Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study
Liu et al. Journal of Hematology & Oncology
Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study
Xinyang Liu 0 1 11
Shukui Qin 1 10
Zhichao Wang 1 11
Jianming Xu 1 16
Jianping Xiong 1 15
Yuxian Bai 1 14
Zhehai Wang 1 13
Yan Yang 1 18
Guoping Sun 1 17
Liwei Wang 1 12
Leizhen Zheng 1 8
Nong Xu 1 9
Ying Cheng 1 6
Weijian Guo 1 7
Hao Yu 1 4
Tianshu Liu 1 11
Pagona Lagiou 0 1 5
Jin Li 1 2 3
0 Department of Epidemiology, Harvard T. H. Chan School of Public Health , 677 Huntington Avenue, Boston, MA 02115 , USA
1 Pagona Lagiou and Jin Li shared senior authorship
2 Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine , No. 150 Ji Mo Road, Shanghai 200120 , People's Republic of China
3 Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine , No. 150 Ji Mo Road, Shanghai 200120 , People's Republic of China
4 Nanjing Medical University , Nanjing , China
5 Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens , 75 M. Asias Street, Goudi GR, 115 27 Athens , Greece
6 Jilin Provincial Cancer Hospital , Changchun , China
7 Fudan University Shanghai Cancer Center , Shanghai , China
8 XinHua Hospital Affiliated to Shanghai Jiaotong University , Shanghai , China
9 First Affiliated Hospital of Zhejiang University , Hangzhou , China
10 People's Liberation Army Cancer Center, 81st Hospital of People's Liberation Army , Beijing , China
11 Fudan University Zhongshan Hospital , Shanghai , China
12 Shanghai First People's Hospital , Shanghai , China
13 Shandong Cancer Hospital , Jinan , China
14 Harbin Medical University Cancer Hospital , Harbin , China
15 First Affiliated Hospital of Nanchang University , Nanchang , China
16 Academy of Military Medical Sciences, 307th Hospital of PLA , Beijing , China
17 First Affiliated Hospital of Anhui Medical University , Hefei , China
18 Gansu Cancer Hospital , Lanzhou , China
Background: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Patients and methods: We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Results: Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. Conclusion: Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.
Apatinib; Gastric cancer; Biomarker; Adverse events
Gastric cancer (GC) is the fourth most common cancer
and the second leading cause of cancer-related deaths
worldwide, with more than 700,000 deaths annually [
Although the global incidence of GC is down-trending,
Asia is still with the highest incidence. China has almost
42% of the GC cases worldwide. Every year, there are
about 679,000 new cases and 498,000 GC related deaths
in China [
], which is a heavy burden to public health.
As symptoms of early GC are usually atypical and
unnoticed, many patients are diagnosed at an advanced
stage accompanied by extensive invasion and lymphatic
metastasis, with an overall survival (OS) of 3 to 5 months
if left untreated [
]. Although first-line chemotherapy
provides a 6-month survival benefit for patients with
advanced GC, second-line chemotherapy with irinotecan
or docetaxel adds only about 1.5 months to OS [
The recent REGARD [
] and RAINBOW [
] trials has
led to the approval of ramucirumab (a monoclonal
antibody VEGFR-2 antagonist) alone and in combination
with paclitaxel, in second-line treatment of GC.
Ramucirumab provided a 1.4 months’ benefit alone [
] and a
2.2 months’ OS benefit in addition to paclitaxel [
However, there is no standard third-line treatment if
second-line chemotherapy fails.
Apatinib, a novel oral small molecule tyrosine kinase
inhibitor targeting VEGFR-2, has demonstrated good
safety, tolerability, and efficacy in the treatment of
patients with advanced metastatic GC based on phase I–III
]. Compared with the placebo group, the
progression-free survival (PFS) and OS of the apatinib
groups were significantly prolonged by around 2 months.
Based on the phase II and III trials [
], apatinib was
approved by Chinese Food and Drug Administration in
advanced GC in 2014.
Apatinib provides a promising treatment for patients
who have failed second-line chemotherapy. The
investigation into predictive biomarkers of its anti-antiogenic
activity is therefore a challenge and gains high priority.
In a phase III trial [
], we observed that GC patients
with anti-angiogenesis related adverse events (AEs),
namely hypertension (HTN), proteinuria, and hand and
foot syndrome (HFS), tended to have better clinical
outcomes. These AEs are frequently reported in treatments
with other angiogenesis inhibitors and have been
suggested as surrogates of the anti-angiogenic activity.
