430109

2012
TAW322042098611430109C Kurkjian and ES KimTherapeutic Advances in Drug Safety

Therapeutic Advances in Drug Safety Review

Risks and benefits with bevacizumab: Ther Adv Drug Saf

(2012) 3(2) 59­–69

evidence and clinical implications DOI: 10.1177/

2042098611430109

© The Author(s), 2012.

Reprints and permissions:
Carla Kurkjian and Edward S. Kim http://www.sagepub.co.uk/
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Abstract: With the 1997 filing of an investigational new drug application for the first agent
to target angiogenesis, bevacizumab entered into phase I clinical trials and has now become
a mainstay in the treatment of several cancers. Bevacizumab has changed the treatment
approach for cancers due to its efficacy as well as toxicity. This article serves as a review of
current efficacy data including recently published safety analyses and the direction of future
pharmacodynamic evaluation to hopefully better guide its utilization.

Keywords: bevacizumab, efficacy, pharmacodynamics, safety

Introduction [Hurwitz et al. 2004]. With an unprecedented Correspondence to:

In 2004, bevacizumab (Avastin®, South San median survival of 20.3 months in the experimen- Edward S. Kim, MD
Chief, Section of Head and
Francisco, Genentech, CA, USA), a humanized tal arm, the efficacy of bevacizumab when com- Neck Medical Oncology,
monoclonal antibody directed against circulating bined with the IFL regimen ushered in a new Director, Clinical Research
Operations, Department
vascular endothelial growth factor (VEGF) A, era in targeted cancer therapeutics. Subsequent of Thoracic/Head and
became the first anti-angiogenic agent approved integration of bevacizumab into oxaliplatin/ Neck Medical Oncology,
University of Texas M. D.
by the US Food and Drug Administration (FDA) fluoropyrimidine-based regimens resulted in Anderson Cancer Center,
for the treatment of cancer. After this initial FDA median survival times of up to and beyond 2 years Houston, TX, USA
edkim@mdanderson.org
approval for use as first-line therapy in metastatic [Hochster et al. 2008] in first-line regimens and
Carla Kurkjian, MD
colorectal cancer (CRC) patients, it subsequently 13 months in second-line therapy [Giantonio Section of Hematology/
was approved for use in first-line metastatic, non- et al. 2007]. Unfortunately, the introduction of Oncology, University of
Oklahoma Health Sciences
squamous, non-small cell lung cancer (NSCLC), bevacizumab into the adjuvant treatment of Center, Oklahoma City,
second-line glioblastoma therapy, and in combi- patients with stage II and III CRC has not been OK, USA

nation with interferon alpha for metastatic renal successful as yet. No statistically significant
cell carcinoma (RCC). In 2008, bevacizumab was improvement in disease-free or overall survival
given accelerated approval for use in combination was found at the 3-year timepoint when bevaci-
with paclitaxel in patients with HER2-negative zumab was administered in combination with
breast cancer. On 16 December 2010, the FDA 6 months of infusional/bolus fluorouracil, leucov-
recommended removal of breast cancer from bev- orin and oxaliplatin (modified FOLFOX6) and
acizumab labeling based on a lack of evidence followed by an additional 6 months of bevaci-
demonstrating an overall survival efficacy in this zumab alone in the National Surgical Adjuvant
disease. Herein, we describe the current role of Breast and Bowel Project (NSABP) C-08 trial
bevacizumab in cancer therapy with a focus on its [Allegra et al. 2011]. While a transient effect was
emerging adverse event profile and the ongoing apparent in the cohort of bevacizumab exposed
search for reliable biomarkers predictive of its patients as evidenced by an initial lower event
efficacy. rate, this effect did not persist beyond the
15-month landmark. Also investigating the activ-
ity of bevacizumab in the adjuvant setting, the
Colorectal cancer Adjuvant FOLFOX4 Versus Bevacizumab and
Based on promising phase II data, Hurwitz and FOLFOX4 Versus Bevacizumab, Oxaliplatin,
colleagues investigated the addition of bevaci- and Capecitabine in Patients With High-Risk
zumab to bolus 5-fluorouracil and irinotecan Stage II or Stage III Colon Cancer (AVANT) trial
(IFL) with IFL alone as the comparator arm enrolled nearly 3500 patients who had undergone

