Review

Bevacizumab—current status and future directions

Rachel Midgley* & David Kerr

Department of Clinical Pharmacology and Cancer Therapeutics, Racliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK

Received 13 January 2005; accepted 2 February 2005

Angiogenesis is crucial to tumour initiation, survival and metastasis. Vascular endothelial growth

factor (VEGF) is one of the most important pro-angiogenic factors in cancer development. Bevacizu-

mab (a humanised monoclonal antibody against VEGF) has a reasonable safety profile and proven

efficacy in a phase III trial in advanced colorectal cancer. Efficacy of Bevacizumab also looks

promising in non small cell lung cancer, renal cancer and a variety of other solid tumours. Questions

still surround optimal dosing and the appropriate selection of patients who are most likely to benefit.

Future trials will address these questions and provide further translational insights.

Key words: angiogenesis, bevacizumab, vascular endothelial growth factor

Introduction to angiogenesis and VEGF

Angiogenesis (the growth of new blood vessels from existing

vessels) is absolutely essential during embryogenesis and in

the growth of long bones in children and adolescents. There-

after, in adult life, angiogenesis occurs in a restricted number

of pathological situations including wound healing, endome-

triosis and the growth of cancers and establishment of their

metastases.

The primary stimulus to angiogenesis is oxygen deprivation.

When this occurs pro-angiogenic factors are released which

activate the formation of new blood vessels through a number

of downstream effects, such as proliferation and migration of

vascular endothelial cells, survival of immature endothelial

cells and induction of vascular permeability in capillaries.

Candidate pro-angiogenic factors include vascular endothelial

growth factor (VEGF), basic fibroblast growth factor (bFGF)

and transforming growth factors alpha and beta (TGFa and

b), the most important of these being VEGF [1, 2]. There are

also anti-angiogenesis factors that have an opposite effect and

it is the balance of pro- and anti-angiogenic factors that deter-

mines the angiogenesis balance (Figure 1).

There are six described members of the VEGF family but

VEGF-A (also known as vascular permeability factor [3] or

just VEGF) appears to exert the greatest influence of angio-

genesis during the carcinogenic process. VEGF-A exerts its

influence through binding principally to the VEGF receptor-2,

expressed principally on endothelial cells (Figure 2). This

receptor shares many common characteristics with other mem-

bers of a family of receptors having tyrosine kinase activity,

including several extracellular Ig-like domains, a transmem-

brane region and an intracellular tail with tyrosine kinase

activity. Induction of the kinase activity by VEGF binding

causes a cascade of phosphorylation of at least 46 signalling

molecules.

In the pathogenesis of cancer, VEGF has a number of key

roles. It stimulates excessive angiogenesis, allowing the

tumour to embark upon its exponential growth phase. This

vascularisation also provides an exit route for haematogenous

metastases and allows them to establish themselves at their

final destination. The critical importance of VEGF during

tumorigenesis has been illustrated by a number of obser-

vations: VEGF expression is elevated in the tissues or circula-

tion in many solid tumours [4]; a significant correlation has

been found between plasma VEGF levels and disease stage or

metastasis [5]; pre-clinical experiments showed that anti-

VEGF antibodies inhibited the growth of human tumour cell

lines injected into nude mice [6].

History of bevacizumab

Given this key role, it is not surprising that much effort has

been made to develop agents that block the effects of VEGF,

in an attempt to abrogate the carcinogenic process. The most

well developed of these to date is Bevacizumab (Avastinw),

which is a humanised murine monoclonal antibody against the

VEGF molecule.

The first phase I trial of Bevacizumab began in 1997 [7].

Twenty-five patients with measurable or assessable solid

tumours (sarcoma = 8, renal cell carcinoma (RCC) = 7, breast

cancer = 5, lung cancer = 2) were enrolled and five dose levels

were assessed—0.1, 0.3, 1.0, 3,0 and 10mg/kg. Bevacizumab

was delivered intravenously over 90 minutes on days 0, 28, 35

and 42. One patient with RCC achieved a minor response

with an approximate 25% reduction in the sum of perpendicu-

lar diameters of the pulmonary and lymph node metastases.

