safety and pharmacokinetics of lenvatinib in patients with ...cancer therapy: clinical safety and...

Cancer Therapy: Clinical

Safety and Pharmacokinetics of Lenvatinib inPatients with Advanced HepatocellularCarcinomaMasafumi Ikeda1, Takuji Okusaka2, Shuichi Mitsunaga1, Hideki Ueno2, Toshiyuki Tamai3,Takuya Suzuki3, Seiichi Hayato4, Tadashi Kadowaki5, Kiwamu Okita6, andHiromitsu Kumada7

Abstract

Purpose: To determine the maximum tolerable dose (MTD),safety, pharmacokinetics, pharmacodynamics, and preliminaryefficacy of lenvatinib in patients with advanced hepatocellularcarcinoma (HCC).

Experimental Design: This multicenter, open-label, phase I,dose-escalation study included patients aged 20 to 80 years,refractory to standard therapy, and stratified by hepatic functionmeasured using Child–Pugh (CP) scores: CP-A (score, 5–6) andCP-B (score, 7–8). Lenvatinib was administered continually oncedaily for 4-week cycles. MTD was defined as the maximum doseassociatedwith� 1dose-limiting toxicity (DLT) occurring in cycle1 among 6 patients.

Results: In total, 20 patients (9 in CP-A and 11 in CP-B) wereenrolled. TheMTDwas 12 and 8mg once daily in CP-A and CP-B,respectively; DLTs included proteinuria, hepatic encephalopathy,

and hyperbilirubinemia. The most common grade 3 toxicitiesincluded hypertension in CP-A and hyperbilirubinemia in CP-B.Lenvatinib plasma concentration at 24 hours after administration(C24 h) for 12mg once daily was higher in patients with HCC thanin patients with other solid tumors shown in a previous phase Istudy, but C24 h for 25 mg once daily lenvatinib was comparable.After lenvatinib treatment, the number of circulating endothelialand c-Kitþ cells decreased and the levels of interleukin (IL)-6, IL10,granulocyte-colony stimulating factor, and vascular endothelialgrowth factor increased (P < 0.05). Partial responses were observedin 3 patients and tumor shrinkage occurred in 14 patients.

Conclusions: Lenvatinib (12 mg once daily) demonstratedpreliminary efficacy with manageable toxicity and is the recom-mended dose for phase II studies in patients with HCC and CP-A.Clin Cancer Res; 22(6); 1385–94. �2015 AACR.

IntroductionAccording to World Health Organization estimates in 2012,

primary liver cancer is the fifth most common cancer, affectingover 780,000 patients worldwide, and is the second most com-mon cause of cancer-related mortality worldwide, with a higherincidence in Asia (1). Hepatocellular carcinoma (HCC) accountsfor 85% to 90% of primary liver cancer. Compromised hepaticfunction due to the underlying liver disease often complicatestreatment (2). The primary underlying risk factors for HCC arechronic viral hepatitis (types B and C), excessive alcohol intake,and exposure to aflatoxin, the contributions of which may varydepending upon geographical location (3).

HCC progression has been associated with growth factors suchas vascular endothelial growth factor (VEGF), platelet-derivedgrowth factor (PDGF), and fibroblast growth factor (FGF). VEGF

levels have been shown to correlate with angiogenic activity,tumor progression, and poor prognosis; its effects are mediatedby interactions with the tyrosine kinase receptors VEGFR-1,VEGFR-2, and VEGFR-3 (4).

Sorafenib is the current standard of care for advanced HCCpatients. In the SHARP study, the sorafenib group had animproved overall survival (OS) versus placebo (median OS,10.7 months and 7.9 months, respectively; ref. 5). However, theresponse rate was low, and several studies have reported substan-tial toxicities associated with sorafenib such as hand–foot skinreactions (6–10). Therefore, alternative agents with lower toxi-cities and higher efficacy are needed. To date, studies of otheragents, including the mTOR inhibitor (everolimus), and othertyrosine kinase inhibitors (TKI), including sunitinib, linifanib,brivanib, and erlotinib, have failed to demonstrate improvementsin OS (11–15).

