This study evaluated the safety and efficacy of combining aflibercept with FOLFIRI chemotherapy (fluorouracil, leucovorin, irinotecan) in Asian patients with metastatic colorectal cancer who had progressed after prior oxaliplatin-based therapy. Nineteen patients received treatment with aflibercept and FOLFIRI. The combination showed a median progression-free survival of 4.1 months and median overall survival of 11.6 months. The majority of adverse events were grade 1-2 and included neutropenia, anemia, fatigue, and liver enzyme elevation. Grade 3 toxicities included neutropenia and neutropenic complications. All adverse events were managed with supportive care and

1. Asia-Pacific Journal of Clinical Oncology 2016 doi: 10.1111/ajco.12496
ORIGINAL ARTICLE
Safety and efficacy of aflibercept in combination with
fluorouracil, leucovorin and irinotecan in the treatment
of Asian patients with metastatic colorectal cancer
Dawn Q CHONG, Mary MANALO, Marlowe IMPERIAL, Patrick TEO, Grace YONG,
Matthew NG, Iain BH TAN, Su Pin CHOO and Clarinda CHUA
Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
Abstract
Aim: To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan
(FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed
after oxaliplatin-based chemotherapy.
Methods: This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept
(4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singa-
pore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan–Meier method
was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were
summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software.
Results: The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with
63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%)
achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6
months [95% confidence interval (CI), 2.2–13.1 months], the median OS was 11.6 months (95% CI, 6.1 to
not-estimable), and median PFS was 4.1 months (95% CI, 2.2–5.9). Majority of the toxicities were grade 1–2,
and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The
most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%).
All adverse events resolved with supportive management.
Conclusion: The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian pa-
tients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate
therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen.
Key words: aflibercept, FOLFIRI, irinotecan-based therapy, metastatic colorectal cancer, Named Patient Pro-
gram, Singapore
Correspondence: Dr Dawn Q CHONG, Associate Consultant,
National Cancer Centre Singapore, Division of Medical
Oncology, 11 Hospital Drive, Singapore 169610, Singapore.
Email: dawn.chong.q.q@nccs.com.sg
The authors have provided signed confirmations to the
publisher of their compliance with all applicable legal and
ethical obligations in respect to declaration of conflicts of
interest, funding, authorship and contributorship and
compliance with ethical requirements with respect to treatment
of human and animal test subjects.
Financial support: Editorial support was provided by
Sanofi-aventis.
INTRODUCTION
Globally, colorectal cancer (CRC) is the third most com-
mon cancer, with approximately 1.4 million new cases
diagnosed in 2012.1
During the past few decades, Asian
countries, including China, Japan, South Korea and Sin-
gapore, demonstrated a two- to four-fold increase in
the incidence of CRC.2,3
CRC is the most common
Conflicts of Interests: The authors have no conflicts of interest
to disclose.
Accepted for publication 13 March 2016.
C 2016 John Wiley & Sons Australia, Ltd

2. 2 DQ Chong et al
cancer in Singapore, with approximately 9324 cases re-
ported between 2010 and 2014.4–6
According to the lat-
est figures released by the Singapore Cancer Registry Re-
port (2010–2014), CRC is the most common cancer in
men (17.2%) and the second most common cancer in
women (13.3%), with age-standardized rates of 38.2%
and 26.7%, respectively.5
This trend may be attributed
to environmental and lifestyle changes, due to an increase
adoption of a “Western” dietary pattern. High intake of
red meat, lower consumption of vegetables and intake of
foods high in refined sugars have been associated with
an increase risk of CRC.7
In addition, screening and early
detection also contributed to the increased incidence.8
Singapore is a multiracial, multicultural and multi-
faceted society, with a population comprising of Chinese
(75%), Malays (13%), Indians (9%) and Asians from dif-
ferent origins (3%). The age-standardized incidence rate
of CRC was reported to be higher in Chinese residents
compared to Malay and Indian residents, thereby reflect-
ing a higher risk of the cancer in Chinese individuals.5
Although the incidence and mortality rates of CRC are