48% of the remaining patients achieved disease stabili-

sation. Bevacizumab showed a linear pharmacokinetic profile

*Correspondence to: Dr R. Midgley, Cancer Research UK, ChurchillHospital, Headington, Oxford, UK, OX3 7LJ.E-mail: Rachel.Midgley@cancer.org.uk

Annals of Oncology 16: 999–1004, 2005

doi:10.1093/annonc/mdi208

Published online 6 June 2005

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and a terminal half life of 21 days. A phase Ib trial then asse-

ssed Bevacizumab in combination with a number of standard

cytotoxics—doxorubicin, carboplatin, paclitaxel and 5-fluoro-

uracil (5FU)/leucovorin (LV). Bevacizumab was administered

at 3mg/kg weekly for 8 weeks. This trial demonstrated that

adding the anti-VEGF antibody did not significantly increase

the known cytotoxic adverse event rates [8].

Subsequently five parallel phase II trials were commenced,

three of single agent Bevacizumab (in hormone-refractory

prostate cancer, relapsed metastatic breast cancer and IL2-

refractory renal cell cancer) and two in combination with

standard first line therapy (in inoperable non small cell lung

cancer—NSCLC and metastatic colorectal cancer). The most

encouraging trials were in renal cancer, NSCLC and colorectal

cancer [9, 10, 11].

In renal cancer a randomised double blind phase II trial was

performed recruiting 116 patients to one of three groups—

placebo, bevacizumab 3mg/kg or bevacizumab 10mg/kg,

administered every 2 weeks. The time to disease progression

was significantly prolonged in the high dose but not the low

dose group compared to the placebo group. The percentage of

patients being progression-free was 64% in the high dose

group compared to 34% and 20% in low dose and placebo

groups respectively. Toxicity included increased blood press-

ure and asymptomatic proteinuria [9].

In the phase II trial in advanced NSCLC ninety-nine

chemotherapy-naı̈ve patients were randomised to receive

carboplatin and paclitaxel plus or minus bevacizumab (at 7.5

or 15mg/kg), all agents being administered every three weeks.

Bevacizumab was given until disease progression or to a

maximum of one year; six cycles of chemotherapy were

administered. The trial indicated no significant increase in

toxicity compared to chemotherapy alone and, in the 15mg/kg

arm, suggested an increase in time to progression (7.4 versus

4.2 months) and modest increase in survival (17.7 versus 14.9

months) in patients receiving bevacizumab compared to che-

motherapy alone [10].

In the first phase II trial in metastatic colorectal cancer, 104

previously untreated patients were randomised to receive

5FU/LV (for 6 weeks of an 8-week cycle) plus bevacizumab,

5mg/kg (n= 35) or 10mg/kg (n= 33) every 2 weeks or

placebo (n = 36) until disease progression. Interestingly the

objective response rate was superior for the 5mg/kg bevacizu-

mab arm (40% compared to 24% and 17% in the 10mg/kg

bevacizumab dose and the placebo arms respectively). This

stands in contrast to the results above in the renal cancer trial

where a dose-response relationship was apparent. Whether the

colorectal result was due to a subtle randomisation imbalance

with more poor prognosis patients receiving the high dose or

whether the result was due to a physiological phenomenon, in

which the high dose bevacizumab caused excessive regression

and destruction of blood vessels and therefore poorer

chemotherapy penetration is not known. Again thrombosis

was the most significant toxic effect, but hypertension, protei-

nuria and epistaxis were also observed.

A second phase II trial in CRC was then commenced, prin-

cipally because the IFL regime (bolus 5FU/LV plus irinote-

can) had become the new standard first line treatment for

metastatic CRC in the United States. Ninety-two patients with

advanced CRC received bevacizumab (10mg/kg infusion

every 2 weeks) in combination with IFL (bolus IV for 4 of 6

weeks). Seventy-two further patients received the same dose

of bevacizumab but reduced irinotecan and 5FU starting

doses; these doses were then escalated as long as no greater

than grade 1 neutropenia or diarrhoea was observed. Overall

Figure 1. The angiogenic balance in cancer.