Lenvatinib is an orally active inhibitor of multiple receptortyrosine kinases, VEGFR 1-3, FGFR 1-4, PDGFRa, RET (Rear-ranged during Transfection), and KIT (16–18). Lenvatinib hasshown promising antitumor efficacy in advanced solid tumors(16, 17, 19, 20). Preliminary studies suggested the use of up to 25mg once daily lenvatinib for solid tumors in phase I studies (19,20) and 24mg once daily was used as the starting dose in patientswith solid tumors in subsequent studies. Recently, Schlumbergerand colleagues in a phase III, double-blind, placebo-controlledtrial in patients with radioiodine-refractory differentiated thyroidcancer (SELECT) demonstrated improved progression-free sur-vival and manageable safety profiles with lenvatinib 24 mg once

1National Cancer Center Hospital East, Chiba, Japan. 2National CancerCenter Hospital, Tokyo, Japan. 3Clinical Development, Eisai Co., Ltd.,Tokyo, Japan. 4Clinical Pharmacology, Eisai Co., Ltd., Tokyo, Japan.5Biomarkers and Personalized Medicine Core Function Unit, Eisai Co.,Ltd., Tsukuba, Japan. 6Shunan Memorial Hospital, Yamaguchi, Japan.7Toranomon Hospital, Tokyo, Japan.

Corresponding Author: Masafumi Ikeda, National Cancer Center Hospital East,6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. Phone: 81-4-7133-1111; Fax:81-4-7133-0335; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-15-1354

�2015 American Association for Cancer Research.

ClinicalCancerResearch

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daily (21). However, since lenvatinib is metabolized in the liver(22) through a cytochrome P450 3A (CYP3A)-based mechanism(23), the impaired hepatic function in patients with HCC mayaffect lenvatinib exposure, and drug doses used in other tumortypes may not be appropriate in this patient group (24, 25).Therefore, dose-finding studies have been recommended inpatients with HCC stratified by Child–Pugh (CP) classes A andB (26).

We evaluated the maximum tolerable dose (MTD) of len-vatinib administered continually once daily for 4-week cyclesin patients with advanced HCC stratified by hepatic function,CP scores 5 to 6 (CP-A) and 7 to 8 (CP-B). In addition, weanalyzed biomarkers to evaluate the effect of lenvatinib onantiangiogenesis.

Materials and MethodsStudy design

This phase I, open-label, dose-escalation study of lenvatinibwas conducted at two investigational sites in Japan. All patientsprovided written informed consent, and the study was approvedby the institutional review boards of the respective medicalinstitutions. The study was conducted in accordance with theDeclaration of Helsinki and Good Clinical Practice guidelines.

After screening for eligibility, patients were divided into twogroups based on their CP scores. In the CP-A group, the startingdose was 12 mg once daily, which was approximately 50% ofthe MTD recommended for solid tumors (19, 20, 22); whenthis dose was considered tolerable [�1 dose-limiting toxicity(DLT) in 6 patients in cycle 1], dose escalation to 16 mg oncedaily and subsequently to 20 mg once daily was allowed foreach 6-patient cohort. Three CP-B group patients were assignedper dose level, starting with the lowest tolerable dose confirmedin CP-A. In both CP-A and CP-B groups, a lower dose level of 8mg once daily was planned if 12 mg once daily was nottolerable. DLTs observed in cycle 1 were defined as � grade4 hematologic toxicities, grade 3 thrombocytopenia requiringblood transfusion, any � grade 3 nonhematologic toxicity[except for laboratory abnormalities without treatment, con-trolled hypertension, aspartate aminotransferase (AST) or ala-nine aminotransferase (ALT) � 10 � upper limit of normal(ULN), or diarrhea/vomiting/nausea controlled by treatment),or any toxicity that necessitates the interruption of lenvatinib

for > 7 days. MTD was defined as the maximum dose associatedwith � 1 DLT occurring in cycle 1 among 6 patients.

Starting on day 1/cycle 1, each cycle comprised 4 weeks(28 days) of continuous lenvatinib administration until diseaseprogression, development of unacceptable toxicity, withdrawal ofconsent, subject request, or end of study. Once-daily oral doses oflenvatinib (Eisai Co., Ltd.) were administered on an emptystomach each morning. The concomitant use of strong CYP3A4inhibitors was prohibited. If a DLT or other toxicity occurred,lenvatinib was interrupted until recovery and restarted at areduced dose. All subjects who demonstrated a DLT or completedcycle 1 could continue treatment after additional writteninformed consent for continuation in the study was obtained.