still higher in the Western population, the mortality-to-
incidence ratio for patients from Singapore is advancing
with age, denoting a poor survival rate (cancer deaths in
2010–2014: 13.8% in males and 15.3% in females).5,9
However, despite a noticeable increase in the incidence
rates in Singapore, mortality rates have started to de-
crease, specifically in the younger age groups. The age-
standardized mortality rate for CRC appeared to have
declined in both genders over the recent years, probably
attributed to advances in treatment and improvement in
systems-based practice in healthcare, including compli-
ance with the opportunistic screening program (National
Colorectal Cancer Screening Programme, 2011).9
Over the past decade, patients with mCRC have shown
significant improvements in the median survival and ob-
jective response rates because of advancements in surgical
techniques, coupled with combination of new chemother-
apeutics and targeted biological therapies.10–12
The stan-
dard chemotherapy backbone for mCRC comprises of
fluorouracil (FU) plus leucovorin with oxaliplatin (FOL-
FOX) or irinotecan (FOLFIRI).13,14
Aflibercept, a novel recombinant fusion protein, acts
as a high-affinity ligand trap, inhibiting the activity of
the ligands VEGF-A, VEGF-B and placental growth fac-
tor (PIGF1 and PIGF2), and thus preventing downstream
biological effects.15–17
Aflibercept has a higher VEGF-A
binding affinity than bevacizumab. Moreover, PIGF lev-
els increases with bevacizumab exposure and the abil-
ity of aflibercept to additionally target PIGF-1, PIGF-2
may be of potential significant interest in the treatment
of angiogenesis.18,19
A phase III clinical trial (VELOUR)
randomized patients to receive FOLFIRI with or without
aflibercept. The addition of aflibercept to FOLFIRI led
to an improvement in response rate (RR; 19.8% [95%
confidence interval (CI), 16.4–23.2] vs. 11.1% [95% CI,
8.5–13.8]; P < 0.0001], when compared to FOLFIRI
and placebo. The aflibercept and FOLFIRI group had su-
perior progression-free survival (PFS; hazard ratio [HR]
0.76; 95% CI, 0.66–0.87; P < 0.0001), and OS (HR 0.82;
95% CI, 0.71–0.94; P = 0.0032], relative to the placebo
and FOLFIRI group.17
Joulain et al. extrapolated survival
curves obtained from the VELOUR trial and concluded
that the mean OS gain for aflibercept in the trial was at
least 3 months for the intent-to-treat population.20
Importantly, despite the established efficacy of afliber-
cept in the Western population, the drug has not been
adequately evaluated in Asian patients, who may have
intrinsically dissimilar pharmacokinetics and pharmaco-
dynamics leading to different toxicity profile compared
to the Western population. The only study conducted in
the Asian population was a phase I trial that included 16
Japanese patients with mCRC, and demonstrated that the
combination of aflibercept and FOLFIRI was well toler-
ated, with a RR of 8.3%, and PFS of 7.59 months.21
We
sought to evaluate the efficacy and toxicities of afliber-
cept in combination with FOLFIRI in Asian patients with
mCRC, after failure of oxaliplatin-based therapy.
MATERIALS AND METHODS
Study design
This is a retrospective analysis conducted in a single in-
stitution (National Cancer Centre Singapore) in Singa-
pore. Between April 2012 and December 2013, 19 pa-
tients with mCRC who met the eligibility criteria were
granted access to aflibercept through the Named Patient
Program (NPP), supported by Sanofi. Eligibility for the
NPP was based on the same patient eligibility criteria in
the VELOUR trial, except for performance status (PS),
whereby the NPP is restricted to patients with an ECOG
score of 0 to 1. Eligible patients received 4 mg/kg of
aflibercept intravenously (IV), over a period of 1 hour ev-
ery 2 weeks starting on day 1, followed immediately by
the FOLFIRI regimen (irinotecan 180 mg/m2
IV over a
period of 90 min with leucovorin 400 mg/m2
IV over a pe-
riod of 2 h,followed by FU 400 mg/m2
bolus and FU 2400
mg/m2
continuous infusion over a period of 46 h). Pa-
tients were given premedication with atropine and anti-
emetics. Concomitant administration of other investiga-
tional therapies or devices, radiotherapy, anticonvulsant
agents (CYP 3A4 inducers: phenytoin, phenobarbital,
C 2016 John Wiley & Sons Australia, Ltd Asia-Pac J Clin Oncol 2016

3. Safety of FOLFIRI/aflibercept in metastatic colorectal cancer patients 3
carbamazepine; CYP 3A4 inhibitors: ketoconazole) were
avoided during the treatment period. Dose adjustments
and/or cycle delays (up to 2 weeks) were permitted in the
event of toxicity. Once resolved, drug treatment was re-
instituted as per physician’s clinical judgment. Treatment
was continued for every 2 weeks in the absence of disease
progression or unacceptable toxicity.