Similarly, a study of 80 apatinib-treated advanced breast
cancer patients showed that both HTN and high
expression of p-VEGFR2 could be biomarkers for good
treatment efficacy [
Based on these observations, we conducted a
retrospective cohort study to investigate the association of
anti-angiogenesis related AEs with clinical outcomes in
metastatic GC patients, using data from phase II and III
trials. More specifically, we aimed to investigate
whether HTN, proteinuria, and HFS during the first
cycle of apatinib treatment could predict longer OS of
metastatic GC patients and serve as a biomarker of
To investigate the relationship between adverse effects
and antitumor efficacy, we pooled data from 269
apatinib-treated metastatic GC patients in the two
prospective multicenter clinical trials [
]. One study was
a randomized, double-blind, placebo-controlled phase II
trial  in which 93 patients received oral apatinib
850 mg once daily or 425 mg twice daily. The other study
was a randomized, double-blind, placebo-controlled phase
III trial [
], and 176 patients in the treatment arm of this
study received apatinib 850 mg once daily. One treatment
cycle was 28 days long. Treatment interruptions, dose
reductions, and supportive care were allowed for the
management of AEs.
Eligibility criteria for all patients in the present
analyses included age between 18 and 70 (inclusive) years;
histologically confirmed advanced GC or metastatic GC
(including gastroesophageal junction adenocarcinoma);
prior lack of response or intolerance to at least two lines
of chemotherapy; at least one measurable lesion as
defined by Response Evaluation Criteria in Solid Tumors
(RECIST); an Eastern Cooperative Oncology Group
performance status (ECOG PS) of 0 or 1; and acceptable
hematologic, hepatic, and renal function. Patients with
uncontrolled blood pressure on medication (> 140/
90 mmHg), those with a bleeding tendency, and those
receiving thrombolytics or anticoagulants were excluded.
Tumor assessments were performed based on
computed tomography and/or magnetic resonance imaging
at baseline, after cycles two and three, and every 8 weeks
thereafter until disease progression and were evaluated
according to RECIST (version 1.0 [
] in phase II trial
and 1.1 [
] in phase III trial). Efficacy measures
included OS, PFS, objective response rate (ORR; including
rate of complete response plus partial response), and
disease control rate (DCR; including complete response,
partial response, and stable disease). AEs (classified and
graded using the National Cancer Institute Common
Terminology Criteria for Adverse Effects version 3.0
]) were assessed at baseline until at least 28 days after
the last dose of study drug was administered.
The primary exposure was the presence of any of the
three AEs (HTN, proteinuria, and HFS) in the first
4 weeks of treatment. The cut-off was chosen at 4 weeks
(1 cycle) after initiation of therapy because of high
prevalence in the first 4 weeks and clinical relevance that
efficacy measurements and change of treatment plans
usually occur according to cycles. Other exposures of
interest included different times of onset and different
combinations of AEs. Baseline characteristics were
compared using t test, Wilcoxon rank sum test, chi-square
test, and Fisher exact test.
The primary outcome was OS, defined as time from
random assignment to death or withdrawal or end of
study, whichever occurred first. Secondary outcomes
included PFS, DCR, and ORR. Time-to-event endpoints
were assessed using Kaplan–Meier methods and
compared between groups using the log-rank test. Cox
proportional hazard regression models were used to estimate
hazard ratios (HR). Proportional hazard assumption was
assessed by including the exposure as a time-dependent
covariate. Binary endpoints were assessed using logistic
regression models. Potential confounders including age, sex,
ECOG PS, and number of metastatic sites were adjusted
in multivariable regression models. Effect modification by
age, sex, and ECOG PS were tested by including
interaction terms in the analyses.
To avoid the bias caused by the time-dependent
definition of exposures of interest, landmark analyses were
performed by excluding subjects who died or had
disease progression or death before the landmark (set at
1 month after initiation of apatinib therapy) from the
OS and PFS analyses, respectively, as sensitivity analyses.
A predictive model was developed using Cox
proportional hazards, with each factor investigated in univariate
and then multivariate analyses with a forward stepwise
algorithm. Factors in the univariate analysis with a P value
of less than 0.01 were entered into the multivariate model.
Risk scores were calculated according to the model.
Calibration and discrimination were evaluated [
Missing values were handled using complete case
analysis for exposure and outcomes and available case
analysis for other covariates. Two-sided tests were used, and
a P value < 0.05 was considered statistically significant.
All statistical analyses were carried out with Stata 14.0,
R 3.0 and Revman 5.