Patient eligibilityPatients aged 20 to 80 years with a histologically or clinically

confirmed diagnosis of advanced HCC [hypervascularity in arte-rial phase and washout in venous or delayed phase by dynamiccomputed tomography (CT)] that was resistant to standard ther-apy e.g., transarterial chemoembolization, sorafenib (i.e., pro-gressive disease or intolerance to standard therapy) or for whichno standard therapy existed, with Eastern Cooperative OncologyGroup performance status (ECOG PS) of 0 to 1, < grade 2 toxicityfrom prior therapy, absolute neutrophil count (ANC) � 1.5 �103/mL, hemoglobin � 9.0 g/dL, platelet count � 50 � 109/L,serum albumin � 2.8 g/dL, total bilirubin � 3.0 mg/dL, ALT andAST � 5 times the ULN, international normalized ratio � 2.3,serum creatinine� 2.0mg/dL or calculated creatinine clearance�40 mL/minute. Perimenopausal women with amenorrhea for �12 months or women of childbearing potential, who were notpregnant, were eligible for inclusion. All women and fertile menhad to use adequate contraceptive methods during the study.

Patients were excluded if they had a history of medical condi-tions that could affect investigational drug absorption, brainmetastasis or meningeal carcinomatosis, pericardial or pleuraleffusion, ascites, a hemorrhagic or thrombotic event within 4weeks of study entry, significant cardiovascular disease, protein-uria,� grade 2 nausea, psychotic disorder, drug or alcohol abuse,progressive central nervous system disease, human immunode-ficiency virus (HIV) or other serious infections, an inadequatewashout period from prior therapy, treatments that affect theCYP3A4 enzyme, or were judged by the investigator to be med-ically unfit. Patients were withdrawn from the study if theyrequired dose reduction <4 mg, upon disease progression, or ifthey experienced an adverse event (AE) that prohibited continu-ation of study treatment or needed >14 days for recovery, or iftreatment compliance was <75%.

AssessmentsBlood samples were obtained for pharmacokinetic (PK) anal-

ysis on day 1 (predose and 0.5, 1, 2, 4, 6, 8, and 24 hourspostdose), day 8 (predose), day 15 (predose and 0.5, 1, 2, 4, 6,8, and 24 hours postdose), and day 22 (predose) of cycle 1.Lenvatinib was quantified using a validated liquid chromatogra-phy/mass spectrometrymethod. Predose blood samples for phar-macodynamic (PD) markers were collected on days 1, 8, 15, and22 (cycle 1). Circulating endothelial cells (CEC) and circulatingendothelial progenitor cells (CEP), which indicate active vascularturnover and angiogenesis (16, 27), were measured, as describedpreviously (20). Briefly, peripheral bloodmononuclear cells were

Translational Relevance

This phase I study is the first trial to investigate the efficacy,safety, pharmacokinetic, and pharmacodynamic of lenvatinibin patients with advanced hepatocellular carcinoma (HCC).This study demonstrated favorable safety and tolerability, andpreliminary antitumor activity of lenvatinib in patients withadvanced HCC. Pharmacodynamic studies suggested thatmultistep angiogenesis was inhibited by administration oflenvatinib at the doses used in this study. Antitumor activitywas demonstrated and tumor shrinkage was observed in 14patients. The findings also provide preliminary recommenda-tions for the use of 12-mg once-daily and 8-mg once-dailyregimens in CP-A and CP-B, respectively, in future studies inpatients with advanced HCC.

Ikeda et al.

Clin Cancer Res; 22(6) March 15, 2016 Clinical Cancer Research1386




incubatedwithfluorescein isothiocyanate-conjugated antihumanCD34 (Beckman Coulter, Inc.), PerPC-conjugated anti-humanCD45 (Becton Dickinson), phycoerythrin-conjugated antihumanCD117 (c-kit; Beckman Coulter, Inc.), and APC-conjugatedantihuman CD133 (Miltenyi Biotec K.K). The cells were thenwashed with phosphate-buffered saline and fixed in 4% parafor-maldehyde prior to fluorescence-activated cell sorting (FACS)analysis and measured by LSI Medience Corporation using aBD FACS Calibur HG cytometer and CellQuest software(Becton Dickinson). Plasma samples were analyzed in triplicatefor baseline and posttreatment levels of 10 angiogenic proteinsand cytokines using BioPlex PRO� human group I cytokine 6-Plex [VEGF, PDGF-BB, IL6, IL8, IL10, and granulocyte-colonystimulating factor (G-CSF)] and group II 3-plex [stem cell factor(SCF), stromal cell–derived factor-1a, and HGF] panel assays(Bio-Rad Laboratories Inc.) and the Invitrogen� FGF-basic sin-gleplex beadkit (Life Technologies) by LSIMedienceCorporation.

