ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT
Phase 2 study of lenvatinib in patients with advanced
hepatocellular carcinoma
Kenji Ikeda
1
•
Masatoshi Kudo
2
•
Seiji Kawazoe
3
•
Yukio Osaki
4
•
Masafumi Ikeda
5
•
Takuji Okusaka
6
•
Toshiyuki Tamai
7
•
Takuya Suzuki
7
•
Takashi Hisai
7
•
Seiichi Hayato
7
•
Kiwamu Okita
8
•
Hiromitsu Kumada
1
Received: 27 April 2016 / Accepted: 6 September 2016 / Published online: 4 October 2016
Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract
Background Lenvatinib is an oral inhibitor of vascular
endothelial growth factor receptor 1–3, fibroblast growth
factor receptor 1–4, platelet-derived growth factor receptor
alpha, RET, and KIT. This phase 2, single-arm, open-label
multicenter study evaluat ed lenvatinib in advanced hepa-
tocellular carcinoma (HCC).
Methods Patients with histologically/clinically confirmed
advanced HCC who did not qualify for surgica l resection
or local therapies received lenvatinib at a dosage of 12 mg
once daily (QD) in 28-day cycles. The primary efficacy
endpoint was time to progression (TTP) per modified
Response Evaluation Criteria in Solid Tumors v1.1; sec-
ondary efficacy endpoi nts included objective response rate
(ORR), disease control rate (DCR), and overall survival
(OS).
Results Between July 2010 and June 2011, 46 patients
received lenvatinib at sites acro ss Japan and Korea. The
median TTP, as determined by independent radiological
review, was 7.4 months [95 % confidence interval (CI):
5.5–9.4]. Seventeen patients (37 %) had partial response
and 19 patients (41 %) had stable disease (ORR: 37 %;
DCR: 78 %). Median OS was 18.7 months (95 % CI:
12.7–25.1). The most common any-grade adverse events
(AEs) were hypertension (76 %), palmar-plantar ery-
throdysesthesia syndrome (65 %), decreased appetite
(61 %), and proteinuria (61 %). Dose reductions and dis-
continuations due to AEs occurred in 34 (74 %) and 10
patients (22 %), resp ectively. Median body weight was
lower in patients with an early (\30 days) dose withdrawal
or reduction than in those without.
Conclusions Lenvatinib 12-mg QD showed clinical activ-
ity and acceptable toxicity profiles in patients with
advanced HCC, but early dose modification was necessary
in patients with lower body weight. Further development of
lenvatinib in HCC should consider dose modification by
body weight.
Trial registration ID
www.ClinicalTrials.gov NCT009
46153.
Keywords Hepatocellular carcinoma Lenvatinib
Tyrosine kinase inhibitor E7080 Vascular endothelial
growth factor inhibitor
Introduction
In hepatocellular carcinoma (HCC), which accounts for
85–90 % of primary liver cancers [1], increased expression
of vascular endothelial growth factor (VEGF) levels has
Electronic supplementary material The online version of this
article (doi:
10.1007/s00535-016-1263-4) contains supplementary
material, which is available to authorized users.
& Kenji Ikeda
ikedakenji@tora.email.ne.jp
1
Department of Hepatology, Toranomon Hospital, Toranomon
2-2-2, Minato-ku, Tokyo 105-8470, Japan
2
Department of Gastroenterology and Hepatology, Kinki
University School of Medicine, Osaka, Japan
3
Department of Hepatobiliary and Pancreatology, Saga-Ken
Medical Centre KOSEIKAN, Saga, Japan
4
Department of Gastroenterology and Hepatology, Osaka Red
Cross Hospital, Osaka, Japan
5
Department of Hepatobiliary and Pancreatic Oncology,
National Cancer Center Hospital East, Kashiwa, Japan
6
Department of Hepatobiliary and Pancreatic Oncology,
National Cancer Center Hospital, Tokyo, Japan
7
Eisai Co., Ltd.,, Tokyo, Japan
8
Shunan Memorial Hospital, Yamaguchi, Japan
123
J Gastroenterol (2017) 52:512–519
DOI 10.1007/s00535-016-1263-4
been correlated with angiogenic activity, tumor progres-
sion, and poor prognosis [
2, 3].