Patient population
All patients with mCRC who received FOLFIRI/
aflibercept combination as second-line treatment through
the NPP in NCCS were included. The inclusion crite-
ria include: patients aged ࣙ18 years; mCRC previously
treated with an oxaliplatin-containing regimen (only one
prior metastatic regimen was allowed); ECOG PS of 0–
1. The study allowed the inclusion of patients who had
disease progression during or after receiving oxaliplatin-
containing regimen for mCRC (a relapse of the disease
within 6 months of adjuvant oxaliplatin completion was
permitted). Follow-up assessments and monitoring of all
the patients were carried out at regular intervals. Pa-
tients were followed up until disease progression, death
or discontinuation of the program. Patients were ex-
cluded from the study if they were previously treated with
irinotecan; had inadequate hematologic, hepatic or renal
function; reported urine protein–creatinine ratio of >1
on morning spot urinalysis or proteinuria of >500 mg/24
h; had undergone prior radiation therapy, chemotherapy
or any of the investigational drug therapy or any other
major surgery or deep vein thrombosis (DVT) within the
past 4 weeks; reported any cardiovascular disease within
6 months before treatment; were on anticoagulant ther-
apy with unstable dose of warfarin and/or having an
out-of-therapeutic range international normalized ratio
of >3 within 4 weeks before treatment; had contraindi-
cations to any of the active substances (irinotecan, 5-
FU or folinic acid) or their excipients; had active can-
cer, bowel disorders with uncontrolled symptoms, unre-
solved toxicity from previous anticancer treatment, intol-
erance to atropine sulfate or loperamide or appropriate
anti-emetics; were undergoing treatment with anticonvul-
sants and women who were pregnant or breast-feeding.
Informed consent
This study was approved by the local institutional review
board and local Ethics Review Board of the hospital (Na-
tional Cancer Centre Singapore, Singapore). All patients’
data were de-identified. Signed patient consent form and
eligibility criteria form were completed for all patients
who were included in the NPP. The study methods were
conducted in accordance with approved national and
international guidelines.
Safety and efficacy assessments
Eligible patients underwent comprehensive baseline as-
sessments, which included a detailed medical history (in-
cluding cancer history and earlier anticancer treatments),
physical examination and tumor assessments by appro-
priate imaging techniques. All patients were evaluated
for vital signs, ECOG PS and development of AEs. Se-
rial laboratory tests, including blood pressure (BP) assess-
ment, blood chemistry, morning urine spot for evaluation
of proteinuria and liver and kidney function tests were
performed in all the patients. Patients were evaluated for
clinical response every 8 weeks or as per the physician’s
discretion. A baseline computed tomography scan was
performed 4 weeks before the commencement of protocol
treatment to determine the extent of disease. Serial clin-
ical measurements were performed every 8 weeks until
clinical disease progression. RR was summarized based
on the best response observed among all the computed
tomography scans performed on each patient. Tumor re-
sponse was assessed by the Response Evaluation Crite-
ria in Solid Tumors (RECIST) 1.1.22
Toxicity data were
summarized based on the highest grade ever reported for
each AE in each patient and were graded according to
the NCI-CTC AE V. 4.0 criteria.23
OS was defined as the
time from study enrollment until death from any cause.
PFS was defined as the time from study enrollment un-
til objective tumor progression or death from any cause.
Patients with AEs were followed up until resolution of
symptoms. Patients who were alive or lost to follow-up
were censored at their last follow-up date.
Statistical analyses
Safety data was analyzed in all patients who received at
least one dose of aflibercept. Continuous data were re-
ported as median, whereas categorical data were summa-
rized as frequencies and percentages. The Kaplan–Meier
method was used to estimate OS and PFS. All analyses
were performed using the STATA 12.0 software (Stata
Corp, College Station, TX, USA).