Safety assessments measured during the study included AEs,laboratory variables [hematology, chemistry, urinalysis, viraltests (HIV, hepatitis B and C), prothrombin time, thyroid-stim-ulating hormone (TSH), free thyroxine (FT)3, FT4, KL-6, humanchorionic gonadotropin], vital signs (systolic and diastolic

bloodpressure, pulse rate, and body temperature), height, weight,and physical examination. The severity of AEs was gradedaccording to Common Terminology Criteria for Adverse Events(CTCAE, version3.0). All AEswere codedby standardizedmedicalterminology using the Medical Dictionary for Regulatory Activ-ities (MedDRA version 17.0). Efficacy was assessed usingResponse Evaluation Criteria in Solid Tumors (RECIST, version1.1) by the investigator, and assessments were conducted every 8weeks.

Statistical analysisAll patients who received at least one dose of lenvatinib were

eligible for safety, efficacy, and PK analyses. Demographic andbaseline characteristics were summarized using descriptive statis-tics. The main efficacy parameter was time to progression (TTP),defined as duration from the time of study entry to the firstdocumentation of disease progression. Median TTP with 95%confidence interval (CI)was calculated andplotted using Kaplan–Meier product limit estimates stratified by the hepatic functiongroup.

The objective response rate (ORR) and disease control rate(DCR) were evaluated according to RECIST 1.1 and presented

Table 1. Demographic and baseline characteristics

Child–Pugh A Child–Pugh B Overall(n ¼ 9) (n ¼ 11) (N ¼ 20)

Median age, years (range) 62 (52–74) 65 (47–72) 63.5 (47–74)Gender, n (%)Female 3 (33) 0 (0) 3 (15)Male 6 (67) 11 (100) 17 (85)

ECOG-PS, n (%)0 5 (56) 8 (73) 13 (65)1 4 (44) 3 (27) 7 (35)

Child–Pugh score, n (%)5 4 (44) 0 (0) 4 (20)6 5 (56) 0 (0) 5 (25)7 0 (0) 10 (91) 10 (50)8 0 (0) 1 (9) 1 (5)

Ascites, n (%)Yes 3 (33) 11 (100) 14 (70)No 6 (67) 0 (0) 6 (30)

Portal vein invasion, n (%)Yes 5 (56) 3 (27) 8 (40)No 4 (44) 8 (73) 12 (60)

Extrahepatic metastasis, n (%)Yes 7 (78) 7 (64) 14 (70)No 2 (22) 4 (36) 6 (30)

Hepatic encephalopathy, n (%) 0 (0) 0 (0) 0 (0)BCLC stage, n (%)Stage B 1 (11) 2 (18) 3 (15)Stage C 8 (89) 9 (82) 17 (85)

Cause of HCC, n (%)Hepatitis B 4 (44) 3 (27) 7 (35)Hepatitis C 4 (44) 5 (46) 9 (45)Alcohol 1 (11) 2 (18) 3 (15)Unknown 0 1 (9) 1 (5)

Median AFP, ng/mL (range) 265 (4.3–52,000) 202 (2.3–43,800) 257.5 (2.3–52,000)Prior therapy, n (%)Surgery 3 (33) 5 (46) 8 (40)Chemoembolization 6 (67) 10 (91) 16 (80)Hepatic arterial chemotherapy 4 (44) 4 (36) 8 (40)Radiation 2 (22) 3 (27) 5 (25)

Prior systemic chemotherapy, n (%)Sorafenib 5 (56) 6 (55) 11 (55)Others chemotherapy 1 (11.1) 1 (9.1) 2 (10)None 3 (33.3) 4 (36.4) 7 (35.0)

Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG-PS, Eastern Cooperative Oncology Group performance status.

