Aflibercept in combination with fluorouracil, leucovorin, and irinotecan in the treatment of Asian patients with metastatic colorectal cancer

Aflibercept
in
combina/on
with
fluorouracil,

leucovorin,
and
irinotecan
in
the
treatment
of

Asian
pa/ents
with
metasta/c
colorectal
cancer

Mary
Ondinee
U
Manalo1,
Dawn
Chong
Qingqing1,
Marlowe
Imperial1,
Patrick
Teo
Tze
Hern1,
Grace
Yong

Sook
Kwin1,
Choo
Su
Pin1
,
Iain
Tan
Bee
Huat1,
MaChew
Ng
Chau
Hsien1
,

Clarinda
Chua
Wei
Ling1

1Department
of
Medical
Oncology,
NaLonal
Cancer
Centre
Singapore

Correspondence:
marymanalo_md@yahoo.com
/
dawn.chong.q.q@nccs.com.sg

Variable n (%)
Total 19 (100.0)
Age (years) 59 (27-74)
Gender
Male 11 (57.9)
ECOG performance status
0 3 (15.8)
1 11 (57.9)
Hypertension
Yes 6 (31.6)
No 13 (68.4)
Histology subtype
Well-differentiated adenoCA, NOS 1 (5.3)
Moderately differentiated adenoCA, NOS 14 (73.7)
Poorly differentiated adenoCA, signet cells 1 (5.3)
Mucinous adenoCA 3 (15.8)
Metastasis site at the time of enrollment
Lung 9 (47.4)
Liver 9 (47.4)
Lymph node 8 (42.1)
Peritoneum 10 (52.6)
Bone 3 (15.8)
Other sites (spleen, mesentery) 2 (10.5)
Exposure to oxaliplatin
<6 months 10 (52.6)
>6 months 9 (47.4)
Previous bevacizumab
Yes 3 (15.8)
No 16 (84.2)
Previous cetuximab
Yes 1 (5.3)
No 18 (94.7)

Adverse
Events

FOLFIRI
/
aflibercept
(n=19)
Treatment-‐

Related
Serious

Adverse
Event
All
Grades

n
(%)

Grade
1-‐2

n
(%)

Grade
3

n
(%)

Any

Diarrhea

13 (68.4) 11 (57.9) 2 (10.5) Yes

FaLgue
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

StomaLLs
and
ulceraLon
11 (52.6) 10 (52.6) 1 (5.3) Yes

Palmar-‐plantar
erythrodysesthesia

6 (31.6) 6 (31.6) 0

VomiLng
6 (31.6) 6 (31.6) 0

Nausea
5 (26.3) 5 (26.3) 0

ConsLpaLon
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
obstrucLon
2 (10.5) 0 2 (10.5) No

Edema
1 (5.3) 1 (5.3) 0

InfecLons
and
infestaLons
2 (10.5) 0 2 (10.5) Yes
An/-‐VEGF-‐associated
events

Hoarseness
6 (31.6) 6 (31.6) 0

Hypertension
6 (31.6) 5 (26.3) 1 (5.3) Yes

Perirectal
bleeding
2 (10.5) 2 (10.5) 0

Perianal
fistula
1 (5.3) 0 1 (5.3) Yes

Pulmonary
embolism
1 (5.3) 0 1 (5.3) Yes

Deep
vein
thrombosis
1 (5.3) 1 (5.3) 0
Hematologic

Leukopenia
17 (89.4) 16 (84.2) 1 (5.3) Yes

Anemia
16 (84.2) 14 (73.7) 2 (10.5) Yes

Neutropenia
10 (52.6) 7 (36.8) 3 (15.8) Yes

Neutropenic
complicaLons
3 (15.8) 0 3 (15.8) Yes

Thrombocytopenia
6 (31.6) 5 (26.3) 1 (5.3) Yes
Non-‐hematologic

Liver
enzyme
elevaLon
15 (78.9) 13 (68.4) 2 (10.5) Yes

Renal
impairment
6 (31.6) 6 (31.6) 0

Hypoalbuminemia
1 (5.3) 1 (5.3) 0

Hyponatremia
10 (52.6) 10 (52.6) 0

Hypokalemia
7 (36.8) 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
Best

Overall

Response

VELOUR

(n=612)

Na/onal
Cancer

Centre
Singapore

(n=19)

Indian

Data

(n=29)

UK

Data

(n=21)

ParLal
response
20%
21%
24%
36%

Stable
disease
66%
42%
42%
26%

Progressive
disease
10%
32%
34%
37%

Not
evaluable
4%
5%
0
0

BACKGROUND
BASELINE
CHARACTERISTICS
ADVERSE
EVENTS

COMPARISON
OF
RESPONSE
RATES

According
to
the
Singapore
Cancer
Registry

Report,
metastaLc
colorectal
cancer
(mCRC)

had
the
second
highest
cancer
mortality
rate

among
males
and
the
third
highest
cancer

mortality
rate
among
females
in
Singapore

from
2010
–
2014.