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Therapeutic Advances in Drug Safety 3 (2)

resection. Patients were randomized to receive lung cancer was based on the results from a trial
FOLFOX4 alone for 24 weeks or FOLFOX4 or (E4599) conducted by the Eastern Cooperative
XELOX with bevacizumab for 24 weeks followed Oncology Group (ECOG) [Sandler et al. 2006].
by bevacizumab alone for an additional 24 weeks. Nearly 900 treatment-naïve patients were rand-
The primary endpoint was disease-free survival, omized to receive chemotherapy consisting of
which was not met with a median duration of carboplatin with paclitaxel for six cycles or the
follow up of 48 months. Efficacy analysis results same chemotherapy with the addition of bevaci-
favored the chemotherapy alone cohort. At the zumab. In the latter arm, patients received bevaci-
2011 Annual American Society of Clinical zumab maintenance until disease progression or
Oncology (ASCO) meeting, subgroup analysis toxicity after completion of the six cycles of chem-
results were presented and all favored the chemo- otherapy with bevacizumab. A statistically signifi-
therapy alone arm. Overall survival analysis has cant and clinically meaningful survival benefit
not yet matured. While a transient bevacizumab (12.3 months versus 10.3 months, p = 0.003) was
effect was demonstrated in patients with N2 dis- found in the patients who received bevacizumab
ease, this effect did not persist. with chemotherapy. Patients receiving the combi-
nation also demonstrated a significantly higher
When utilized in a neoadjuvant regimen includ- response rate of 35% compared with 15% in the
ing 5-fluorouracil with radiation in 32 patients chemotherapy-only treatment group (p < 0.001).
with rectal cancer, the addition of bevacizumab While patients with high-risk features were
yielded a 5-year disease-free survival rate of 75% excluded from trial participation (e.g. squamous
with no local recurrences [Willett et al. 2009]. No cell histology, history of hemoptysis), clinically
grade 4 or 5 toxicities were reported. While post- significant bleeding events were higher in the bev-
operative complications including anastomotic acizumab-treated patients compared with those
leak, delayed healing of incision and wound infec- who received chemotherapy alone (4.4% versus
tion were reported, the relationship of bevaci- 0.7%; p < 0.001). A subsequent retrospective
zumab to these morbidities was unclear. analysis of the tumor histologies included in the
E4599 cohort confirmed a survival advantage
Based on data suggesting the potential for long- imparted by the inclusion of bevacizumab in
term survival with resection of liver metastases in patients with adenocarcinoma but could not draw
patients with a history of colon cancer [Choti et al. any definitive conclusions with regard to other
2002; Fong and Salo, 1999], a phase II, single insti- histologies secondary to low patient numbers
tution trial combining bevacizumab with oxalipl- [Sandler et al. 2010]. In a similar design, the
atin and capecitabine prior to liver resection was AVAiL trial sought to investigate the utility of bev-
performed [Gruenberger et al. 2008]. In this study, acizumab in patients with nonsquamous NSCLC
56 patients were enrolled and received bevaci- in combination with a chemotherapy regimen of
zumab therapy until 5 weeks prior to surgical resec- cisplatin with gemcitabine (CG) [Reck et al.
tion.The response rate was 73.2% with a pathologic 2009]. Enrolling approximately 1000 patients,
complete response rate of 8.9%. There was no Reck and colleagues tested not only the 15 mg/kg
increase in perioperative adverse events including dose as had been used in the E4599 trial but
bleeding or wound complications, and no treat- also randomized a cohort of patients to receive a
ment-related deaths were reported. Postoperative 7.5 mg/kg dose of bevacizumab. The lower dose
liver regeneration and function were assessed with arm of bevacizumab was included secondary to
blood tests and computed tomography (CT) scans, lack of extensive safety data for the agent’s use in
and 98% of those enrolled exhibited full recovery combination with CG. With a primary endpoint of
further suggesting that bevacizumab can be safely progression-free survival, both bevacizumab con-
administered prior to liver resection. A single taining arms demonstrated a statistically signifi-
patient who did not demonstrate normal liver func- cant advantage compared with the CG arm alone
tion following bevacizumab exposure had been 6.7 months versus 6.1 months (p < 0.003) and 6.5
noted to have concurrent steatohepatitis by pathol- months versus 6.1 months (p < 0.03) for the low-
ogy from liver resection specimen. dose and high-dose bevacizumab containing arms,
respectively. Adverse events were similar to those
observed in the E4599 trial with no novel safety
Non-small cell lung cancer signals reported. Although the primary endpoint
The incorporation of bevacizumab into the treat- of progression-free survival was achieved, the
ment of patients with advanced, nonsquamous overall survival failed to demonstrate a benefit in