Figure 2. VEGF and its receptor.

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the complete response rate, partial response rate and stabilis-

ation rate were 5.4%, 38% and 36% respectively, giving a

promising overall disease control rate of 79.4% [12].

Based on the results of these two phase II trials and some

ongoing concerns about the safety of the IFL regime, a double

blind randomised phase III three arm study was commenced.

Patients received IFL plus placebo (n= 411), IFL plus bevaci-

zumab (n = 402) or 5FU/LV plus bevacizumab (n= 110).

When acceptable safety of the IFL/bevacizumab combination

was established the third arm stopped recruitment. The

results of the trial are summarised in Table 1. The addition of

bevacizumab to IFL chemotherapy produced significant

improvements in response rate (44.8 versus 34.8%; P = 0.004),

time to progression (10.6 versus 6.2 months; P<0.001) and

median survival (20.3 versus 15.6 months; P<0.001) [13].

Toxicity is still of some concern with this combination. IFL

alone produces grade 3/4 toxicity rates of 30% and 25% for

neutropenia and diarrhoea respectively. Adding bevacizumab

significantly increased grade 3 hypertension rates (11% versus

2.3%, P<0.01), but interestingly did not impact significantly

upon the rates of proteinuria, thrombosis and bleeding. One

major concern was six gastrointestinal perforations occurring

in patients receiving IFL/bevacizumab and this possibility

needs to be highlighted to clinicians who are using the combi-

nation and potential symptom profiles outlined to patients to

allow early intervention.

A number of re-analyses of the toxicity data from these

combined trials were presented at ASCO 2004 (see Table 2).

The authors looked at thrombo-embolism in the phase II and

III CRC trials in more detail and found that although arterial

thrombo-embolism may be slightly increased with bevacizu-

mab (10% versus 4.8% and 3.3% versus 1% in the phase II

and phase III trials respectively), incidence of venous

thrombo-embolism was not increased. They also assessed

whether remaining on bevacizumab during subsequent full

dose anti-coagulation increased the risk of bleeding and,

although numbers were small, there was no evidence to

suggest this. The authors also re-analysed wound healing and

bleeding complications in patients who had undergone pri-

mary cancer surgery between 28 and 60 days prior to com-

mencing bevacizumab therapy. 187 subjects on chemotherapy

plus bevacizumab had undergone surgery compared to 155

subjects on receiving chemotherapy alone. The incidence of

grade 3/4 wound healing problems/bleeding was 1 patient

(0.65%) in the bolus IFL alone arm, 3 patients in the bevaci-

zumab plus IFL arm and no subjects in the bevacizumab plus

5FU/LV arm, revealing no statistically significant difference.

Table 1. Results of the Phase III trial of IFL ± bevacizumab in first line

treatment of advanced colorectal cancer [13]

IFL plusplacebo

IFL plusbevacizumab

P value

Median survival (months) 15.6 20.3 <0.001

One year survival rate (%) 63.4 74.3 <0.001

Progression-freesurvival (months)

6.2 10.6 <0.001

Overall response rate—CR + PR (%)

34.8 44.8 0.004

Median duration of response(months)