RESULTS
Patient demographics and clinical
characteristics
Between April 2012 and December 2013, 19 pa-
tients with mCRC received FOLFIRI/aflibercept post
oxaliplatin failure and were analyzed for safety, survival
Asia-Pac J Clin Oncol 2016 C 2016 John Wiley & Sons Australia, Ltd

4. 4 DQ Chong et al
(OS and PFS) and efficacy outcomes (RR). Of the 19 pa-
tients with mCRC, 11 (57.9%) were men, and the me-
dian age of all the patients was 59 years (range: 27–74
years) with majority having an Eastern Cooperative On-
cology Group (ECOG) status of 1 (63.2%). Most patients
were nonsmokers (57.9%). Diabetes (21.0%), hyperten-
sion (31.6%) and hyperlipidemia (42.1%) were some of
the commonly observed comorbidities. Approximately
79% of the patients had well to moderately differenti-
ated adenocarcinoma, and the most frequent metastatic
sites include liver (47.4%) and lung (47.4%). KRAS and
BRAF mutations were observed in eight (42.1%) pa-
tients and one (5.3%) patient, respectively. Most patients
(89.5%) underwent previous resection of primary tumor,
and 42.1% received adjuvant chemotherapy after cura-
tive resection. The median course of FOLFIRI/aflibercept
in this study was 5 cycles. Details of patient demographics
and clinical characteristics are presented in Table 1.
Aflibercept-related toxicities and
management
Of the 19 patients, 14 had tumor progression follow-
ing FOLFIRI/aflibercept. Death was reported in eight pa-
tients and all were attributed to progressive disease. There
were no treatment related deaths reporting during NPP.
Most of the treatment-related toxicities were low-grade
ranging from 5.3% to 84.2%. Grade 3 toxicities were
reported to be at 5.3–15.8%, and there was no grade
4 toxicity reported (Table 2). The most common grade
1–2 toxicities were leukopenia (84.2%), anemia (73.7%),
liver enzyme elevation (68.4%) and fatigue (68.4%). The
most common grade 3 toxicities were neutropenia and
its associated complications (15.8% each). Other Grade
3 toxicities include diarrhea, stomatitis, bowel obstruc-
tion, infections, hypertension, perianal fistula, pulmonary
embolism, leukopenia, anemia, neutropenia and its com-
plications, thrombocytopenia and liver enzyme elevation.
Baseline assessment of ECOG and vital signs were per-
formed and subsequently prior to each cycle. For grade
1–2 hematological toxicities, the patient’s chemotherapy
cycle was delayed for about 3–7 days until counts have re-
covered and subsequent dose reduction of FOLFIRI was
at physician’s discretion.
Febrile neutropenia was managed as per local treat-
ment guidelines. For patients who had grade 3 neu-
tropenic infections, patients were managed as per
Infectious Diseases Society of America (IDSA) recom-
mendations or as per local treatment guidelines with the
appropriate antibiotics, granulocyte colony-stimulating
factor (G-CSF) and supportive management. In these pa-
Table 1 Demographics and clinical characteristics of patients
with mCRC
Variable n (%)
Total 19 (100.0)
Age (years) 59 (27-74)†
Gender
Male 11 (57.9)
Female 8 (42.1)
ECOG performance status
0 7 (36.8)
1 12 (63.2)
Smoking
Yesb
5 (26.3)
No 11 (57.9)
Unknown 3 (15.8)
Alcohol intake
Yes‡
2 (10.5)
No 11 (57.9)
Unknown 6 (31.6)
Comorbidities
Diabetes
Yes 4 (21)
No 15 (79)
Hypertension
Yes 6 (31.6)
No 13 (68.4)
Hyperlipidemia
Yes 8 (42.1)
No 11 (57.9)
Tumor characteristics
Histology subtype
Well-differentiated
adenocarcinoma, NOS
1 (5.3)
Moderately differentiated
adenocarcinoma, NOS
14 (73.7)
Poorly differentiated
adenocarcinoma, signet cells
1 (5.3)
Mucinous adenocarcinoma 3 (15.8)
Primary tumor site
Colon 18 (94.7)
Rectum 1 (5.3)
Metastasis site at time of enrolment
Lung 9 (47.4)
Liver 9 (47.4)
Lymph node 8 (42.1)
Peritoneum 10 (52.6)
Bone 3 (15.8)
Other sites§
2 (10.5)
Molecular status of KRAS
Wild type 10 (52.6)
Mutations 8 (42.1)
Unknown 1 (5.3)
Molecular status of BRAF
Wild type 8 (42.1)
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5. Safety of FOLFIRI/aflibercept in metastatic colorectal cancer patients 5
Table 1 Continued
Variable n (%)
Mutations 1 (5.3)
Unknown 10 (52.6)
Treatment
Previous resection of primary tumor
Yes 17 (89.5)
No 2 (10.5)
Previous bevacizumab
Yes 3 (15.8)
No 16 (84.2)
Exposure to oxaliplatin
< 6 months 10 (52.6)
> 6 months 9 (47.4)
Previous cetuximab
Yes 1 (5.3)
No 18 (94.7)
Adjuvant regimen
Yes 8 (42.1)
No 11 (57.9)
†
The data is presented as median (range).