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 C Kurkjian and ES Kim

the bevacizumab containing arms when compared Renal cell carcinoma

to CG plus placebo [Reck et al. 2010]. That The inactivation of the tumor suppressor gene
patients with an inherently better prognosis (8% von Hippel Lindau, characteristic of RCC with
were stage IIIB without pleural effusion) were subsequent downstream activation of angiogene-
enrolled, the increased use of second-line therapy sis, has provided mechanistic support for the
prior to evidence of disease progression as well efficacy of angiogenesis-targeting agents in the
as the high percentage of patients (60%) who treatment of RCC. The prolongation of survival
received subsequent therapy, a rate higher than using single-agent bevacizumab in a randomized
other contemporary lung cancer treatment trials, trial of treatment refractory patients with RCC
were all cited as potential reasons for the disparate led to two phase III trials investigating its use in
results when compared with the positive E4599 treatment-naïve patients [Yang et al. 2003]. In
outcomes. The subsequently published survival CALGB 90206, over 700 patients with previously
analysis of the AVAiL trial did not yield any new untreated RCC with a clear cell component were
safety events. randomized to receive interferon (IFN)-α-2b
with or without bevacizumab [Rini et al. 2008].
Based on data suggestive of synergism between Bevacizumab was administered at a dose of 10 mg
angiogenesis inhibitors and the anti-folate agent, per kg every 14 days of each 28-day cycle. IFN-
pemetrexed, a phase II study of the combination α-2b at a dose of 9 million units thrice weekly was
was undertaken in bevacizumab-naïve patients administered alone or at the identical dose and
with advanced NSCLC whose disease had pro- administration in combination with bevacizumab.
gressed after one line of therapy [Adjei et al. 2010]. Results published in 2008 demonstrated a pro-
The primary objective of the study was to assess gression-free survival in patients who received the
the rate of progression-free survival at 3 months, combination therapy with a median progression-
an objective which was met by 57% of the first free survival of 8.5 months (95% CI 7.5–9.7
42 patients enrolled. Median overall survival was months) compared with 5.2 months (95% CI
reported to be 8.6 months (95% confidence inter- 3.1–5.6 months, p < 0.001) in the IFN-alone
val [CI] 6.6–13.7 months). In a phase II study of group with a near doubling of the response rate in
the combination as first-line therapy, patients the bevacizumab-treated cohort [Rini et al. 2008].
received carboplatin and pemetrexed with bevaci- However, subsequent overall survival analysis did
zumab for six cycles followed by pemetrexed with not meet criteria for significance, likely secondary
bevacizumab until toxicity or progression [Patel to the treatment of patients with tyrosine kinase
et al. 2009]. With median progression-free and inhibitors (TKIs) after disease progression on
overall survival rates of 7.8 months (95% CI 5.2– the trial. In a similarly designed trial known as
11.5 months) and 14.1 months (95% CI 10.8– AVOREN, nearly 650 patients with advanced
19.6 months), respectively, a randomized phase RCC were randomized to receive either bevaci-
III trial of this combination compared with six zumab plus IFN or IFN alone in identical dosage
cycles of carboplatin/paclitaxel/bevacizumab fol- and administration schedule as in the CALGB
lowed by bevacizumab alone was performed and 90206 trial [Escudier et al. 2010]. As with the
results are pending. CALGB trial, overall survival analysis yielded no
significant difference between the two arms, an
A phase I/II trial of erlotinib in combination with outcome also confounded by the availability of
bevacizumab demonstrated the safety of this multiple active agents upon progression. At the
combination in patients with relapsed or refrac- 2011 ASCO Genitourinary Cancers Symposium,
tory NSCLC [Herbst et al. 2005]. With 85% of Likun and Ba presented a meta-analysis of the
patients demonstrating at least stable disease in CALGB and AVOREN trials and did demon-
this preliminary study, the combination was tested strate a statistically significant overall survival
in a phase III, placebo-controlled study. Over 650 benefit for the patients who received bevacizumab
patients were randomized in a blinded manner to containing therapy (hazard ratio [HR] 0.86, 95%
erlotinib with or without bevacizumab. No overall CI 0.76–0.97, p = 0.02) [Likun and Ba, 2011].
survival benefit was detected with the addition of
bevacizumab. While progression-free survival and In a recent retrospective analysis of the AVOREN
overall response rate appeared to favor the bevaci- trial, subsequent survival data of patients who
zumab group, a prespecified overall survival ben- went on to receive TKI therapy after disease pro-
efit had to be demonstrated before any secondary gression on either bevacizumab plus IFN or IFN
analyses could be determined. alone was undertaken [Bracarda et al. 2011].