A Phase I Study of Lenvatinib in Advanced HCC

www.aacrjournals.org Clin Cancer Res; 22(6) March 15, 2016 1387




using (Clopper–Pearson) 95% CIs. ORR was defined as thenumber of patients with complete response (CR) þ partialresponse (PR) divided by the number of patients in the analysisset. DCR was defined as the number of patients with CR þ PR þstable disease (SD) divided by the number of patients in theanalysis set. PK parameters were estimated by noncompartmentalmethods on WinNonlin (version 6.2.1 or later) software. The PKprofile of lenvatinib in patientswithHCC from this studywas alsocompared with the PK profile of lenvatinib in patients withadvanced refractory solid tumors from a previously publishedstudy (19).

For the PD analysis, pretreatment versus posttreatment changesin the levels of each parameter were analyzed using the Wilcoxonsigned rank test. Statistical analyses were performed using SAS forWindows (version 8.2 or later), WinNonlin (version 6.2.1 orlater), and R (version 3.1.1 or later).

ResultsPatients

A total of 20 patients, 9 in the CP-A and 11 in the CP-B group,were enrolled in this study between August 3, 2009, and Novem-ber 22, 2011; all patients received the study treatment andcompleted the study. The median age (range) was 63.5 (47–74) years, 85% were men, and all patients were Asian. The ECOGPS was 0 in 65% patients and 1 in the remaining 35%. All 20patients had target lesions according toRECIST 1.1, and amajority(80%) of them exhibited� 4 liver tumors at baseline. In addition,8 (40%) patients had portal vein invasion and 14 (70%) hadextrahepatic metastasis. The most frequently reported carcino-genic factors for HCCwere hepatitis C (45% patients), hepatitis B(35% patients), and alcohol abuse (15% patients). No patienthad hepatic encephalopathy. Baseline and disease characteristicswere comparable between the CP-A and CP-B groups (Table 1).

Most patients (65%) had undergone targeted therapy/systemicchemotherapy, predominantly with sorafenib. Other prior anti-

cancer treatments included local therapy, such as transarterialchemoembolization (80%) and radiofrequency ablation (40%),hepatic intra-arterial chemotherapy (40%), surgery (40%), andradiotherapy (25%).

DLT and MTDOverall, DLTs occurred in 5 (25%) patients, 3 in the CP-A and 2

in theCP-B group. The initial dosewas 12mgonce daily in theCP-A group; since only 1 patient experienced a DLT (� grade 2 fever/vomiting) among 6 patients, the dose in the next cohort wasincreased to 16 mg. There were 2 reported DLTs in the 16-mgcohort (grade 3 proteinuria and grade 3 hepatic encephalopathy)among 3 patients. Thus, 16 mg was considered not tolerable and12 mg was determined to be the MTD for the CP-A group.

After theMTDdose was evaluated for the CP-A group, this dosewas evaluated in the CP-B group. One patient experienced grade 3hepatic encephalopathy and one patient experienced grade 3increased AST, grade 3 hyperbilirubinemia, and grade 2 increasedcreatinine as DLTs in 5 patients of the 12-mg cohort in the CP-Bgroup. Therefore, the dose was reduced to 8 mg. No DLTs wereexperienced among the 6 patients who received 8 mg lenvatinib;therefore, 8 mg lenvatinib was determined to be the MTD forpatients with CP-B hepatic function.

SafetyIncidences of AEs were generally comparable between the CP-A

and CP-B groups with the exception of hyperbilirubinemia of anygrade and grade 3 (CP-A, 22.2% and 11.1%; CP-B, 72.7% and27.3%, respectively), and any-grade increase in TSH levels (CP-A,66.7%; CP-B, 27.3%; Table 2). The most frequent treatment-emer-gent AEs included diarrhea (all grades, 90%; grade 3–4, 10%),fatigue (90%; 5%), decreased appetite (80%; 10%), hypertension(75%; 50%), hyperbilirubinemia (60%; 20%), palmar-plantarerythrodysesthesia syndrome (PPES; (65%; 5%), nausea (60%;0%), and vomiting (50%; 0%). Grade 3–4 AEs were reported in 7(77.8%) patients in the CP-A and 8 (72.7%) patients in the CP-B

Table 2. Most frequently reported adverse events in each dose cohort, presented as n (%)