‡
Inclusive of current and previous.
§
Other sites include spleen and colonic anastomotic site.
tients, chemotherapy was delayed until the patient was
well enough to receive another course. Blood counts were
monitored and treatment was not administered until neu-
trophil (ࣙ1.5 × 109
/L) and platelet (ࣙ75 × 109
/L) counts
have recovered, and the grade was recovered to ࣘ1 for
other toxicities.
For patients with liver enzyme elevation, dose reduc-
tion or delay in chemotherapy was considered in those
who had grade 3 AE. However, it is noted that all the pa-
tients with grade 1–3 liver enzyme elevations had high
disease burden in the liver, and some elevation is at-
tributable to the progression of the metastasis.
In patients who reported grade 1–2 hypertension, an-
tihypertensive therapy was initiated immediately and
blood pressure was closely monitored for further ad-
justments, with no dose modification or delay in
chemotherapy. One patient reported grade 3 hyperten-
sion which was attributed to his poor compliance to anti-
hypertensive medications. The importance of adherence
to anti-hypertensive medications was emphasized. Stom-
atitis was treated with oral sucralfate, lidocaine and an-
tibacterial mouthwash. In patients who had higher grades
of stomatitis, 5-FU bolus was omitted in the subsequent
cycles with no change in the dose of aflibercept. For
patients who suffered from grade 3 diarrhea, a known
effect of FOLFIRI, prompt replacement of fluids and
electrolytes was administered. This was accompanied by
other supportive measures which include low residue diet
and anti-motility drugs.
A patient who suffered from grade 3 perianal abscess
was immediately started on empiric antibiotics, and was
given 2 doses of G-CSF to treat neutropenia, followed
by drainage of perianal abscess and fistulectomy. The pa-
tient completed 10 days of piperacillin–tazobactam IV,
and upon discharge was prescribed with oral amoxicillin-
clavulanic acid for 14 days. Aflibercept was permanently
discontinued following this event.
Bowel obstruction was observed in 2 patients who
had significant peritoneal disease. These patients
experienced similar episodes of bowel obstruction
prior to enrollment into NPP. Obstruction was man-
aged conservatively with bowel rest, anti-emetics,
stool softeners and pain control and there was no
intestinal perforation noted in the NPP.
Efficacy
The median follow-up duration was 9.6 months (range:
2.2–13.1 months). The median OS was 11.6 months
(95% CI, 6.1–not-estimable; Figure 1 and Table 3)
and the median PFS was 4.1 months (2.2–5.9 months;
Figure 1 and Table 3) following FOLFIRI/aflibercept
treatment. The 6-month OS rate was 77.3% (95% CI,
50.1–90.8) and the PFS rate was 26.3% (95% CI, 9.6–
46.8), whereas the 12-month OS rate was 43.6% (95%
CI, 14.5–70.0) and the PFS rate was 15.8% (95% CI,
3.9–34.9). Approximately 21.1% of the patients had par-
tial response (PR), 42.1% had stable disease (SD), with a
disease control rate of 63.2%. The summary of response
is reported in Table 4.