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Therapeutic Advances in Drug Safety 3 (2)

Median overall survival of patients who received were compared with a control cohort of patients
any TKI was 38.6 months in those who had who received temozolomide with radiation as
received bevacizumab plus IFN versus 33.6 front-line therapy followed by bevacizumab at the
months in the IFN plus placebo treated patients time of progression. An improved progression-
(HR 0.80, 95% CI 0.56–1.13, p = 0.203), a find- free survival was noted in the patients receiving
ing which did not reach statistical significance. bevacizumab as part of first-line treatment; how-
Although not sufficiently powered or prospec- ever, this did not translate into an overall survival
tively defined, this analysis suggested ongoing benefit when compared with the control cohort.
benefit from anti-angiogenesis exposure even
with subsequent therapy.
Breast cancer
On 22 February 2008, bevacizumab gained accel-
Glioblastoma erated approval from the FDA for the treatment
Based on the demonstration of high VEGF of patients with HER2-negative, metastatic, treat-
expression in glioblastoma (GBM) cells as well as ment-naïve breast cancer in combination with
in vivo bevacizumab activity in a murine model, a paclitaxel. This accelerated approval was based on
phase II trial was undertaken in patients with results from the E2100 trial in which patients who
recurrent disease [Vredenburgh et al. 2007]. The received the combination of agents demonstrated
response rate of 57% in the 35 patients enrolled a statistically significant prolongation in progres-
with nearly half of patients progression free at 6 sion-free survival when compared with patients
months was a significant improvement over his- who received paclitaxel alone, although no overall
torical controls with published response rates of survival advantage was noted [Miller et al. 2007].
approximately 10% and 6 month progression-free Patients treated with the combination regimen
interval rates of approximately 20% [Ballman et demonstrated a median progression-free survival
al. 2007;Yung et al. 2000]. A more extensive, mul- of 11.8 months versus 5.9 months in the patients
ticenter, phase II randomized, noncomparative treated with paclitaxel alone (HR 0.60, p < 0.001).
trial involving 167 patients supported bevacizum- Median overall survival was 26.7 versus 25.2
ab’s approval by the FDA for use in patients with months (HR 0.88, p = 0.16). With disappointing
recurrent glioblastoma [Friedman et al. 2009]. In results from subsequent trials investigating the
this trial, patients in first or second relapse who use of bevacizumab in combination with other
had progressed on temozolomide were rand- chemotherapy agents in this setting (see Table 1),
omized to receive either bevacizumab (10 mg/kg) the FDA recommended removal of the breast
alone or in combination with irinotecan in every cancer indication from product labeling on 16
2-week cycles. Objective response rates of 28% in December 2010 after the Oncology Drug
the single-agent arm and 38% in the combination Advisory Committee (ODAC) voted 12 to 1 in
arm were reported. Six-month progression-free July 2010 in favor of such action. The FDA
and overall survival rates were reported as 43% granted a public hearing in June 2011 after
and 50% and 9.2 months and 8.7 months in Genentech/Roche submitted an application to
the bevacizumab alone and combination arms, appeal this ruling. After a 2-day hearing, ODAC
respectively. Treatment was well tolerated with unanimously voted again to uphold the FDA’s
hypertension, seizure, neutropenia and fatigue earlier decision to remove the accelerated approval
being the most frequently reported events. Of the of bevacizumab in combination with paclitaxel in
five patients with intracranial hemorrhage, one patients with HER2-negative advanced disease.
was grade 4 and the remaining cases were grade 1 A final decision by FDA commissioner Margaret
or 2. Updated survival data presented at the Hamburg is awaited.
annual ASCO meeting in 2010 demonstrated a
30-month survival rate in 16% of patients treated
with bevacizumab plus irinotecan with no new Histologies without bevacizumab activity
safety signals reported [Cloughesy et al. 2010]. In While bevacizumab has demonstrated activity in
an effort to investigate the use of bevacizumab as a variety of tumor histologies, two prominent
part of first-line therapy, a phase II trial was examples of cancers in which it has not shown
undertaken in 70 patients with newly diagnosed efficacy based on current data include prostate
GBM. Bevacizumab was administered biweekly cancer and pancreatic cancer. Based on clinical
in combination with daily temozolomide and data demonstrating increasing levels of VEGF in
radiation therapy [Lai et al. 2010]. Outcomes the plasma and urine of patients with metastatic

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 C Kurkjian and ES Kim

Table 1. Bevacizumab trials in HER2-negative metastatic breast cancer.