Child–Pugh A Child–Pugh B12 mg (MTD) 16 mg 8 mg (MTD) 12 mg

AEs (n ¼ 6) (n ¼ 3) (n ¼ 6) (n ¼ 5)

Frequent AEs Any grade Grade 3–4 Any grade Grade 3–4 Any grade Grade 3–4 Any grade Grade 3–4Diarrhea 6 (100.0) 0 (0) 3 (100.0) 0 (0) 6 (100.0) 1 (16.7) 3 (60.0) 1 (20.0)Fatigue 5 (83.3) 0 (0) 3 (100.0) 0 (0) 5 (83.3) 0 (0) 5 (100.0) 1 (20.0)Decreased appetite 6 (100.0) 1 (16.7) 2 (66.7) 0 (0) 3 (50.0) 0 (0) 5 (100.0) 1 (20.0)Hypertension 5 (83.3) 4 (66.7) 3 (100.0) 2 (66.7) 3 (50.0) 2 (33.3) 4 (80.0) 2 (40.0)Palmar-plantar erythrodysesthesia syndrome 5 (83.3) 1 (16.7) 3 (100.0) 0 (0) 3 (50.0) 0 (0) 2 (40.0) 0 (0)Hyperbilirubinemia 2 (33.3) 1 (16.7) 1 (33.3) 0 (0) 5 (83.3) 1 (16.7) 4 (80.0) 2 (40.0)Nausea 2 (33.3) 0 (0) 3 (100.0) 0 (0) 3 (50.0) 0 (0) 4 (80.0) 0 (0)Vomiting 3 (50.0) 0 (0) 3 (100.0) 0 (0) 2 (33.3) 0 (0) 2 (40.0) 0 (0)Increased TSH 5 (83.3) 0 (0) 1 (33.3) 0 (0) 2 (33.3) 0 (0) 1 (20.0) 0 (0)Decreased weight 3 (50.0) 0 (0) 1 (33.3) 0 (0) 3 (50.0) 0 (0) 2 (40.0) 0 (0)Dysphonia 2 (33.3) 0 (0) 1 (33.3) 0 (0) 2 (33.3) 0 (0) 3 (60) 0 (0)Abdominal pain 2 (33.3) 0 (0) 1 (33.3) 0 (0) 3 (50.0) 0 (0) 2 (40.0) 0 (0)Peripheral edema 0 (0) 0 (0) 2 (66.7) 0 (0) 5 (83.3) 0 (0) 1 (20.0) 0 (0)Increased AST 4 (66.7) 1 (16.7) 0 (0) 0 (0) 0 (0) 0 (0) 3 (60.0) 2 (40.0)Pyrexia 2 (33.3) 0 (0) 1 (33.3) 0 (0) 3 (50.0) 0 (0) 1 (20.0) 0 (0)Proteinuria 2 (33.3) 0 (0) 2 (66.7) 1 (33.3) 1 (16.7) 0 (0) 2 (40.0) 0 (0)Ascites 0 (0) 0 (0) 0 (0) 0 (0) 3 (50.0) 0 (0) 3 (60.0) 0 (0)Stomatitis 3 (50.0) 0 (0) 0 (0) 0 (0) 2 (33.3) 0 (0) 1 (20.0) 0 (0)Thrombocytopenia 2 (33.3) 0 (0) 1 (33.3) 0 (0) 1 (16.7) 1 (16.7) 2 (40.0) 0 (0)Increased ALT 3 (50.0) 1 (16.7) 0 (0) 0 (0) 0 (0) 0 (0) 3 (60.0) 0 (0)Hypoalbuminemia 3 (50.0) 0 (0) 1 (33.3) 0 (0) 1 (16.7) 1 (16.7) 1 (20.0) 0 (0)

Ikeda et al.





group.Patientswere exposed toamean5.5 cycles of lenvatinib, anddose reductions were required in 14 (70%) patients.

Serious AEs (SAE)were reported in 4 patients in the CP-A and 6in the CP-B group. There were 2 deaths in the CP-B group thatoccurred due to hematemesis (8mg) or hepatic failure (12mg) asa result of progression of HCC after discontinuation of the studydrug. Both deaths were considered unrelated to the study drug bythe investigator. Other SAEs were hyperbilirubinemia (1 patientin the CP-A group and 1 patient in the CP-B group), tumorhemorrhage (2 patients in the CP-B group), and hepatic enceph-alopathy (1 patient in the CP-A and 1 patient in the CP-B group).

