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Safety and efficacy of first-line bevacizumab combined with taxane therapy in
Chinese patients with HER2-negative locally recurrent or metastatic breast
cancer: findings from the ATHENA study
Binghe XU, Zefei JIANG, Zhenzhou SHEN, Zhongzhen GUAN, Zhengdong CHEN,
Ying CHENG, Hong ZHENG, Jun JIANG, Xiaojia WANG, Zhongsheng TONG,
Shukui QIN, Yi LUO, Min YAO, Liwei WANG and Jing HE
Cancer Hospital and Institute, Chinese Academy of Medical Sciences, No. 17
Panjiayuan Nanli Chaoyang District, 100021 Beijing, PR China (B XU MD), Breast
Cancer Department, 307 Hospital Cancer Center, AMMS No. 8, Dongdajie,
Fengtai District,Beijing, 100071, PR China (Z JIANG MD), Fudan University
Shanghai Cancer Center, Xuhui District, Shanghai No. 270 Dongan Road,
Shanghai, 200032, PR China (Z SHEN MD), Cancer Center, SunYat-Sen
University, 651 Dongfeng Road East, Guangzhou, Guangdong Province, 510060,
PR China (Z GUAN MD), Department of Oncology, The First Affiliated Hospital
of Anhui Medical University, No. 218 Jixi Road, Hefei, Anhui Province, 230022, PR
China (Z CHEN MD), Jilin Province Cancer Hospital, No. 1018 Huguang Road,
Chaoyang District, Changchun, Jilin Province, 130012, PR China (Y CHENG MD),
West China Hospital, Sichuan University, Floor 6, The Third In-patient Building,
No. 37, Wainan Guoxue Road, Chengdu, Sichuan Province, 610041, PR China (H
ZHENG MD), Breast Surgery Center, Chongqing Southwest Hospital, No. 30
Gao Tan Yan Main Street, Sha Pin Ba District, Chongqing, 400038, PR China (J
JIANG MD), 15th Division of Hematology & Oncology, Zhejiang Cancer Hospital,
No. 38 Guangji Road, Hangzhou, Zhejiang Province, 310022 PR China (X WANG
MD), Breast Cancer Department, Tianjin Cancer Hospital, Huanhuxi Road,
1
Tiyuanbei, Hexi District, Tianjin, 300060, PR China (Z TONG MD), Department of
Oncology, PLA Cancer Center of Nanjing Bayi Hospital,
No. 34-34,
Yanggongjing, Nanjing, Jiangsu Province, 210002, PR China (S QIN MD), Hunan
Cancer Hospital, No. 582 Xianjiahu Road, Changsha, Hunan Province, 410013, PR
China (Y LUO MD), Department of Oncology, The First Affiliated Hospital of
Soochow University, 188 Shizi Street, Suzhou Jiangsu Province, 215006, PR
China (M TAO MD),
Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, No.
85, Wujin Road, Shanghai, 200082, PR China (L WANG MD) , Roche Product
Development in Asia Pacific, Room 501, Yintai Center, No 2 Jianguomenwai Avenue,
Beijing, 100022, PR China (J HE MD).
Correspondence to: Dr Binghe XU, Cancer Hospital and Institute, Chinese Academy
of Medical Sciences, No. 17 Panjiayuan Nanli Chaoyang district, 100021 Beijing,
China
Tel: +86 10 87788726; Email: [email protected]
Key words : Bevacizumab, Metastatic breast cancer, Angiogenesis, First-line ,
Chinese, docetaxel
2
Abstract
Background
Three randomised trials have demonstrated that combining bevacizumab with firstline
chemotherapy
significantly
improves
progression-free
survival
versus
chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer
(LR/mBC). However, data from Chinese populations are limited and possible
differences between ethnic and geographic populations are unknown. This study
was conducted to determine whether there were differences in safety and efficacy in
patients with HER2-negative LR/mRC received first-line bevacizumab combined with
taxane-based therapy between Chinese and Western populations
Methods
In the single-arm, open-label, ATHENA (Avastin Therapy for Advanced Breast
Cancer) study (NCT00448591), patients with HER2-negative LR/mBC received firstline bevacizumab (investigator’s choice of 10 mg/kg every 2 weeks or 15 mg/kg
every 3 weeks) combined with taxane-based therapy. The primary endpoint was
safety; time to progression (TTP) was a secondary endpoint. We conducted a
subpopulation analysis to assess safety and efficacy in Chinese patients.