Median PFS HR p-value RR (%) p-value Median OS

(Months) (95% CI) (months)
E2100 (first line) [Miller et al. 2007]
Paclitaxel 5.9 21.2 25.2
paclitaxel + bevacizumab 11.8 0.60 <0.001 36.9 26.7
(0.51–0.70)
AVADO (first line) [Miles et al. 2010]
Docetaxel + placebo 8.2 46.4 31.9
Docetaxel + bevacizumab 7.5 mg/kg 9.0 0.86 0.12 55.2 0.07 30.8
(0.72–1.04)
Docetaxel + bevacizumab 15 mg/kg 10.0 0.77 0.006 64.1 <0.001 30.2
(0.64–0.93)
RIBBON-1 [Robert et al. 2011]*
Capecitabine + placebo 5.7 23.6
Capecitabine + bevacizumab 8.6 0.69 <0.001 35.4 0.0097 0.85 (95%
(0.56–0.84) CI 0.63–1.14;
p = 0.27)
Anthra or taxane + placebo 8.0 37.9
Anthra or taxane + bevacizumab 9.2 0.64 <0.001 51.3 0.0054 1.03 (95%
(0.52–0.8) CI 0.77–1.38;
p = 0.83)
RIBBON-2 [Brufsky et al. 2009]
Chemotherapy + placebo 5.1 29.6 16.4
Chemotherapy + bevacizumab 7.2 0.78 0.0072 39.5 0.019 18.0
(0.64–0.93)
Anthra, anthracycline; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RR, response rate
* Stratified HR for OS.

prostate cancer (both independent predictors of et al. 2010]. Presented at the annual ASCO meeting
decreased survival) as well as the correlation of in 2010, results were disappointing. Over 1000
increased VEGF expression with progression patients with metastatic, castration resistant,
of disease [Bok et al. 2001; Duque et al. 1999; treatment-naïve prostate cancer were enrolled.
Ferrer et al. 1997; George et al. 2001], CALGB The study did not meet its primary endpoint
90006 was undertaken [Picus et al. 2011]. This to detect an increase in median survival from
multi-institution study enrolled 79 patients with 19 months to 24 months. Patients who received
castration-resistant prostate cancer. Subjects were bevacizumab demonstrated a statistically signifi-
treated with a combination of estramustine, doc- cant increase in median progression-free survival
etaxel and bevacizumab. Activity was promising at 9.9 months compared with 7.5 months in the
with three quarters of patients demonstrating a docetaxel/prednisone alone arm (HR 0.77, 95%
50% or greater prostate-specific antigen (PSA) CI 0.68–0.88, p < 0.0001). A statistically signifi-
decline and 59% of patients with measurable dis- cant increase in the rate of treatment-related
ease exhibiting a partial or complete response. death was observed in the bevacizumab contain-
The median overall survival of 24 months lent ing arm (4.4% versus 1.1%, p = 0.0014). In their
further support to its subsequent investigation. presentation, investigators stressed the longer
Toxicity, however, was not minimal with 25% of than expected survival rate in the docetaxel/
patients experiencing grade 3 or 4 fatigue and a prednisone alone arm as possibly contributing
thromboembolic complication rate of 9%. to the observed results.

Based on these phase II results, CALGB 90401

was initiated, which was a randomized, double- Ovarian cancer
blind, placebo-controlled trial of docetaxel and Although not approved for use in patients with
prednisone with or without bevacizumab [Kelly ovarian cancer, the use of bevacizumab in this