7.1 10.4 0.001

Table 2. Bevacizumab at ASCO 2004

Abstract no. and authors Questions addressed and trial type Summary of results

3529 Holmgren et al. Thrombo-embolism re-appraisal withBev (from phase II and phase III trials)

Slight increase risk of arterial embolismbut not venous embolism

3530 Scappaticci et al. Wound healing and bleeding re-appraisal withBev post-surgery (from phase II/III trials)

No increase in rate if start treatmentbetween 28 and 60 days post op

578 Wedam et al. ? Bev with chemo for neoadjuvant therapy ofinflammatory breast ca (exploratory)

Good efficacy and MRI evidence of reducedblood flow with Bev alone

3589 Willett et al. Combination Bev plus chemoradiation inneoadjuvant rectal ca (phase I)

No DLT and excellent efficacy

5539 Mauer et al. Combination Bev + erlotinib for advancedSCC head and neck (phase I)

No DLT even at 15mg/kg/3 weeks.Good disease control rate

2000 Sandler et al. Combination Bev + erlotinib advanced NSCLCpreviously treated (phase I/II)

34 treated in phase II part (15mg/kg/3 weeks Bev)PR 22.5%; MR 5%; SD 35%

4502 Hainsworth et al. Combination Bev (10mg/kg/2weeks) + erlotinibadvanced RCC (phase II)

40 evaluable for efficacy PR 25%;MR 15%; DS 47%. Well tolerated

9012 D’Adamo et al. Combination Bev (15mg/kg/3 weeks) + Doxadvanced soft tissue sarcomas (phase II)

13 patients evaluable PR 14%; SD 59%

3013 Yao et al. Bev versus PEG IFNa in carcinoid tumours (phase II) Too immature for efficacy results. fCT showedrapid reduction tumour blood flow

4009 Kindler et al. Bev (10mg/kg/2weeks) + gemcitabine in chemo-naı̈veadvanced pancreatic cancer (phase II)

42 patients evaluable PR21%; SD 45%.Reasonable tolerability

See text for more detail.

Bev = bevacizumab; DLT= dose limiting toxicity; chemo= chemotherapy; SCC= squamous cell carcinoma; NSCLC=non small cell lung cancer;

RCC= renal cancer; MR=minor response rate; PR= partial response rate; DS = disease stabilisation rate; fCT= functional CT.

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This augurs well for the use of bevacizumab in the adjuvant

setting in the future.

Current status of bevacizumab

Based on the results of this phase III trial the IFL/bevaci-

zumab (5mg/kg) combination gained FDA approval for the

first line treatment of advanced CRC by the FDA in the Uni-

ted States in February 2004. However much of the rest of the

academic community are awaiting confirmatory evidence

and evaluation of the combination of bevacizumab with better

tolerated chemotherapy regimes. A phase III trial in combi-

nation with oxaliplatin, 5FU and LV is ongoing.

What about patients that are not fit for irinotecan in the first

line treatment of advanced colorectal cancer? The companion

trial to the phase III trial described above randomised 209

patients to receive Roswell Park 5FU/LV (6 of 8 weeks) plus

placebo or bevacizumab 50mg/kg every 2 weeks [11]. The

addition of bevacizumab produced a statistically significant

prolongation of progression-free survival and a trend towards

improved response rate and survival. However again there was

a 2% gastrointestinal perforation rate in the bevacizumab arm

and this needs careful consideration when assessing the risks

and benefits of the addition of bevacizumab in this population.

In the adjuvant setting of colorectal cancer, bevacizumab is

being assessed in combination with capecitabine (1000mg/m2,

14 of 21 days) and irinotecan (250mg/m2 every three weeks)

in the United Kingdom QUASAR 2 trial.

In advanced breast cancer the first phase III trial (n = 462)

comparing capecitabine plus or minus bevacizumab as third

line chemotherapy (after anthracyclines and taxanes) demon-

strated an improved response rate with bevacizumab but no

impact upon progression-free or overall survival [14]. It is

now being assessed in first line metastatic breast cancer in

combination with paclitaxel. Bevacizumab is also being

assessed in a phase III trial in NSCLC (with carboplatin and

paclitaxel); and in the first line treatment of advanced renal

cancer in combination with interferon-a (CALGB 90 206)

where the dose of bevacizumab will be 10mg/kg based on the

phase II trial data for this disease.

Bevacizumab at ASCO 2004

A number of studies related to bevacizumab were presented at

ASCO this year. These can be divided into exploratory, phase

I and phase II trials (Table 2, reference 15).