DISCUSSION
To our knowledge, this is the first study to assess
the safety and efficacy profile of FOLFIRI/aflibercept
in Asian patients with mCRC who had progressed
on an oxaliplatin-based chemotherapy regimen. In our
study, patients reported mild-to-moderate toxicity, which
was found to be consistent with the previously char-
acterized tolerability and safety profile for aflibercept.
Moreover, in our analysis there were no grade 4 or
treatment-related deaths reported.17,18,24
AEs observed in
this analysis were reversible and manageable, and were
treated during the course of the analysis. Most of the
AEs observed in the current analysis were grade 1–2,
and the most common drug-related AEs were hemato-
logical events (leucopenia [84.2%] and anemia [73.7%]),
followed by liver enzyme elevation (68.4%), fatigue
(68.4%) and diarrhea (57.9%). The occurrence of grade
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6. 6 DQ Chong et al
Table 2 Toxicity and treatment-related serious adverse events following FOLFIRI/aflibercept treatment in patients with mCRC
FOLFIRI/aflibercept (n = 19)
Adverse events†
All grades, n (%) Grade 1–2, n (%) Grade 3, n (%) Treatment-related serious adverse event
Any
Diarrhea 13 (68.4) 11 (57.9) 2 (10.5) Y
Fatigue 13 (68.4) 13 (68.4) 0
Neuropathy 10 (52.6) 10 (52.6) 0
Weight loss/anorexia 10 (52.6) 10 (52.6) 0
Stomatitis and ulceration 11 (52.6) 10 (52.6) 1 (5.3) Y
Palmar-plantar erythrodysesthesia 6 (31.6) 6 (31.6) 0
Vomiting 6 (31.6) 6 (31.6) 0
Nausea 5 (26.3) 5 (26.3) 0
Constipation 5 (26.3) 5 (26.3) 0
Alopecia 4 (21.1) 4 (21.1) 0
Headache/giddiness 2 (10.5) 2 (10.5) 0
Dysgeusia 2 (10.5) 2 (10.5) 0
Dry skin 2 (10.5) 2 (10.5) 0
Dyspnea 2 (10.5) 2 (10.5) 0
Bowel obstruction 2 (10.5) 0 2 (10.5) N
Edema 1 (5.3) 1 (5.3) 0
Infections and infestations 2 (10.5) 0 2 (10.5) Y
Anti-VEGF–associated events
Hoarseness 6 (31.6) 6 (31.6) 0
Hypertension 6 (31.6) 5 (26.3) 1 (5.3) Y
Perirectal bleeding 2 (10.5) 2 (10.5) 0
Perianal fistula 1 (5.3) 0 1 (5.3) Y
Pulmonary embolism 1 (5.3) 0 1 (5.3) Y
Deep vein thrombosis 1 (5.3) 1 (5.3) 0
Biologic abnormalities
Hematologic
Leukopenia 17 (89.4) 16 (84.2) 1 (5.3) Y
Anemia 16 (84.2) 14 (73.7) 2 (10.5) Y
Neutropenia 10 (52.6) 7 (36.8) 3 (15.8) Y
Neutropenic complications 3 (15.8) 0 3 (15.8) Y
Thrombocytopenia 6 5 (26.3) 1 (5.3) Y
Nonhematologic
Liver enzyme elevation 15 13 (68.4) 2 (10.5) Y
Renal impairment 6 (31.6) 6 (31.6) 0
Hypoalbuminemia 1 (5.3) 1 (5.3) 0
Hyponatremia 10 10 (52.6) 0
Hypokalemia 7 7 (36.8) 0
Hyperkalemia 3 (15.8) 3 (15.8) 0
Hypochloremia 1 (5.3) 1 (5.3) 0
Hyperglycemia 3 (15.8) 3 (15.8) 0
Hypoglycemia 1 (5.3) 1 (5.3) 0
FOLFIRI, infusional fluorouracil, leucovorin and irinotecan; VEGF, vascular endothelial growth factor.
†
Grades were determined according to the National Cancer institute Common Terminology Criteria of Adverse Events, version 4.0.
mCRC, metastatic colorectal cancer; Y, yes.
C 2016 John Wiley & Sons Australia, Ltd Asia-Pac J Clin Oncol 2016

7. Safety of FOLFIRI/aflibercept in metastatic colorectal cancer patients 7
Figure 1 Kaplan–Meier estimate of
OS and PFS in mCRC patients
treated with FOLFIRI/aflibercept.