Demographics and baseline characteristics of patients
included in this analysis are presented in Table 1. A total
of 269 patients with metastatic GC were included in the
pooled analysis. The median OS was 139 days
(interquartile range, 82–236 days), and the median PFS
was 78 days (interquartile range, 54–143 days). By the
end of the study, 231 (85.9%) patients had progressed
and 209 (77.7%) had died. The overall DCR was 44.98%
and ORR was 6.32%.
Throughout the follow-up till 28 days after the last
dose of apatinib, no patient had grade 4 (life-threatening
or disabling) or grade 5 (death) HTN, proteinuria, or
HFS, and only 26 patients (9.67%) developed grade 3
(severe) HTN, proteinuria, or HFS. The AEs were
manageable and reversible after treatment interruptions,
dose reductions, and supportive care, supporting the
tolerability and acceptability of AEs as a biomarker of efficacy.
HTN, proteinuria, and HFS were the three most
common AEs and occurred mostly within 4 weeks (cycle 1)
after initiation of therapy (Additional file 1: Figure S1).
One hundred fifty out of 269 patients (55.76%) treated
with apatinib had at least one of the three AEs, HTN,
proteinuria, or HFS, in the first four weeks of treatment,
of whom 88 patients had only 1, 48 had 2, and only 4
had all three of the AEs. These 150 patients with at least
one of the three AEs in the first cycle accounted for
84.7% of patients who had the three AEs during the
whole follow-up. The individual AEs were present in
30.86, 29.74, and 23.42% of patients, respectively. The
presence of HTN was significantly correlated with
proteinuria and HFS (p = 0.001 and p < 0.001 in chi-square
test), but the time of onset of each AE was not
associated with the grade of severity or relatedness of the AE
with the drug (p all > 0.05).
The presence of AEs in the first 4 weeks was strongly
correlated with better clinical outcomes (Table 2).
Patients with vs. without AEs had a median OS of 169 vs.
103 days (log-rank p = 0.0039) and a median PFS of 86.5
vs. 62 days (log-rank p = 0.0309), respectively (Fig. 1).
DCR was significantly higher in patients with AEs
(54.67%) compared to those without (32.77%, p = 0.0003).
ORR was also higher in patients with AEs, but the
difference was not statistically significant.
The results remained similar after adjusting for
potential confounders, including age, sex, ECOG PS, and
number of metastatic sites (Table 2). Presence of AEs in
the first 4 weeks was associated with a 36% reduction in
hazard of death (HR 0.64, 95% CI, 0.48–0.84, p = 0.001),
a 31% reduction in hazard of progression (HR 0.69, 95%
CI, 0.53–0.91, p = 0.007), and a 167% increase in DCR
(odds ratio (OR) 2.67, 95% CI, 1.59–4.47, p < 0.001).
Presence of AEs in the 4 weeks stood the proportional
hazard assumption, so the effect of the exposure
remained constant before and after 400 days
(multi-adjusted p for interaction term with dichotomous time in
Cox regression was 0.081 and > 0.999 for OS and PFS,
respectively). The cut-off of 400 days was chosen by
visually looking at the log-negative log-survival probability
plot (figure not shown). No effect modification was found
by age, sex, or ECOG PS (Additional file 2: Figure S2A).
To address potential bias from misclassification of
patients who may have not remained on study long enough
for AE to be observed, landmark analyses were conducted
at the end of 4 weeks (Additional file 3: Table S1). Median
OS were statistically prolonged in patients with AE in
univariate and multivariate analysis. PFS was not statistically
different in crude analysis, but the difference turned
significant after adjusting for potential confounders.
The analyses of secondary exposures on primary
outcome confirmed the effect of AEs on OS (Additional file 2:
Figure S2B). In the first 4 weeks of treatment, the hazard
of death decreased by 10% (HR 0.90, 95% CI, 0.83–0.98)
for every one week earlier of AE onset, and 23% (HR 0.77,
95% CI, 0.66–0.90) for every one more AE occurred. The
onset of any single AE or any combinations of the three
AEs in the first 4 weeks were all statistically significantly
associated with prolonged OS, except for the presence of
proteinuria (HR 0.81, 95% CI, 0.60, 1.09), which showed a
same trend but did not reach statistical significance.
Different cut-offs of time of AE onset were also explored.
The presence of AEs in the first 2 and 3 weeks of
treatment also strongly correlated with prolonged OS, while
AE in the first week after initiation of treatment failed to
meet statistical significance probably because of the
limited number of outcomes to reach statistical power.
A multivariable Cox regression predictive model was
constructed to predict OS in the study population.