Sorafenib is currently the only systemic VEGF-targeted
therapy to have demonstrated a survival benefit in patients
with advanced HCC [
4, 5]. However, the median overall
survival (OS) and time to progression (TTP) with sorafenib
are only *1 year and *4 months, respectively, with fre-
quent dose reductions or discontinuations due to adverse
events, including severe skin toxicity [
6–8]. Therefore,
there is still an unmet need for better therapeutic options
for patients with advanced HCC. To date, phase 3 trials of
several agents, including sunitinib, brivanib, and linifanib,
have failed to demonstrate benefit in advanced HCC [
6].
Lenvatinib—an oral, multi-tyrosine kinase receptor
inhibitor of VEGF receptors 1–3, fibroblast growth factor
(FGF) receptor 1–4, platelet-derived growth factor (PDGF)
receptor alpha, and KIT and RET proto-oncogenes
[
9–11]—was approved for radioiodine-refractory differen-
tiated thyroid cancer at a dose of 24 mg once daily (QD) in
28-day cycles [
12]. However, for the clinical development
of therapeutics in HCC, re-evaluation of the starting dose
of any investigational agent is recommended [
13]. In a
phase 1 study of lenvatini b in HCC, the maximum tolerable
dose in patients with HCC and Child Pugh (CP) class A
liver function was 12 mg QD [
14]. This dose also showed
blood trough concentrations comparable to those with the
25-mg QD dose determined to be the maximum tolerated
dose in solid tumors [
15] with preliminary evidence of
tumor shrinkage. Here we assessed the antitumor activity
and safety of lenvatinib in this phase 2 study in patients
with advanced HCC.
Methods
Patients
Patients ages 20–80 years had clinically confirmed
advanced HCC with residua l disease no t qualifying for
surgical resection or local therapies, including transarterial
chemoembolization; C1 measurable target lesion by
Response Evaluation Criteria in Solid Tumors version 1.1
(RECIST v1.1); [
16] 1–3 tumor lesions [3 cm in diameter
([5 cm diameter if only one lesion) or four or more lesions
or portal vein invasion, extrahepatic invasion; Eastern
Cooperative Oncology Group performance status of 0 or 1;
CP score of 5 or 6 (CP class A); platelet count C50 9 10
9
/L,
absolute neutrophil count C1.5 9 10
3
/lL; aspartate
transaminase and alanine transaminase B5.0 times the
upper limit of normal; and serum creatinine B2.0 mg/dL or
calculated creatinine clearance C40 mL/min. Patients had
to have had a hepatectomy and local therapy for HCC at
least 6 and 4 weeks, respectively, prior to study enrollment.
Exclusion criteria included clinically symptomatic brain
metastasis or meningeal carcinomatosis; receipt of C1
systemic chemotherapy, including targeted therapy or
transarterial infusion chemotherapy; QT-corrected interval
by the Fredericia method [500 ms at screening; mean
blood pressure C150/90 mmHg; presence of a progressive
central nervous system disease; or a clinically significant
hemorrhagic or thrombotic event within 4 weeks prior to
study enrollment.
Study design and treatment
Patients in this single-arm, open-label multicenter study of
lenvatinib monotherapy for advanced HCC
(NCT00946153) received daily oral administration of 12
mg lenvatinib (12-mg QD) in 28-day cycles until disease
progression, unacceptable toxici ty, or withdrawal of con-
sent. Dose interruption and sequential reduction of lenva-
tinib (to 8- and 4-mg QD) were permitted for drug-related
adverse events (AEs; see Online Resource Table S1). Once
reduced, the dose could not be re-escalated. The study drug
was discontinued if patient recovery time was [2 weeks.
This study was conducted in accordance with local laws,
the Declaration of Helsinki, and International Conference
on Harmonization Good Clinical Practice guidelines, and
with the approval of each institutional review board. All
patients provided written informed consent.