3 toxicity was less frequent, consisting of neutrope-
nia (15.8%), neutropenic complications (15.8%), anemia
(10.5%), diarrhea (10.5%), bowel obstruction (10.5%),
other infections and infestations (10.5%) and liver en-
zyme elevation (10.5%). A total of 14 patients had tu-
mor progression, of which 8 deaths occurred. VELOUR
trial reported higher number of grade 3–4 AEs with
aflibercept/ FOLFIRI.17
In a phase I Japanese trial, the
most common grade 3 and 4 AE from the combina-
tion of aflibercept and FOLFIRI were neutropenia and
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8. 8 DQ Chong et al
Table 3 OS and PFS following FOLFIRI/aflibercept treatment
in patients with mCRC
Variable OS PFS
Survival
Number of events/
number of
patients
8/19 16/19
Median survival,
months (95% CI)
11.6 (6.1–NE) 4.1 (2.2–5.9)
6-Month survival
rate, % (95% CI)
77.3 (50.1–90.8) 26.3 (9.6–46.8)
12-Month survival
rate, % (95% CI)
43.6 (14.5–70.0) 15.8 (3.9–34.9)
CI, confidence interval; NE, not estimable; mCRC, metastatic colorectal
cancer.
Table 4 Response rate following FOLFIRI/aflibercept treat-
ment in patients with mCRC
Response n (%)
Best response
Partial response 4 (21.1)
Stable disease 8 (42.1)
Progressive disease 6 (31.6)
mCRC, metastatic colorectal cancer.
hypertension.21
Compared to the VELOUR trial, our
study demonstrated a lower rate of diarrhea (10.5% vs.
19%), neutropenia (15.8% vs. 23.1%), palmar-plantar
erythrodysesthesia (0% vs. 2.8%), stomatitis and ulcer-
ation (5.3% vs. 13.6%) and hypertension (5.3% vs.
19.1%).
The median PFS of 4.1 months and median OS of 11.6
months in our study is lower compared to that of the
VELOUR trial (median PFS 6.9 and OS 13.5 months),
and the Japanese trial (median PFS 7.59 months).21
How-
ever, the 6 and 12 months OS rates were relatively com-
parable (77.3% and 43.6% in our study, respectively, vs.
81.9% and 56.1% in the VELOUR trial, respectively).17
However, we must be cautious in interpreting these re-
sults as the small sample size in our study limits power.
The PR rate observed in our analysis (21.1%) was
slightly higher than the RR observed in the VELOUR
trial (19.8%) and in the Japanese trial (8.3%).17,21
Afliber-
cept in combination with FOLFIRI demonstrated a rea-
sonable and acceptable safety profile, with no observa-
tion of any new toxicity other than those reported in the
literature.15,18,21
The strengths of our study include the availability
of detailed demographic and toxicity data. Our study
population is also likely to be representative of the gen-
eral oncology population in Asia, and would provide in-
formation on the future use of FOLFIRI/aflibercept com-
bination in patients with mCRC. Limitations include ret-
rospective nature of analysis and small sample size that
precludes drawing definitive conclusions regarding sur-
vival.
CONCLUSION
The clinical benefit and safety profiles of FOLFIRI/
aflibercept in Asian patients were consistent with those
observed in the pivotal phase III VELOUR trial. AEs ex-
perienced by patients receiving FOLFIRI/aflibercept were
generally reversible and manageable using current clinical
practice and risk-management guidelines. To summarize,
FOLFIRI/aflibercept combination may be an appropriate
therapeutic option in Asian patients with mCRC previ-
ously treated with an oxaliplatin-based regimen.
ACKNOWLEDGMENTS
Editorial support was provided by Sanofi-aventis. Sanofi-
aventis had no role in the study design, data collection
and analysis, decision to publish or preparation of this
manuscript. All the authors planned the study, and con-
tributed to data interpretation, revisions and provided in-
puts at all stages of the study. The authors acknowledge
Mrs. Nishi Gupta and Dr. Amit Bhat (Indegene Lifesys-
tems Pvt Ltd., Bangalore, India) for providing medical
writing assistance in the preparation of this manuscript.
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