Major AEs leading to dose reduction were hyperbilirubinemia(3 patients in CP-B) and decreased appetite, hepatic encephalop-athy, and PPES (1 patient in CP-A and 1 in CP-B). Three patientsdiscontinued lenvatinib due to AEs; grade 2 abnormal hepaticfunction and grade 3 hepatic encephalopathy in 1 patient (CP-A,16 mg), grade 2 ascites in 1 patient (CP-B, 8 mg), and grade 2hyperbilirubinemia in 1 patient (CP-B, 12 mg).

PharmacokineticsFollowing oral administration, lenvatinib was absorbed rap-

idly, with maximum concentration reached within 2 hours. Inbothdose groups, exposure, asmeasuredbyCmax andAUC(0–24 h),increased with increasing lenvatinib dose (Table 3). Similarly,after administration over 15 days in both CP-A and CP-B groups,exposure, as measured by Css, max, C24 h, and AUC(0�t), increasedwith increasing lenvatinib dose. Plasma lenvatinib concentrationsincreased after repeated dosing, with a mean accumulation index(Rac) of AUC(0–24 h) andCmax ranging from1.23 to 2.11. The PKoflenvatinib did not appear to be affected by CP score.

Most of thePKparameterswere comparable between the12-mgCP-A and the 12-mg groups of patients with solid tumors, exceptC24 h, which was higher in the 12-mg CP-A group but comparablewith that of the 25mgMTD in solid tumors (Fig. 1).No conclusivecomparisons could be made in the 12-mg CP-B group because ofinsufficient data (n ¼ 2).

PharmacodynamicsThe total number of CEPs significantly decreased 15 days

posttreatment with lenvatinib compared with the baseline levels

(P < 0.05); this was attributable to a significant decrease in thenumber of c-Kitþ CEPs (P < 0.01), but not c-Kit� CEPs (P >0.05; Fig. 2A). The total number of CECs remained unchanged(P > 0.05), but the number of c-Kitþ CECs decreased significantly(P < 0.001) whereas c-Kit� CECs increased significantly (P <0.01; Fig. 2B).

Among the blood/plasma angiogenic factors and cytokinestested, the levels of IL6, IL10, G-CSF, and VEGF increased signif-icantly (P� 0.01), whereas those of SCF decreased (P < 0.001) onday 15 posttreatment compared with baseline levels (Fig. 2Cand D).

Efficacy (Antitumor Response)Therewas no complete response. Partial responsewas observed

in 1 patient in each of the CP-A 12-mg, CP-A 16-mg, and CP-B8-mg groups. The ORR was 22.2% (2/9) in the CP-A and 9.1%(1/11) in the CP-B group. Overall, 10 patients (50.0%) had a bestoverall tumor response of stable disease: 4 in the CP-A group(2 each in the 12-mg and 16-mg cohorts) and 6 in the CP-B group(4 in the 8-mg and 2 in the 12-mg cohorts). Progressive diseaseoccurred in 2 (22.2%), 4 (36.4%), and 6 (30.0%) patients in theCP-A group, CP-B group, and in the overall study, respectively.The DCR was 66.7% in the CP-A and 63.6% in the CP-B group.The overall ORR and DCR were 15.0% (95% CI, 3.2–37.9) and65.0% (95% CI, 40.8–84.6), respectively. Any tumor shrinkagefrom baseline was observed in 14 patients, 7 each in the CP-AandCP-B groups (Fig. 3A). Themedian TTPwas 5.4months (95%CI, 1.10–7.50) in the CP-A and 3.6 months (95% CI, 1.00–9.20)in the CP-B group (Fig. 3B). Figures 3C and D depict CT imagesof a single patient treated with lenvatinib. The levels of alpha-fetoprotein (AFP) had reduced for a majority of patients andaligned with improvement in tumor response (Supplemen-tary Fig. S1).