First-‐line
chemotherapy
for
the
treatment
of

m C R C
t y p i c a l l y
c o m p r i s e
o f
a

fluoropyrimidine-‐based
regimen.
Aflibercept

is
a
recombinant
fusion
protein
that
binds
to

vascular
endothelial
growth
factor
(VEGF)-‐A,

VEGF-‐B,
and
placental
growth
factor
(PIGF)

and
inhibits
angiogenesis.
The
landmark

VELOUR
study
demonstrated
that
the

addiLon
of
aflibercept
to
FOLFIRI
improved

overall
survival
(OS)
by
1.4
months,
when

compared
to
placebo
plus
FOLFIRI
in
mCRC

paLents
who
were
previously
treated
with
an

oxaliplaLn-‐based
chemotherapy
regimen.

However,
majority
(87.4%)
are
Caucasians
in

this
study,
and
thus
the
safety
and
tolerability

in
Asian
paLents
remain
unknown.

PURPOSE

Current
analysis
evaluated
the
safety
and

efficacy
of
the
combinaLon
of
FOLFIRI
and

aflibercept
in
Asian
paLents
with
mCRC
who

have
progressed
aker
an
oxaliplaLn-‐based

chemotherapy.

This
is
a
retrospecLve,
single-‐center
analysis

which
was
conducted
through
a
Named

PaLent
Program
(NPP)
in
Singapore.
PaLents

were
screened
for
eligibility
and
informed
of

potenLal
access
to
aflibercept
as
an

unlicensed
therapy
(aflibercept
was
not

registered
with
the
Health
Sciences
Authority

at
the
Lme
of
study)
via
the
NPP
supported
by

Sanofi,
as
per
VELOUR
inclusion
criteria

except
that
PS=2
was
excluded.

Nineteen
Asian
paLents
with
metastaLc
CRC

who
were
previously
treated
with
an

oxaliplaLn-‐based
regimen
were
given

aflibercept
4mg/kg
intravenously
every
2

weeks
in
combinaLon
with
FOLFIRI.
Prior
use

of
bevacizumab
or
cetuximab
was
allowed
in

this
study.
ToxiciLes
and
survival
outcome

were
analysed.
Treatment
was
administered

unLl
disease
progression
or
unacceptable

toxicity.

PATIENTS
AND
METHODS

RESULTS

Out
of
the
19
paLents,
majority
were

Chinese
(84%),
male
(57.9%),
with
a
median

age
of
59
yrs
and
with
good
performance

status
of
ECOG
1.
The
median
course
of

FOLFIRI/aflibercept
was
5
cycles.
Diabetes

(21.0%),
hypertension
(31.6%)
and

hyperlipidemia
(42.1%)
were
the
most

common
comorbidiLes.
KRAS
and
BRAF

mutaLons
were
observed
in
8
(42.1%)

paLents
and
1
(5.3%)
paLent,
respecLvely.

Aker
a
median
follow-‐up
of
9.6
months,
the

median
OS
was
11.6
months
(95%
confidence

interval
(CI):
6.1-‐non-‐esLmable
[NE])
and
PFS

was
4.1
months
(95%
CI:
2.2-‐5.9).
The

response
rate
was
21.1%,
with
42.1%

achieving
stable
disease.

CONCLUSION

The
combinaLon
of
FOLFIRI
and
aflibercept
was
well-‐tolerated.

Adverse
events
were
manageable
and
were
in
line
with
those

previously
reported
in
the
Western
populaLon.
Survival
and

response
rates
were
also
comparable
with
other
studies.

FOLFIRI
/
aflibercept
is
a
safe
and
acceptable
therapeuLc
opLon

in
Asian
paLents
with
mCRC
previously-‐treated
with
an

oxaliplaLn-‐based
regimen.

OVERALL
SURVIVAL

Median
OS:

11.6
months
(6.1
–
NE)

6-‐month
OS:

77.3%
(95%
CI,
50.1
–
90.8%)

1-‐yr
OS:

43.6%
(95%
CI,
14.5
–
70%)

Median
PFS:

4.1
months
(2.2
–
5.9)

6-‐month
PFS:

26.3%
(95%
CI,
9.6
–
46.8%)

1-‐yr
PFS:

15.8%
(95%
CI,
3.9
–
34.9%)

PROGRESSION-‐FREE
SURVIVAL

Fourteen
paLents
had
tumor
progression
following
FOLFIRI/
aflibercept.
Death
was
reported
in
8
paLents,
all
found
to
be
due

to
tumor
progression.

Majority
of
the
adverse
events
were
grade
1-‐2
(5.3
–
84.2%)

and
included
leucopenia
(84.2%),
anemia
(73.7%),
faLgue
and

liver
enzyme
elevaLon
(68.4%
each),
while
grade
3
adverse

events
were
mainly
neutropenia
and
its
associated
complicaLons

(15.8%
each).

Other
serious
AEs
included
diarrhea,
stomaLLs,
infecLons,

hypertension,
perianal
fistula,
pulmonary
embolism
and

cytopenias.
No
new
toxiciLes
were
noted
other
than
those
that

have
been
previously
reported
in
literature.

There
were
no
grade
4
adverse
events
as
well
as
deaths
due
to

treatment.

*Grades were determined according to the National Cancer Institute Common
Terminology Criteria of Adverse Events (NCI-CTCAE), version 3.0

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