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Therapeutic Advances in Drug Safety 3 (2)

gynecologic malignancy has been the topic of survival analysis was performed and presented at
extensive investigation. Preclinical and clinical the 2011 ASCO annual meeting. Initially pre-
studies have supported the role of VEGF in sented at the 2010 European Society of Medical
disease progression and ascites formation with Oncology (ESMO) meeting, a progression-free
evidence demonstrating its overexpression as survival benefit was demonstrated with a trend
prognostic for inferior outcomes [Ferrara, 1999; for overall survival improvement. Over 1500
Gasparini et al. 1996; Paley et al. 1997; Yoneda women with high-risk early stage disease or
et al. 1998]. In a phase II trial conducted by the advanced disease were enrolled. Patients were
Gynecologic Oncology Group (GOG), single- randomized to receive six cycles of carboplatin
agent bevacizumab in patients with refractory with paclitaxel with or without concurrent bevaci-
epithelial ovarian cancer or primary peritoneal zumab followed by bevacizumab to complete
cancer yielded median progression-free survival 1 year of therapy. The results presented demon-
of 4.7 months and median overall survival of 17 strated a continued progression-free survival
months [Burger et al. 2007]. Of the 62 patients advantage with a trend in overall survival
treated, 13 demonstrated a clinical response with improvement. Final overall survival results are
25 patients surviving beyond 6 months without anticipated in 2013.
progression. Also published in 2007, Cannistra
and colleagues published their results of single-
agent bevacizumab in a more heavily pretreated Bevacizumab toxicity
population of patients with ovarian cancer or pri- While early trials of bevacizumab brought much
mary peritoneal cancer [Cannistra et al. 2007]. excitement to the oncology community, this
The median progression-free survival and overall enthusiasm was tempered with the observation of
survival were 4.4 months and 10.7 months, rare, but serious adverse events. In AVF0757g,
respectively. Of the 44 patients who received a randomized phase II study of patients with
bevacizumab, 7 patients (15.9%) had a partial NSCLC treated with carboplatin and paclitaxel
response. with or without bevacizumab, six patients devel-
oped major, life-threatening hemorrhage [Johnson
Both presented at the annual ASCO meeting in et al. 2004]. Four of the six patients were noted to
2011, the OCEANS trial and ICON7 lent further have squamous cell carcinoma, a finding which
support to the activity of bevacizumab in patients led to the halting of bevacizumab testing in
with advanced ovarian cancer. The OCEANS patients with squamous histology. Hypothesizing
trial enrolled 484 patients with recurrent, plati- that delayed inclusion of bevacizumab until
num-sensitive ovarian cancer [Aghajanian et al. after initial cycles of chemotherapy are adminis-
2011]. Patients were randomized to carboplatin tered may prevent pulmonary hemorrhage; the
with gemcitabine and either bevacizumab or BRIDGE study investigated such a treatment
placebo for six cycles followed by bevacizumab approach in patients with predominantly squa-
or placebo until disease progression or toxicity. mous histology. [Hainsworth et al. 2011]. Patients
The primary endpoint of the trial was primary with cavitary thoracic lesions, gross hemoptysis in
progression-free survival as by investigator assess- the past 3 months, and tumor impingement or
ment. Secondary endpoints included overall sur- involvement of major vessels or vascular struc-
vival. Median progression-free survival in the tures, were excluded from trial participation. The
bevacizumab containing arm was reported to be primary endpoint of the trial was the incidence of
12.4 months (95% CI 11.4–12.7 months) com- grade 3 pulmonary hemorrhage in patients treated
pared with 8.4 months (8.3–9.7 months) in the with two cycles of carboplatin and paclitaxel with
placebo arm (HR 0.484, 95% CI 0.388–0.605, subsequent addition of bevacizumab for cycles
p < 0.0001). Review of results by an independent three through six and followed by bevacizumab
review committee was concordant. Overall sur- alone for cycle seven and onward. The incidence
vival events were not yet mature. of grade 3 or greater pulmonary hemorrhage was
3.2% in patients who received at least one dose of
The ICON7 study sought to determine the activ- bevacizumab. The incidence of any grade pulmo-
ity of bevacizumab in combination with carbopl- nary hemorrhage was 6.5%. Pulmonary hemor-
atin/paclitaxel in patients with newly diagnosed rhage in these patients appeared to be associated
epithelial ovarian, primary peritoneal or fallopian with the development of cavitation subsequent
tube cancer [Kristensen et al. 2011]. As requested to treatment initiation. Although no definitive
by regulatory authorities, an interim overall conclusions could be drawn regarding the safety