Results
Of 2264 patients treated in ATHENA, 202 were enrolled in China. Bevacizumab was
combined with docetaxel in 90% of Chinese patients and paclitaxel in 10%. The most
common grade 3/4 adverse events were diarrhoea (5.0% of patients) and hypertension
(2.5%). Grade 3/4 proteinuria occurred in 0.5%. After median follow-up of 17.6 months and
events in 56% of patients, median TTP was 9.0 months (95% CI 8.4–11.1).
survival data are immature.
Conclusions
3
Overall
We found no evidence of increased bevacizumab-related toxicity or reduced efficacy
in Chinese LR/mBC patients receiving first-line bevacizumab–taxane therapy
compared with predominantly Western populations. The safety profile was generally
similar to previously reported LR/mBC trials. Subtle differences may be attributable
to differing lifestyle and cardiovascular risk factors in Chinese patients compared
with the overall population. It appears reasonable to extrapolate findings from
bevacizumab-based randomised trials to Chinese populations.
4
INTRODUCTION
Angiogenesis is an essential process in the growth and development of solid
tumours. Vascular endothelial growth factor (VEGF) is an important mediator of
angiogenesis, is overexpressed in a wide range of tumours and is associated with
poor prognosis.1 Several agents targeting the VEGF pathway have been developed,
including the monoclonal antibody bevacizumab. Bevacizumab inhibits angiogenesis
by binding specifically to VEGF, preventing interaction with receptors on vascular
endothelial cells and thus inhibiting pro-angiogenic effects.2,3
To date, bevacizumab has demonstrated significantly improved efficacy in colorectal,
non-small cell lung, renal, breast and ovarian cancers. Bevacizumab is an important
component of first-line therapy for HER2-negative locally recurrent/metastatic breast
cancer (LR/mBC), and has consistently demonstrated significantly improved
progression-free survival (PFS) and response rate compared with chemotherapy
alone in three randomised, phase 3 trials in the first-line setting (E2100, AVADO,
RIBBON-1).4–7 The risk of progression was reduced by 31–52% in these trials
(hazard ratios of 0.48–0.69) and median PFS was consistently between
approximately 9 and 12 months. Importantly, the significant improvements in PFS
and response rate were achieved with only a limited impact on the safety profile of
chemotherapy. The safety profile of bevacizumab has been well characterised and
the typical side effects, such as hypertension and proteinuria, are easily
manageable.
The E2100 and AVADO trials provided randomised data demonstrating the benefit of
combining bevacizumab with weekly paclitaxel and docetaxel, respectively. More
recently, the RIBBON-1 trial demonstrated that the significant benefit of combining
bevacizumab with chemotherapy applies more broadly to capecitabine monotherapy,
5
anthracycline-based combination regimens and nab-paclitaxel. However, it was
considered important to evaluate the safety profile of first-line bevacizumabcontaining therapy in a broader patient population more representative of routine
oncology practice than those enrolled in phase 3 clinical trials. Therefore the large,
single-arm, open-label, ATHENA safety study was initiated to provide further
information on the safety of bevacizumab in combination with standard (nonanthracycline) chemotherapy regimens in the first-line setting.8 The ATHENA study
had fewer exclusion criteria than the randomised phase 3 trials: most notably,
patients with Eastern Cooperative Oncology Group (ECOG) performance status 2
were eligible. In addition, the possibility of combining bevacizumab with the
investigator’s choice of chemotherapy enabled enrolment of a broader patient
population.