An exploratory study in inflammatory breast cancer patients

assessed response and angiogenesis after treatment with

bevacizumab (15mg/kg). Sixteen patients received a cycle of

bevacizumab alone followed by six cycles of neoadjuvant

bevacizumab, doxorubicin and docetaxel. Post-mastectomy

and radiation, patients were administered eight further cycles

of bevacizumab (plus or minus hormone therapy depending on

ER status). Tumour biopsies and dynamic contrast-enhanced

MRI were obtained prior to treatment, after the single cycle

of bevacizumab alone and then after cycles 4 and 7 of

combination treatment. Of 10 evaluable patients, nine

achieved a partial response and one demonstrated progressive

disease. Preliminary data suggested a decrease in vascular per-

meability (MRI) and endothelial cell proliferation (Cd31/Ki67

expression) even after the single cycle of bevacizumab alone.

In responding patients there was a trend towards a decrease in

VEGF after bevacizumab alone and in tumour cell prolifer-

ation (Ki67) after chemotherapy and bevacizumab. This is an

interesting mechanistic study and suggests that bevacizumab

warrants further exploration in this setting where treatment is

often difficult and inadequate.

Also presented were two phase I trials. The first was a

study of neoadjuvant bevacizumab, 5FU and radiation fol-

lowed by surgery for primary rectal cancer in nine patients

with T3 or T4, Nx, Mo tumours. Patients received bevaci-

zumab at a dose of 5mg/kg (n= 6) or 10mg/kg (n= 3) every

2 weeks, with bevacizumab therapy commencing 2 weeks

prior to chemoradiation. Surgery was performed 7 weeks after

completion of all therapy. All patients to date had completed

the course of treatment without DLT and pathological review

of the surgical specimens of six of the seven evaluable

patients showed only limited microscopic disease (in keeping

with the lack of macroscopic disease visualised on follow-up

endoscopy prior to surgery). These results demonstrate safety

of the combination and significant clinical activity, again

suggesting that further investigation would be appropriate.

The second phase I study assessed the combination of beva-

cizumab and an epidermal growth factor receptor (EGFR)

inhibitor erlotinib in patients with advanced squamous cell car-

cinoma of the head and neck cancer receiving no more than

one previous therapy for their disease. The rationale for the

combination lies in the observation in pre-clinical studies that

resistance to EGFR inhibitors appears related to angiogenesis.

A fixed dose of erlotinib (150mg orally daily) was adminis-

tered with an escalating dose of bevacizumab (5, 10 and

15mg/kg every 3 weeks). 10 patients were enrolled. Grade 3

diarrhoea, skin rash and lymphopenia were seen in one patient

each. Grade 4 haemorrhage from a tongue tumour was

observed in one patient. No dose limiting toxicity was seen.

One patient gained a partial response with 7 patients achieving

disease stabilisation and a phase II trial is now underway.

The combination was similarly assessed in advanced/recur-

rent NSCLC. A phase I trial first set a maximum tolerated

dose (MTD) of 15mg/kg bevacizumab every 3 weeks in com-

bination with erlotinib 150mg once daily orally. Thirty-four

patients were treated at the MTD in the phase II portion of the

trial. Twenty-four of these patients had received at least two

chemotherapeutic regimes. The partial response rate was

22.5% with minor response in a further 5% and stable disease

in 35%, giving an overall disease control rate of 62.5%, which

compares very well with historical controls treated in this set-

ting. A randomised phase II trial is now planned in a similar

cohort of patients.

Another group assessed the same combination in advanced

renal cancer who had received a maximum of one previous

regimen. Bevacizumab was given at a dose of 10mg/kg every

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2 weeks and erlotinib 150mg once daily until progression.

Fifty-seven patients were treated, 40 of which were evaluable

for efficacy (at least 8 weeks of therapy). Progression-free sur-

vival at 6 months was 71% with a partial response rate of

25%, a minor response rate of 15% and a disease stabilisation

rate of 47%. Grade 3/4 toxicity rates were low—hypertension

11%, diarrhoea 9%, rash 7% and nausea/vomiting 7%. Again

the substantial clinical activity means that randomised phase

II or even phase III trials should now be initiated.