Covariates selected based on subject matter knowledge included
absence of AEs in the first 4 weeks, sex, every 10-year
increase in age, ECOG PS, more than two metastasis sites,
and every 5-cm increase in tumor size. Three covariates,
absence of AEs in the first 4 weeks, more than two
metastatic sites, and ECOG PS > 0 entered the model after
stepwise selection (Table 3). A linear predictor was
calculated as a weighted sum of the variables in the model,
where the weights were the regression coefficients. The
patients were then categorized into three risk groups.
Fractional polynomial regression was used to approximate
the log baseline cumulative hazard function as previously
]. The predicted mean survival curves were
compared with the Kaplan–Meier survival curves in the
three risk groups to visually assess calibration and
discrimination (Fig. 2a). The observed Kaplan–Meier curves
in the three risk groups were widely separated, suggesting
good discrimination. Calibration was reasonable as the
estimated and observed curves in each group were almost
identical for all except the high-risk risk group, where the
model consistently underpredicted the risk.
events (n = 150)
events (n = 119)
Adverse events are defined as hypertension, proteinuria, or hand and foot syndrome in the first 4 weeks of treatment
HR hazard ratio, OR odds ratio, IQR interquartile range
aAdjusted for sex, every 10-year increase in age, number of metastatic sites and ECOG PS
bHR for overall survival and progression survival; OR for disease control rate and objective response rate
cP values calculated from log-rank test for overall survival and progression survival, and chi-square test for disease control rate and objective response rate
dP values calculated from Cox regression for overall survival and progression survival, and logistic regression for disease control rate and objective response rate
Fig. 1 Overall survival and progression-free survival of patients treated with apatinib according to the presence of hypertension, proteinuria, or
hand and foot syndrome in the first 4 weeks of treatment. a Overall survival. b Progression-free survival. mOS median overall survival; mPFS median
HR hazard ratio, CI confidence interval, AE adverse event, ECOG PS Eastern Cooperative Oncology Group performance status
aAdverse events (AE) are defined as hypertension, proteinuria, or hand and foot syndrome in the first 4 weeks of treatment
For easier prediction in clinical settings, a point
scoring system was applied by assigning 2, 2, and 3 points to
the three risk factors in the model, absence of AEs in
the first 4 weeks, more than two metastatic sites, and
ECOG PS > 0, according to the corresponding HRs in
the multivariate model (Table 3). Patients with risk
scores of ≤ 5 were assigned as low-risk group, and others
were in high-risk group (Additional file 3: Table S2).
High-risk patients had more than 2 months shorter OS
(107 vs. 179 days, Fig. 2b) and more than 100% higher
hazard of death (HR 2.03, 95% CI, 1.53–2.67) compared
to low-risk patients. External validation of the model will
be conducted after completion of the ongoing phase
Several anti-VEGF/VEGFR drugs have been studied in GC.
As bevacizumab failed to benefit overall survival in
firstline treatment [
], researchers are not optimistic about an
anti-VEGF/VEGFR strategy in the first-line setting. As
anti-VEGFR-2 drugs, ramucirumab and apatinib were both
studied in previously treated GC. The difference between
the two drugs lies in two aspects. First, apatinib was given
as third-line treatment and ramucirumab was given as
second-line therapy. Second, in terms of patient
population, both REGARD [
] and RAINBOW [
are worldwide studies that enrolled patients including
Caucasians and Asians. However, in the RAINBOW study
], ramucirumab did not show additional survival benefit
in the Asian population. The trials of apatinib were
conducted in China. Although the global significance is limited
until it has been tested and proven to be effective in other
populations, apatinib provides a promising treatment for
GC who have failed second-line chemotherapy.
A challenge to the use of apatinib is the need to find
biomarkers to predict drug efficacy. In this retrospective
cohort analysis, apatinib treatment-induced HTN,
proteinuria, and HFS during the first cycle of treatment was
associated with statistically significant and clinically
meaningful improvement in clinical outcomes, including more
than 2-month increase in OS, almost 1-month increase in
PFS, and 167% increase in DCR. These findings support
the hypothesis that early presence of apatinib
treatmentinduced AEs is a viable biomarker of antitumor efficacy in
metastatic GC patients.