64 http://taw.sagepub.com
 C Kurkjian and ES Kim

of bevacizumab in patients with squamous histol- time to progression of 9.1 months observed in
ogy, the rate of pulmonary hemorrhage was lower this trial supported median progression-free
than in prior series when this delayed bevaci- survival reported in other phase III trials.
zumab approach was utilized. Reliable clinical
markers to predict for bevacizumab toxicity Ranpura and colleagues set out to determine
remain to be defined such that use of bevaci- the incidence of fatal adverse events in a meta-
zumab in patients with lung cancer of squamous analysis of all published randomized clinical trials
histology remains investigational. across a variety of tumor types [Ranpura et al.
2011]. Over 10,000 patients were included from
Safety assessment in tumor-specific trials includ- trials in which bevacizumab with chemotherapy
ing lung cancer and breast cancer were recently was compared with chemotherapy alone. The
published and incorporate data from a broad incidence of fatal events with bevacizumab use
range of treated patients. The safety of bevaci- was 2.9% (95% CI 2.0–4.2%) resulting in an
zumab in the treatment of lung cancer patients in absolute risk increase of 0.7% (relative risk [RR]
a community setting was the subject of a phase IV 1.33, 95% CI 1.02–1.73, p = 0.04). The associa-
study entitled SaIL, which was initiated in 40 tion of bevacizumab with higher treatment-related
countries worldwide [Crino et al. 2010]. Patients mortality was significant for type of chemother-
with nonsquamous, NSCLC received six cycles apy agent, but not tumor type or bevacizumab
of bevacizumab-containing therapy with investi- dose. Of the chemotherapy agents utilized, tax-
gator-chosen first-line chemotherapy. The pri- ane-based therapy was most highly associated
mary objective of the study was assessment of with fatal adverse event with a RR of 3.49 (95%
bevacizumab safety in combination with first-line CI 1.82–1.66). Of the fatal events associated with
chemotherapy with secondary objectives includ- bevacizumab, those with highest rates were hem-
ing efficacy analysis as well as safety outcomes in orrhage followed by neutropenia. Although the
patients who developed CNS metastases during incidence of treatment-associated mortality was
or within 6 months of bevacizumab therapy. The not an endpoint in the individual studies, this
rate of adverse events was as expected based on meta-analysis provided the most extensive analy-
prior clinical trials. The incidence of febrile neu- sis of bevacizumab safety to date and confirmed
tropenia, grade 3 neutropenia, thrombosis, and at the importance of not only early monitoring
least grade 3 hypertension were all less than 10%. for adverse events but also exercising caution in
The incidence of clinically significant pulmonary patient selection.
hemorrhage (≥grade 3) was 1% and only 5 of 281
patients who developed CNS metastases suffered That bevacizumab is associated with an increased
from any grade of cerebral hemorrhage. Median risk of bleeding and the inherent elevated risk of
overall survival was 14.6 months, which corrobo- venous thromboembolism (VTE) in patients with
rated prior results in a population of patients with malignancy has led to concern for the safety of
mainly adenocarcinoma. This study confirmed anticoagulation in the patients undergoing active
the safety of bevacizumab in a population more treatment with bevacizumab. Most clinical trials
representative of that encountered in daily clini- of bevacizumab exclude patients who are receiv-
cal practice. ing anticoagulation from participation, thus lim-
iting existing data on the safety of therapeutic
Also with the intent of determining safety of anticoagulation in this treatment setting. Leighl
bevacizumab in a patient population typically and colleagues recently published results of a ret-
encountered in an oncology practice, the primary rospective analysis of three randomized, placebo-
endpoint of the ATHENA trial was safety of beva- controlled trials in which patients who developed
cizumab in combination with first-line therapy in VTE after initiation of protocol therapy were
patients with metastatic breast cancer [Smith allowed to continue on trial [Leighl et al. 2011].
et al. 2011]. In this study of 2251 patients, bevaci- The trials included in the analysis included two
zumab was combined most commonly with tax- trials of bevacizumab use in CRC and one trial in
ane-based therapy. No new safety signals were lung cancer. The overall risk of bleeding in the
observed. Of the 205 patients who developed pooled placebo-treated group was 4.1% versus
CNS metastases, 2.0% of these patients devel- 4.2% in the pooled bevacizumab-treated cohort.
oped intracranial bleeding during study follow up. No fatal bleeding events were reported in any of
Incidence of bevacizumab-related toxicities were the patients who received therapeutic anticoagu-
similar to previously reported rates. The median lation. Similar results from the NSCLC patients