In China, breast cancer is the most common cancer among women and the
incidence is rising more rapidly than for any other cancer. 9 Widespread adoption of a
westernised lifestyle (eg, diet, alcohol consumption, reduction in physical activity,
obesity, older age at childbearing), particularly in urban populations, is thought to
contribute to this increase. The most realistic strategies for reducing mortality from
breast cancer are earlier detection of disease and improved treatment. 9
Consequently breast cancer, together with lung cancer, has been identified as a
priority for cancer prevention, early detection and therapy in China. 10
Publications in the literature suggest variation in the safety and efficacy of some
anticancer therapies between different ethnic and geographic populations. 11–15 While
evidence is accumulating to suggest differences in the distribution of genetic
polymorphisms that influence enzymes involved in DNA repair and drug metabolism,
as well as cellular transporters of chemotherapy, it is not known whether these
variations also apply to bevacizumab therapy. Despite extensive and thorough
6
evaluation of first-line bevacizumab-containing therapy in LR/mBC, there are no
published data specifically from Chinese patients with breast cancer. Therefore, to
provide better understanding of the safety and efficacy profiles of first-line
bevacizumab-containing therapy in Chinese patients, we conducted a subpopulation
analysis of data from the ATHENA study.
METHODS
The study design of ATHENA (NCT00448591) has been described in detail
previously.16 In brief, ATHENA was a single-arm, open-label, multinational study
evaluating first-line bevacizumab in combination with taxane-based therapy. The
primary objective was to assess the safety profile in patients with HER2-negative
LR/mBC treated in the context of routine oncology practice. Secondary endpoints
included time to progression (TTP), overall survival and safety in patients developing
central nervous system (CNS) metastases. Bevacizumab was given at a dose of 10
mg/kg every 2 weeks or 15 mg/kg every 3 weeks at the discretion of the investigator
and depending on the chemotherapy schedule chosen. Of note, patients recruited in
China were to receive bevacizumab in combination with a taxane (either paclitaxel
90 mg/m2 weekly for 3 of every 4 weeks or docetaxel 75 mg/m2 every 3 weeks). Nontaxane therapy was not permitted in China, whereas in other participating countries,
alternative first-line regimens (excluding anthracycline-based regimens) were
allowed if a taxane was not the physician’s standard of care.
As part of ATHENA trial, this study was conducted in accordance with the
Declaration of Helsinki and approved by the local ethical committee, and informed
consent was obtained from all patients.
Role of the funding source
7
The study sponsor was involved in the study design and analysis of the data and
funded medical writing support. The authors made the decision to submit the
manuscript for publication.
RESULTS
Patient population
The trial included 2264 patients, of whom 202 were enrolled in China between 24
April 2008 and 31 March 2009. The rest of the ATHENA study population included
large numbers of patients from France (n=360), Italy (n=278), Russia (n=171),
Canada (n=138), Germany (n=155), and Spain (n=119). Table 1 shows baseline
characteristics in the Chinese patients. The majority of these patients (94%) had
metastatic disease at the time of study entry. The remaining 6% had locally
advanced disease. Baseline characteristics for the entire ATHENA population,
including the Chinese patients, are also presented in table 1 to place the data in
context. Compared with the overall population, the Chinese population was slightly
younger with poorer performance status. Fewer patients had bone or liver
metastases and a substantially smaller proportion had hypertension before initiating
bevacizumab therapy.
Treatment exposure
The majority of patients (n=181; 90%) received bevacizumab in combination with
docetaxel. The remainder (n=21; 10%) received bevacizumab combined with
paclitaxel. Four patients switched chemotherapy before disease progression: two
patients receiving docetaxel switched to paclitaxel and two receiving paclitaxel
switched to docetaxel.
8
The median duration of bevacizumab therapy was 6.4 months (range 0.0–24.9).. The
median duration of chemotherapy was 5.5 months (range 0.0–14.9).. Bevacizumab
was continued until disease progression in 86 patients (43% of the 113 patients in
whom disease had progressed).. At the time of data cut-off, bevacizumab had been
discontinued in all patients. The most common reasons for bevacizumab
discontinuation were: progressive disease (n=99; 49%); adverse event (n=34; 17%);
and withdrawal of consent (n=34; 17%).