Study assessments
The primary efficacy endpoint was TTP per modified
RECIST (mRECIST; modified to evaluate viable lesions)
[
17] by an independent radiologic review committee
(IRRC). mRECIST uses viable target lesions in dynamic
computed tomography and is suitable for the assessment of
tyrosine kinase inhibitors in HCC [
17, 18]. Secondary effi-
cacy endpoints included objective response rate (ORR),
disease control rate (DCR), and OS. Tumor response was
evaluated every 8 weeks using mRECIST v1.1 by both the
IRRC and study investigators. An exploratory analysis to
reassess tumors using RECIST v1.1 was also performed by
the IRRC. Safety was assessed by physical examinations,
clinical and laboratory evaluations, vital signs, and electro-
cardiograms. AEs were graded according to the National
Cancer Institute Common Terminology Criteria for AEs,
version 3.0. A pre-dose blood sample was obtained for
pharmacokinetic (PK) assessment on days 1, 8, 15, and 22 of
cycle 1, and day 1 of cycles 2 and 3, using a validated liquid
chromatography–tandem mass spectrometry method [
19].
J Gastroenterol (2017) 52:512–519 513
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Statistical considerations
Time-to-event endpoints, including TTP and OS, were
summarized using Kaplan–Meier estimat es. The sample
size of 46 patients was based on an 80 % probability that
the lower limit of the two-sided 90 % confidence interval
(CI) of median TTP would exceed the threshold of
2.7 months (based on the Sorafenib HCC Assessment
Randomized Protocol trial [
20]), with an expected median
TTP of 4.1 months for lenvatinib. Sample size determina-
tion also assumed exponential distribution for TTP,
12 months of enrollment, 6 months of follow-up, and a
10 % patient exclusion/dropout rate. An interim evaluation
was conducted when 21–23 patients became evaluable for
the 2-month tumor assessment. If the number of patients
with progressive disease within 2 months was C10
(C80 % Bayesian posterior probability for proportion of
patients with progressive disease at 2 months C35 %),
then study discontinuation would be considered due to
futility. Follow-up was continued until final analysis was
performed when 67 % of patients had died.
Results
Patient characteristics
Overall, 46 patients were enrolled and received lenvatinib
at 14 sites across Japan and Korea between July 2010 and
June 2011. All patients were included in the safety and
efficacy analyses. Patient demographics and baseline
characteristics are listed in Table
1.
Efficacy
Median TTP was 7.4 months (95 % CI: 5.5–9.4) as
assessed by IRRC per mRECIST (Fig.
1a). Median TTP
was 12.8 months (95 % CI: 7.2–14.7) by investigator
assessment. Seventeen patients (37 %) achieved a partial
response and 19 patients (41 %) had stable dis-
ease C8 weeks, with a DCR of 78 % by IRRC (Table
2).
Outcomes using RECIST v1.1 criteria are also provided in
Table
2. Median OS was 18.7 months (95 % CI:
12.7–25.1; Fig.
1b).
Tumor reduction of target lesions, assessed by IRRC,
occurred in 80 % of patients (Fig.