HTN, proteinuria, and HFS are common side effects
associated with treatment with angiogenesis inhibitors that
target the VEGF pathway, including bevacizumab [
sorafenib, sunitinib [
], and the novel agent
]. The mechanisms have not been fully elucidated,
but several studies have suggested the inhibition of VEGF
pathway in non-tumor cells. Inhibition of VEGFR in
vascular endothelial cells decreases the production of nitric
oxide and prostacyclins, leading to increased blood
]. Proteinuria might be induced by inhibition
of VEGF in pedal cells and mesangial cells in glomerula
]. HFS is considered a result of decreased
reconstruction of skin after restriction of vessels and has a
dose-response relationship with the agents . Similar
relationship between angiogenesis inhibitors induced AEs,
and treatment efficacy has been identified in various
cancers, including renal cell carcinoma, colorectal cancer, and
gastrointestinal stromal tumor [
17, 22, 23
AEs induced by angiogenesis inhibitors could partly
reflect the inherent host biology that caused the
difference in VEGF blockade and thus serve as a biomarker of
VEGF pathway inhibition efficacy. Nevertheless, the
possibility that the AEs may be independent of VEGF
inhibition cannot be excluded. An AE occurs after the
initiation of treatment and is not as ideal as the intrinsic
biomarkers present before treatment. It has been
previously reported that high tumor expression of p-VEGFR2
is an independent prognostic biomarker for prolonged
PFS in advanced breast cancer treated with apatinib
]. However, there is currently no intrinsic biomarker
for apatinib in GC. As the AEs presented in this study
are manageable, easy to measure, and of low cost and
occur early after initiation of therapy, if prospectively
validated, they could be a desirable prognostic biomarker
for GC patients treated with apatinib.
Several limitations should be considered when
interpreting the results. First, full pharmacokinetic data was
lacking. It is reasonable to believe that as a target drug,
apatinib functions depending more on the efficacy of
VEGF pathway blockage, which is mostly explained by
individual sensitivity to the drug, than on the
concentration of apatinib. In 11 patients from the phase I trial [
the serum concentration of apatinib at 24 h was not
significantly different between patient with and without
HTN, as well as HFS (unpublished data). Since all
patients received 850 mg per day in total at the beginning,
and subsequent dose reduction was an intermediate and
thus should not be adjusted for, the current study is
valid in showing the association between AEs and
clinical outcomes, although pharmacokinetic data could
further validate the findings. Second, collinearity may exist
among number of metastatic sites, stage, and
pathological grade. We only adjusted for number of metastatic
sites, since missing values were the least in this variable.
In addition, the two trials included in this analysis
included only Chinese patients, so it is possible that these
results are specific to this patient population only.
Whether these results are the same in other population
still needs further validation.
In conclusion, the presence of HTN, proteinuria, or HFS
during the first cycle of apatinib treatment correlates
with clinical outcomes in GC patients. Prospective
studies are warranted in the validation of the presence of
these AEs as a biomarker for apatinib antitumor efficacy.
Additional file 1: Figure S1. Manifestation of hypertension, proteinuria,
hand and foot syndrome during apatinib treatment. HTN: hypertension;
PrU: proteinuria; HFS: hand and foot syndrome. (TIF 1373 kb)
Additional file 2: Figure S2. Subgroup analyses and analyses of
secondary exposures. A. Forest plot of subgroup analyses by age, sex, or
ECOG PS. B. Forest plot of results from adjusted Cox regression analyses
of secondary exposures on overall survival. HTN: hypertension; PrU:
proteinuria; HFS: hand and foot syndrome. (TIF 1373 kb)
Additional file 3: Table S1. Landmark analyses. Table S2. Distribution
of risk scores and risk groups. (DOCX 61 kb)
AE: Adverse event; CI: Confidence interval; DCR: Disease control rate; ECOG
PS: Eastern Cooperative Oncology Group performance status; GC: Gastric
cancer; HFS: Hand and foot syndrome; HR: Hazard ratio; HTN: Hypertension;
ORR: Objective response rate; OS: Overall survival; PFS: Progression-free
survival; RECIST: Response Evaluation Criteria in Solid Tumors
We sincerely thank Jiangsu Hengrui Medicine Co., Ltd., for providing us with
the original data.
This study is funded by the Shanghai Sailing Program of the Science and
Technology Commission of Shanghai Municipality (17YF141900). The funding
body has no role in the design, analysis, or writing of the study.
Availability of data and materials
The datasets used and/or analyzed during the current study are available
from JL on reasonable request.
SQ, JPX, JMX, YB, ZHW, YY, GS, LW, LZ, NX, YC, WG, and JL collected the
original data in clinical trials. XL, ZCW, HY, TL, PL, and JL analyzed and
interpreted the data. XL, PL, and JL wrote the manuscript. All authors read
and approved the final manuscript. PL and JL share senior authorship.
Ethics approval and consent to participate
This study was determined as Not Human Subjects Research by Harvard T. H.
Chan School of Public Health Office of Human Research Administration
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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