Safety
In total, 197 (97.56%) of the 202 patients experienced at least one adverse event.
However, in almost half of these patients, the events were grade 1 or 2. A total of
103 patients (51%) experienced grade ≥3 adverse events, irrespective of relationship
to bevacizumab. Figure 1 depicts all clinical adverse events reported at any grade in
≥15% of patients. The most common were alopecia, fatigue and epistaxis. The most
common grade 3/4 adverse event was diarrhoea in 5% of patients. Of the 3387
events reported (any grade), 184 (91%) resolved. Events were fatal in four patients
(2% of the 202 patients in the Chinese population). The grade 5 events, each
occurring in one patient, were: disseminated intravascular coagulation, lung
infection, acute pulmonary infarction, and unknown cause.
Data on adverse events of special interest (previously reported with bevacizumab in
clinical trials) were collected for 6 months after completion of bevacizumab therapy
and are summarised in table 2. Grade 3 adverse events previously associated with
bevacizumab were rare. Of note, grade 3 hypertension was reported in only 2.5% of
patients and grade 3 proteinuria occurred in only 0.5%. Only one patient experienced
a grade 4 adverse event (wound-healing complications).
9
One of the pre-specified secondary objectives of ATHENA was assessment of the
safety of bevacizumab in patients developing CNS metastases during or within 6
months of completing study treatment. Among 17 patients with signs and symptoms
of CNS disease at one or more visits, there were no cases of CNS bleeding.
Efficacy
At the time of data cut-off (July 2010), disease had progressed in 113 patients
(56%). The median duration of follow-up was 17.6 months (range 0.1–25.6 months).
Median TTP was 9.0 months (95% CI 8.4–11.1) (figure 2). The overall survival data
are immature, with deaths in 77 patients (38%) at the time of data cut-off. All deaths
except the four described above were from breast cancer.. Efficacy results are
shown alongside results from the overall population and the bevacizumab 15 mg/kg
arm of the AVADO trial in table 3.
DISCUSSION
Findings from this analysis suggest that first-line bevacizumab in combination with
taxane therapy is effective and well tolerated in Chinese patients with LR/mBC. We
found no evidence of poorer tolerability or decreased efficacy in Chinese patients
compared with the overall population. The incidences of grade ≥3 adverse events
previously reported with bevacizumab were low (hypertension 2.5%, bleeding events
1.0%, thromboembolic events 1.0%, proteinuria 0.5%, congestive heart failure
0.5%). There was no grade ≥3 CNS bleeding, fistula, reversible posterior
leucoencephalopathy syndrome (RPLS) or gastrointestinal perforation.
Although there was no marked increase in toxicity in the Chinese population, we
observed slight quantitative differences in the safety profile compared with the
10
overall study population of ATHENA. For example, there were fewer grade ≥3
adverse events of special interest (e.g., proteinuria in 0.5% of the Chinese patients
vs 1.7% in the overall population; hypertension in 2.5% vs 4.4%, respectively; arterial
or venous thromboembolism in 1.0% vs 3.2%, respectively). One potential
explanation for these subtle differences in the safety profile is variation in lifestyle
factors and cardiovascular risk factors between Chinese patients and the overall
population of ATHENA. Notwithstanding the relatively minor quantitative differences
in the safety profile, arguably the most important finding is that there is no evidence
of an excess of bevacizumab-related adverse effects in Chinese patients.
