20.6

Cape + BEV better Cape alone better

ITT population.

Overall survival

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Number at riskCape + BEV

Cape

140 126 120 106 95 89 81 67 60 51 44 40 34 24 16 15 12 10 8 6 5 4

140 120 108 94 85 73 62 57 49 37 33 23 19 13 11 10 9 7 6 5 5 3

OS

est

imat

e

Time (months)

2

1

0

0

16.8 mo 20.7 mo

HR=0.79 (95% CI: 0.57–1.09)P=0.182

Cape + BEV (n=140)

Cape (n=140)

ITT population. 75 OS events in each treatment arm.

Subsequent therapies

Subsequent therapy (selected), %Cape + BEV

(n=140)Cape (n=140)

Any additional treatment for malignancy 37.1 37.1

5-Fluorouracil 10.7 9.3

Capecitabine 5.0 7.9

Oxaliplatin-doublet 2.1 0.7

Irinotecan-doublet 5.7 2.9

Bevacizumab 5.7 7.9

Cetuximab 2.9 1.4

Panitumumab 0.7 4.3

ITT population.

Overall response rate

Outcome, %Cape + BEV

(n=140)Cape (n=140)

ORR (CR + PR) 19.3 10.0

P=0.042

CR 2.1 1.4

PR 17.1 8.6

SD 55.0 47.9

PD 10.0 21.4

Disease control rate (CR + PR + SD) 74.3 57.9

P=0.005

Missing 15.7 20.7

ITT population. CR = complete response; PD = disease progression; PR = partial response; SD = stable disease.

Study drug exposureM

edia

n tr

eatm

ent

dura

tion

(mon

ths)

Safety population.

Overview of adverse events

AE, %Cape + BEV

(n=134)Cape

(n=136)

Any AE 95.5 95.6

SAE 30.6 32.4

Grade ≥3 AE 59.0 44.1

Grade 5 AE 8.2 11.8

Any AE leading to dose modification 54.5 43.4

AE leading to discontinuation 25.4 14.0

Safety population. AE = adverse event; SAE = severe adverse event.

AEs of special interest to BEV

Safety population. GI = gastrointestinal; RPLS = reverse posterior leukoencephalopathy syndrome.

AE%Cape + BEV

(n=134)Cape

(n=136)

All grades Grade ≥3 All grades Grade ≥3

Bleeding/hemorrhage 25.4 – 6.6 0.7

Hypertension 19.4 2.2 5.1 1.5

Venous thromboembolic events 11.9 8.2 5.1 4.4

Proteinuria 7.5 1.5 0.7 –

Arterial thromboembolic events 4.5 3.7 2.9 1.5

Wound healing complications 1.5 – – –

Pulmonary hemorrhage/hemoptysis 0.7 – 0.7 0.7

Fistulae 0.7 – – –

Congestive heart failure – – 0.7 0.7

GI perforation – – – –

RPLS – – – –

AEs related to chemotherapy occurring in ≥5% of patients in the Cape + BEV arm (selected)

AE,%Cape + BEV

(n=134)Cape

(n=136)

All grades Grade ≥3 All grades Grade ≥3

Hand-foot syndrome 48.5 14.9 39.7 6.6

Diarrhea 40.3 6.7 35.3 6.6

Asthenia 22.4 5.2 15.4 4.4

Fatigue 23.9 3.7 27.2 0.7

Nausea 23.9 0.7 26.5 –

Vomiting 20.1 1.5 11.0 1.5

Stomatitis 14.9 – 8.1 0.7

Neutropenia 5.2 0.7 1.5 0.7

Safety population. Not listed: decreased appetite, abdominal pain, constipation, pyrexia, epistaxis, mucosal inflammation, lethargy, arthralgia, peripheral oedema, pain in extremity, pain, musculoskeletal pain, skin hyperpigmentation, dizziness, headache, upper abdominal pain, dyspepsia, pulmonary embolism, dry skin, paraesthesia, rhinorrhoea.

Conclusion

• AVEX is the first phase III trial to prospectively evaluate the use of a biologic in mCRC patients ≥70 years, a population that is in general undertreated

• The addition of BEV to cape significantly improved PFS and ORR

– PFS 9.1 vs 5.1 months (HR 0.53; p<0.001)

– ORR 19.3% vs 10.0% (p=0.042)

• A numerically longer OS was observed in the BEV-containing arm, but this did not reach statistical significance

• The safety profile was consistent with previously reported data of BEV in mCRC

• Results from AVEX suggest that the combination of BEV and cape is an effective and well-tolerated regimen for patients ≥70 years with mCRC

Acknowledgments

• The authors would like to thank the patients and their families, the study investigators, study coordinators and nurses

AVEX Study Investigators

Austria

Greil R

Ludwig H

Nitsche D

Canada

Berry S

Brezden-Masley C

Dowden S

Jeyakumar A

Jonker D

Lohrisch C

Welch S

Mexico

Leon Rodríguez E

Magallanes-Maciel M

Poland

Deptala A

Koralewski P

Slovenia

Ocvirk J

South Korea

Park J-H

Park Y-S

Shin D-B

Shin S-J

Spain

Alonso JD

Anton Torres A

Duenas Garcia R

Marcuello E

United Kingdom

Cleator S

Cunningham D

Gollins S

Hopkins K

Potter V

Saunders M

Sizer B

Steward W

Waterston A

HungaryDank MLang IPintér TRuzsa A

Italy

Boni C

Di Costanzo F

Lorusso V

Zeuli M