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Therapeutic Advances in Drug Safety 3 (2)

treated on the phase IV SaIL trial revealed a Analysis of single-nucleotide polymorphisms

bleeding rate of 17.2% (none grade 3 or higher) (SNPs) from germline DNA of metastatic pan-
in patients who received therapeutic anticoagula- creatic cancer patients who were treated with
tion compared with a 17.0% incidence in the gemcitabine and erlotinib with or without bevaci-
overall bevacizumab-treated population. These zumab as part of the AVITA trial revealed a dif-
results have provided preliminary data suggesting ferential sensitivity to anti-angiogenesis therapy
the feasibility of anticoagulation for VTE in the [Lambrechts et al. 2009]. Median survival
setting of bevacizumab treatment. increased from 4.8 months to 10.3 months in
patients with a particular SNP in the VEGFR-1
gene coding for the essential receptor tyrosine
Bevacizumab pharmacodynamics kinase domain. Of interest, no association with
The disappointing efficacy results of bevaci- the above-described VEGF-2578 AA polymor-
zumab trials in advanced prostate and pancreatic phism and survival prolongation was detected
cancer, in adjuvant colon cancer treatment and in this data set from pancreatic cancer patients.
in the advanced breast cancer setting emphasize With the hopes of developing an easily accessible
the importance of developing predictive markers biomarker, circulating VEGF levels have been
to determine which patients will not respond hypothesized as predictive of bevacizumab effi-
and can be spared the economic and health- cacy. However, in an analysis of over 1800
related costs of bevacizumab treatment. While patients from four randomized trials in colorec-
the development of hypertension has been pro- tal, lung and renal cell carcinoma, measurement
posed as a potential predictor of clinical activity of plasma VEGF predicted for worse prognosis
[Maitland et al. 2006; Scartozzi et al. 2009], in a but was not predictive of anti-angiogenesis treat-
meta-analysis of over 12,000 patients conducted ment response.
to assess the risk of hypertension in bevacizumab
treated patients, no improvement in clinical out- Trials such as the Biomarker-integrated
come was associated with the development of Approaches of Targeted Therapy for Lung Cancer
hypertension in the studies analyzed [Ranpura Elimination (BATTLE) in which core biopsies
et al. 2010]. Based on the hypothesis that are performed in order to assess an individual
genotypic differences in VEGF predict for breast patient’s tumor profile, may expedite the discov-
cancer prognosis, an analysis of E2100 out- ery of predictive biomarkers [Kim et al. 2011].
comes based on differential VEGF and VEGFR- A front-line study, BATTLE-FL, is now open and
2 expression was undertaken [Schneider et al. is attempting to study which biologic drug with
2008]. Analyzed from paraffin-embedded tissue, chemotherapy may benefit patients the most as
those subjects with VEGF-2578 AA and VEGF- initial therapy.
1154 AA displayed median overall survival times
of 37.0 (p = 0.035) and 46.5 (p = 0.047) months,
respectively, in the experimental arm, a result Conclusion
statistically significantly longer when compared Bevacizumab is a safe and effective drug utilized
with the control arm. The genotypes associated in several cancers. The quest for reliable predic-
with the lowest risk of grade 3 or 4 hypertension tive markers remains of utmost importance as its
included VEGF-634 CC and VEG-1498 CC. indiscriminate use presents an untenable situa-
These two genotypes which appeared to impart tion when taking into consideration survival ben-
a resistance to the development of hypertension efits, toxicity and cost. Although evidence exists
were mutually exclusive of those portending an to suggest that prolonged therapy with bevaci-
improved outcome with experimental therapy zumab yields improved outcomes as somewhat
suggesting that development of hypertension supported by ovarian and lung cancer data, the
may be a pharmacodynamic marker of efficacy. key to the agent’s longevity as a viable treatment
When analyzed for treatment outcome based on modality lies in current and future endeavors to
the development of hypertension, a statistically appropriately identify potentially responsive
significant improvement in median overall sur- patient subpopulations.
vival time was detected in those patients who
demonstrated an increase in blood pressure. Funding
No association between VEGF protein expres- This research received no specific grant from any
sion by immunohistochemistry and outcomes funding agency in the public, commercial, or not-
was found. for-profit sectors.

66 http://taw.sagepub.com
 C Kurkjian and ES Kim

Conflict of interest statement in persistent or recurrent epithelial ovarian cancer or

The authors declare no conflict of interest in primary peritoneal cancer: a Gynecologic Oncology
preparing this article. Group Study. J Clin Oncol 25: 5165–5171.
Cannistra, S.A., Matulonis, U.A., Penson, R.T.,
Hambleton, J., Dupont, J., Mackey, H. et al. (2007)
Phase II study of bevacizumab in patients with
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