We were also interested in determining whether the efficacy of bevacizumabcontaining therapy was influenced by ethnicity. Although efficacy was not a primary
endpoint of the ATHENA study, TTP was the primary efficacy endpoint. Median TTP
was slightly shorter in the Chinese population than in the overall population, while
response rate in the Chinese subgroup was at least as high as in the overall study
population. There are several potential explanations for the difference in TTP in this
non-randomised comparison. Firstly, there were some noticeable differences in
patient, tumour, and disease characteristics between the Chinese population and the
overall population, as shown in table 1. For example, compared with the full study
population, patients treated in Chinese centres were typically younger, were less
likely to have received endocrine therapy for metastatic disease, were less likely to
have bone or liver metastases, and were more likely to have a poorer performance
status. Several of these differences in baseline characteristics suggest that the
Chinese population may have had slightly more aggressive disease. Indeed, the
design of the ATHENA trial, which gave investigators the discretion to treat patients
with non-taxane-containing regimens if these were considered more appropriate, is
likely to have led to a more heterogeneous patient population, whereas in China the
11
protocol was conducted exclusively in combination with taxane therapy. These
complexities make it difficult to draw any conclusions about potential differences in
efficacy between the Chinese subgroup and the overall population. Nevertheless, the
generally similar TTP and response rate results do not suggest that bevacizumabcontaining therapy is less effective in Chinese patients than in a global population.
As all patients in the Chinese population received bevacizumab in combination with
taxane therapy and the majority received docetaxel, we compared our findings with
results of the AVADO trial, which evaluated first-line bevacizumab in combination
with 3-weekly docetaxel. Generally the patient characteristics in the Chinese
population of ATHENA and the overall population of the AVADO trial were quite
similar, although in our patient population, more patients had received prior taxane
therapy (29% vs 17% in AVADO) and the median age was lower (median 48 vs 55
years, respectively). In addition, there was no evidence that the patient population
was enriched with patients with oestrogen receptor (ER)-positive disease (61% ERpositive), whereas in AVADO, the percentage of patients with ER-positive disease
was 76%. When comparing the results, safety data in our analysis were remarkably
consistent with the AVADO data. In addition, the median TTP in our study is similar
to the 10.0-month median PFS reported in the bevacizumab 15 mg/kg arm in of the
AVADO trial [6], taking into account the shorter duration of follow-up in the Chinese
population (table 3). Response rate was similar in the Chinese subgroup and the
bevacizumab 15 mg/kg arm of AVADO.
The main limitations of the present analysis is the lack of a comparator. As ATHENA
was a single-arm study, it is not possible to comment on the impact of combining
bevacizumab with chemotherapy in Chinese patients.
The major strength of the present analysis is that we provide the first data on the
safety and efficacy of first-line bevacizumab in combination with taxane-based
12
therapy in Chinese patients with breast cancer. The inclusion of more than 200
Chinese patients in the ATHENA study provides a robust dataset and enables better
understanding of the use of first-line bevacizumab-containing therapy populations of
Chinese patients treated in the routine oncology practice setting. A previously
reported subset analysis of progression-free survival among Eastern Asian patients
treated with first-line bevacizumab-containing therapy for nonsquamous non-smallcell lung cancer suggested no reduction in efficacy in this population compared with
the overall population18 and our findings suggest a similar pattern in breast cancer.
In summary, the findings of this analysis provide no evidence of increased
bevacizumab-related toxicity or different efficacy among Chinese patients receiving
first-line bevacizumab in combination with taxane therapy for LR/mBC compared
with predominantly Western populations. Therefore we believe it is reasonable to
extrapolate findings from clinical trials of bevacizumab-containing therapy to Chinese
patient populations.
Contributions
All authors reviewed preliminary drafts and approved the final manuscript. BX, ZJ,
ZS, ZG, ZC, YC, HZ, JJ, XW, ZT, SQ, YL, MT, LW and IS provided patients for the
study. BX and JH were involved in data interpretation. Medical writing support was
provided by Jennifer Kelly, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Conflicts of interest
JH is an employee of Roche Product Development in Asia Pacific.
All other authors declared no conflict of interest
The corresponding author had full access to all the study data and had final
responsibility for the decision to submit the manuscript for publication.
13
Acknowledgements
Funding was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland, and
Shanghai Roche Pharmaceuticals Ltd, Shanghai, China.
14
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Smith IE, Pierga JY, Biganzoli L, Cortés-Funes H, Thomssen C, Pivot X,et al.