Bevacizumab was also assessed in phase II trials in a num-

ber of new indications, including soft tissue sarcoma, carci-

noid tumours and advanced pancreatic cancer. Bevacizumab

(15mg/kg) was combined with doxorubicin (75mg/m2), both

given every 3 weeks, in the treatment of soft tissue sarcomas.

The response rate of 14% was no better than historical con-

trols treated with doxorubicin alone; however the authors felt

that the disease stabilisation rate of 59% was encouraging and

warranted further investigation.

Carcinoid tumour patients were randomly assigned to either

bevacizumab (dose not given in abstract) or PEG interferon

2a for the first 18 weeks followed by the combination of the

two. Tumour blood flow was assessed by functional CT. The

early results demonstrated a rapid decrease in tumour blood

flow in patients treated with bevacizumab as opposed to PEG

interferon 2a but the data were too immature to draw any

conclusions about efficacy.

Updated results from a phase II trial of gemcitabine

(1000mg/m2 weekly for 3 out of 4 weeks)/bevacizumab

(10mg/kg every 2 weeks) in chemotherapy-naı̈ve advanced

pancreatic cancer patients were also presented. Forty-two

patients were evaluable for response with a median follow-up

of 5.7 months. The partial response rate was 21% with a dis-

ease stabilisation rate of 45%. Six-month survival was 74%.

There were two deaths, one due to a gastrointestinal bleed and

one secondary to bowel perforation, so clearly these toxicities

are not confined to patients with colorectal cancer. A random-

ised phase III CALGB study is now under development.

Future considerations for bevacizumaband other VEGF inhibitors

It is clear from the studies presented above that the repertoire

of diseases for which bevacizumab may be applicable is

rapidly expanding. It is also apparent that performing properly

designed randomised phase II trials in this ever expanding

area of novel biological agents might reduce the duplication

of studies and allow quicker translation of the most promising

agents into the phase III setting.

In order to increase our ability to select the most promising

anti-angiogenesis drugs overall, and in particular for indivi-

dual patients a number of surrogate endpoints for effect have

been explored. These include treatment-induced depression in

plasma VEGF, reduction in tumour blood flow on functional

CT or MRI or biopsy proof of a decrease in angiogenesis but

to date none of these has been performed in an adequate num-

ber of patients or been correlated in any statistically robust

way with response to promote routine clinical use. An area of

exploration for the future will be studying polymorphisms of

the VEGF molecule itself or its receptor and attempting to

correlate these with tumour response.

One area of confusion surrounding bevacizumab has been

the differential dosing seemingly required for different

tumours, with colorectal cancers requiring only 5mg/kg/

2 weeks compared to 10mg/kg or greater for NSCLC and

renal cancers. It must be remembered that the dose defined for

colorectal cancer was based on a relatively small phase II

study (about 35 patients/arm) and was defined according to

efficacy. With these numbers a slight swing of two or three

patients in either direction (responders being non-responders

or vice versa) would result in a completely different con-

clusion. In the future consideration should be given to dose-

confirmation for biological agents being integrated into large

randomised phase III trials, perhaps posed in a 2�2 factorial

fashion to reduce the numbers of patients required.

One final question has been the conversion of dosing of

bevacizumab into a three-weekly schedule to fit in with other

chemotherapy regimes. At ASCO this year results from the

CRC and NSCLC phase II trials were combined to assess the

pharmacokinetic effect of two-weekly (5mg/kg) versus three-

weekly (7.5mg/kg) dosing on tumour exposure to bevaci-

zumab. The authors concluded that observed and simulated

drug exposure were similar in both arms, due to the slow

clearance and long elimination half life of 20 days for bevaci-

zumab. This answers any concern about the three weekly

schedule and allows QUASAR 2 and other large phase III

trials to proceed without further deliberation.

Acknowledgement

This article first appeared in Japanese in Gan Bunshi-Hyoteki

Chiryo and is published here in English with permission of

the copyright holder. Citations to this article should be to Gan

Bunshi-Hyoteki Chiryo 2005; 3: 124–132.

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