2a–c). Subgroup anal-
yses indicated that lenvatinib clinical activity was main-
tained regardless of tumor status (with or without
extrahepatic spread or portal vein invasion), type of
underlying hepatitis [hepatitis B virus (HBV) or hepat itis C
virus], receipt of previous chemotherapy, or alpha-feto-
protein levels (AFP; \200 ng/mL or C200 ng/mL; see
Table 1 Patient demographics and baseline characteristics
Characteristic Patients (N = 46)
Median age, years (range) 66.5 (37–80)
Sex, n (%)
Female 13 (28.3)
Male 33 (71.7)
Region, n (%)
Japan 43 (93.5)
South Korea 3 (6.5)
Median weight, kg (range) 56.7 (42.8–85.5)
ECOG PS, n (%)
0 38 (82.6)
1 8 (17.4)
Child Pugh Class, n (%)
A 45 (97.8)
B 1 (2.2)
BCLC staging,n(%)
B 19 (41.3)
C 27 (58.7)
Portal vein invasion, n (%)
Yes 5 (10.8)
No 41 (89.1)
Extrahepatic metastasis, n (%)
Yes 21 (45.7)
No 25 (54.3)
Cause of HCC, n (%)
Hepatitis B 15 (32.6)
Hepatitis C 27 (58.7)
Alcohol 2 (4.3)
Non-alcohol-related fatty liver disease 1 (2.2)
Unknown 2 (4.3)
AFP value at baseline
a
\200 ng/mL 27 (57.7)
C200 ng/mL 18 (39.1)
Prior surgery for HCC, n (%)
No 27 (58.7)
Yes 19 (41.3)
Prior local therapy, n (%)
No 4 (8.7)
Yes 42 (91.3)
RFA 32 (69.6)
PEI 12 (26.1)
TACE 39 (84.8)
TAE 3 (6.5)
Prior chemotherapy, n (%)
Sorafenib 6 (13.0)
Other systemic chemotherapy 5 (10.9)
Hepatic intra-arterial chemotherapy 5 (10.9)
BCLC Barcelona Clinic Liver Cancer, ECOG-PS Eastern Cooperative
Oncology Group Performance Status, HCC hepatocellular carcinoma,
AFP alpha-fetoprotein, PEI percutaneous ethanol injection, RFA
radiofrequency ablation, TACE transcatheter arterial chemoembolization,
TAE transarterial embolization
a
AFP data were unavailable for one patient
514 J Gastroenterol (2017) 52:512–519
123
Online Resource Table S2). On the other hand, AFP levels
may affect the prognosis for patients with HCC (Online
Resource Figure S1).
Safety
Median and mean durations of lenvatinib treatment were
7.3 and 9.0 months, respectively. All 46 patients experi-
enced at least one AE. The most common any-grade AEs
(Table
3) were hypertension (76 %), palmar-plantar ery-
throdysesthesia syndrome (PPES; 65 %), decreased appe-
tite (61 %), and proteinuria (61 %). The incidence of
serious AEs (SAEs) was 48 %, and the most frequently
reported SAE was hepatic encephalopathy (11 %). No
treatment-related deaths were reported. Two patients died
within 30 days of receiving their last dose of lenvatinib—
one from pneumonia and one from liver tumor rupture.
AEs were generally manageable with dose modifica-
tions. Lenvatinib dose reductions due to AEs occur red in
34 patients (74 %). Ten patients (22 %) discontinued study
treatment due to toxicity. The most frequently reported AE
leading to study drug withdrawal was proteinuria (11 %).
Twenty-two patients (48 %) experienced AEs leading to
dose withdrawal or dose reduction \30 days after starting
lenvatinib. In an exploratory analysis of differences in
baseline characteristics between patients who did and did
not require an early dose withdrawal or reduction, body
weight and minimum concentration of lenvatinib (C
trough
)
were identified as potential differentiators (Fig.
3). Median
body weight was lower for patients who experienced an
early dose withdrawal or reduction (54.1 kg) than for those
who did not (67.6 kg) (Fig.
3a). The median C
trough
values
on cycle 1 day 15 (C1D15) in patients with and without
dose modi fications were 62.4 and 33.9 ng/mL, respectively
(Fig.
3b). The Spearman correlation coefficient between
body weight and lenvatinib C
trough
at C1D15 was -0.64.
Discussion
Multi-tyrosine kinase inhibitors have shown limited suc-
cess in advanced HCC, with reported TTP ranging from 2.8
to 5.4 months and ORR from 6.9 to 9 % [
4, 5, 7, 21, 22]. In
this study, lenvatinib 12-mg QD showed promising clinical
activity in patients with advanced HCC, with a median
TTP of 7.4 months as assessed by IRRC (12.8 months by
investigator). Lenvatinib also demonstrated tumor shrink-
age in 80 % of patients, with a response rate of 37 % per
mRECIST and 24 % per conventional RECIST.