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or metastatic breast cancer: safety and efficacy in an open-label study in 2251
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16
Table 1: Baseline characteristics
Characteristic
Chinese
(current
subgroup Overall population16
analysis) (n=2251)
(n=202)
Median age, years (range)
48 (22–74)
53 (21–93)
Hormone receptor status
Oestrogen-receptor positive (%)
124 (61.4)
1471 (66.1)a
Progesterone-receptor positive (%)
111 (55.0)
1183 (53.1)a
52 (25.7)
577 (25.6)
158 (78.2)
1696 (75.3)
112 (55.4)
1268 (56.3)
58 (28.7)
552 (24.5)
131 (64.9)
1428 (63.4)
Prior (neo)adjuvant endocrine therapy (%)
97 (48.0)
1066 (47.4)
Prior endocrine therapy for metastatic
28 (13.9)
532 (23.6)
64 (31.7)
662 (29.4)
Bone (%)
79 (31.7)
1101 (48.9)
Lung (%)
78 (38.6)
812 (36.1)
Liver (%)
57 (28.2)
808 (35.9)
135 (71.1)c
1440 (64.0)
0 (%)
91 (45.0)
1306 (58.0)
1 (%)
105 (52.0)
819 (36.4)
2 (%)
6 (3.0)
124 (5.5)
Triple negative (%)
Prior (neo)adjuvant chemotherapyb (%)
Anthracycline (%)
Taxane (%)
Other (%)
disease (%)
Disease-free interval ≤24 months (%)
Metastatic sites
>3 (%)
ECOG performance status
Medical history at study entry (active)
17
Hypertension (%)
Diabetes (%)
a
n=2227
b
Multiple entries possible.
c
Data missing for 12 patients.
ECOG–Eastern Cooperative Oncology Group.
18
15 (7.4)
490 (21.8)
4 (2.0)
114 (5.1)
Table 2: Adverse events of special interest, irrespective of relationship to bevacizumab
No. of patients (%)
Adverse event of special interest
Hypertension
Grade 1
Grade 2
Grade 3
20 (9.9)
13 (6.4)
5 (2.5)
0
0
2 (1.0)a
0
0
0
2 (1.0)b
0
ATE/VTE
1 (0.5)
Proteinuria
27 (13.4)
9 (4.5)
haemorrhage
69 (34.2)
12 (5.9)
Grade 4
Wound-healing complications
1 (0.5)
0
0
1 (0.5)c
Congestive heart failure
2 (1.0)
0
0
0
Gastrointestinal perforation
0
0
0
0
Fistulae
0
0
0
0
Central nervous system bleeding
0
0
0
0
RPLS
0
0
0
0
a
Myocardial infarction (n=1) and venous thrombosis (n=1); bEpistaxis (n=1) and vaginal
haemorrhage (n=1); cWound dehiscence.
VTE–venous thromboembolic event. ATE–arterial thromboembolic event. RPLS–
reversible posterior leucoencephalopathy syndrome.
19
Table 3: Summary of efficacy: side-by-side comparison with data from the overall population
treated in ATHENA16 and the 15 mg/kg arm of the AVADO trial17
Outcome
ATHENA
ATHENA
AVADO
Chinese
overall
(n=247)
subpopulation population
(n=202)
Median
duration
of
follow-up,
(n=2251)
17.6
20.1
(0.1–25.6)
(0.1–43.6)
Complete/partial response
70
52
Stable disease
22
33
NR
4
9
NR
34
6
–
months (range)
25
(NR)
Response, %
Progressive disease
Not evaluable/not assessed
64a
TTP (PFS in AVADO)
Events, n (%)
113 (55.9)
1640(72)
Median
9.0
9.7
95% CI
8.4–11.1
9.4–10.1
199 (81)
10.0
NR
a
Patients with measurable disease, n=206.
TTP–time to disease progression. PFS–progression-free survival. NR–not reported.
20
Figure 1: All clinical adverse events in ≥15% of patients
21
Figure 2: Time to disease progression (median duration of follow-up: 17.6 months)
Sursurvival distribution function
Ti
Time to
(months)
disease
progression
22