Although progression-free survival is the pref erred OS
surrogate endpoint in most solid tumor trials, it is a par-
ticularly unreliable endpoint in HCC studies, because death
from the natural history of cirrhosis may confound resu lts;
Fig. 1 Kaplan–Meier estimates of a TTP and b OS. Median TTP was
7.4 months as assessed by an IRRC comprising four independent
radiologists. Median OS was 18.7 months. IRRC independent radi-
ologic review committee, TTP time to progression
Table 2 Tumor responses
Response category Investigator assessment
(mRECIST), n = 46
IRRC assessment
(mRECIST), n = 46
IRRC assessment
(RECIST 1.1), n = 46
Best response, n (%)
Complete response 0 (0) 0 (0) 0 (0)
Partial response 17 (37) 17 (37) 11 (24)
Stable disease 21 (46) 19 (41) 25 (54)
Progressive disease 5 (11) 6 (13) 6 (13)
Not evaluable 3 (7) 4 (9) 4 (9)
Objective response rate, n (%) 17 (37) 17 (37) 11 (24)
Disease control rate, n (%) 38 (83) 36 (78) 36 (78)
IRRC independent radiologic review committee, mRECIST modified response evaluation criteria in solid tumors
J Gastroenterol (2017) 52:512–519 515
123
TTP is therefore the recommended endpoint for early-stage
trials of HCC [
13]. In HCC, response rates derived from
mRECIST have been shown to better correlate with OS than
those from conventional RECIST [
18]. Notably, despite a
similarity in best overall responses between investigator
and independent assessment s, the median TTP was sub-
stantially different, suggesting a bias by the investigators in
determining the timing of disease progression, ostensibly so
that their patients could continue therapy.
The median OS in this study was 18.7 months. Although
subgroup analyses indicated that median TTP was com-
parable regardless of baseline AFP levels, OS was longer in
the 61 % of patients with lower vs. higher AFP levels (23.5
vs. 13.3 months, respectively). Therefore, it is possible that
the long median OS observed in this study may have been
driven by those patients with lower baseline AFP levels,
because elevated AFP levels are associated with an
increased mortality rate in HCC [
23]. Other risk factors
examined included extrahepatic spread and HBV. In this
study, lenvatinib activity was observed even in these
patients with poor prognoses; however, this conclusion is
limited by the small numbers of patients in each subgroup.
Another limitation is the single-arm design of the study,
and the possibility that results may be influe nced by patient
selection. However, we note that patient characteristics in
this study were typical of the population of patients with
HCC who required sorafenib therapy in Japan [8, 24].
The most common AEs in this study included hyper-
tension, PPES, decreased appetite, proteinuria, and fatigue,
which are well-known class effects of VEGF-targeted
therapies and are consistent with the known safety profile
of lenvatinib. Although the incidence of grade 3 hyper-
tension was high (54 %), this included patients whose
blood pressure was controlled by two or more antihyper-
tensive drugs. No patient required a dose modification or
discontinuation due to hypertension; therefore, it was
considered to be manageable. Although 65 % of patients
experienced PPES, the incidence of grade 3 PPES was only
9 %. The incidence of grade 3 or 4 thrombocytopenia was
also high (22 %); however, in all but one patient who
discontinued lenvatinib, thrombocytopenia was control-
lable with dose modifications. There was no report of grade
3 or higher bleeding related to the study drug. Although
hepatic encephalopathy was the most common SAE (five
patients) in this study, all five patients also had constipa-
tion, and three had dehydration—known risk factors for
Fig. 2 a Waterfall plot of
changes in tumor size by IRRC
assessment. One patient was
excluded from the plot due to
lack of IRRC assessment of
target legion at baseline. The
patient marked with an asterisk
showed a best overall response
of SD. b Representative liver
lesion of HCC at baseline on
arterial phase CT.
c Representative liver lesion on
arterial phase CT after 1 year of
lenvatinib treatment. CT
computed tomography,
HCC hepatocellular carcinoma,
IRRC independent radiologic
review committee,
PD progressive disease,
PR partial response,
SD stable disease, NE not
evaluable
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