DiscussionThis is the first study to investigate the efficacy, safety, PK, and

PD of lenvatinib in patients with advanced HCC. Based on theoccurrence ofDLTs, theMTD for theCP-A andCP-B groupswas 12mg once daily and 8 mg once daily, respectively. These MTDs are

Table 3. Summary of pharmacokinetic parameters

HCC, Child–Pugh A HCC, Child–Pugh B Solid tumor12 mg (MTD) 16 mg 8 mg (MTD) 12 mg 12 mg 25 mg (MTD)

Parameter Unit (n ¼ 6) (n ¼ 3) (n ¼ 6) (n ¼ 5) (n ¼ 11) (n ¼ 24)

Single dose AUC(0–24 h) ng�h/mL 2020 (170) 3280 (961) 1250 (399) 2140 (1030) 1655 (555) 4075 (1666)Cmax ng/mL 212 (70.8) 344 (166) 146 (56.9) 254 (169) 260 (108) 631 (234)tmax h 2.00 (0.97, 5.95) 1.97 (0.97, 4.00) 2.02 (0.50, 3.93) 2.00 (1.00, 3.98) 2.53 (0.98, 5.05) 1.53 (0.98, 3.00)t1/2 h 7.19 (0.77)a 8.18 (2.36) 9.10 (2.28) 10.1 (4.1) 6.0 (0.5)b,f 5.9 (1.0)c

CL/F L/h 5.30 (0.34)a 4.33 (0.83) 5.99 (2.25) 5.76 (3.35) 6.6 (1.3)f 6.9 (3.4)c

Multiple dose AUC(0�t) ng�h/mL 3120 (566)a 5110 (976)d 1770 (340) 3960 (1990)d 2059 (792)e 4236 (1127)g

Css, max ng/mL 346 (75.4)a 402 (62.9)d 167 (40.4) 349 (180)d 291 (146)e 545 (183)g

C24 h ng/mL 43.1 (21.7)a 84.6 (33.1)d 29.9 (13.4) 64.0 (34.7)d 22.3 (7.4)f 45.1 (20.2)a

tss, max h 1.95 (1.00, 3.98)a 3.92d (3.83, 4.00) 2.03 (1.98, 4.02) 2.00 (1.97, 2.02)d 1.54 (0.97, 4.98)e 2.84 (1.33, 4.92)g

t1/2, ss h 8.76 (2.62)a 8.98 (2.15)d 10.2 (3.1) 9.74 (0.933)d 6.9 (1.2)e 6.0 (0.7)g

CLss/F L/h 3.95 (0.78)a 3.19 (0.608)d 4.69 (1.07) 3.47 (1.75)d 6.9 (3.4)e 6.4 (2.3)g

NOTE: AUC(0–24 h), area under the concentration–time curve from zero time to 24 hours; AUC(0�t), area under the concentration–time curve over the dosing intervalon multiple dosing; Css, max, maximum observed concentration at steady state; CL/F, oral clearance; CLss/F, oral clearance at steady state; tmax, time at which drugconcentration is the highest; tss, max, time at which the highest drug concentration occurs at steady state; t1/2, terminal elimination phase half-life; C24 h, plasmaconcentration at 24 hours after administration. The number of patients receivingmultiple doses in each of the following groups: CP-A 12mg, CP-A 16mg, CP-B 8mg,CP-B 12 mg, solid tumor 12 mg, and solid tumor 25 mg equals 5, 2, 6, 2, 8, and 4, respectively.Data are represented as mean (SD), except for tmax and tss, max, which are represented as median (minimum � maximum).an ¼ 5; bn ¼ 11; cn ¼ 23; dn ¼ 2; en ¼ 8; fn ¼ 10; gn ¼ 4.






recommended for further clinical studies of lenvatinib in patientswithHCC stratifiedby liver function.DLTs in this study included aclass effect of VEGF-R inhibitors (i.e., proteinuria) in the CP-Agroup and hepatic events such as hepatic encephalopathy andincreased AST and bilirubin levels in both CP-A and CP-B groups.Thesefindings deviate fromprevious studies of patientswith solidtumors (and unspecified hepatic function); hepaticDLTs have notbeen reported in other phase I studies of once-daily regimen oflenvatinib and only rarely in those with twice-daily regimens (19,20). Although previous phase I studies have evaluated theMTD as25mgonce daily or 10 to 13mg twice dailywith orwithout anoff-treatment period, 25 mg once daily has been recommended forfuture studies because this dose permits higher exposure (19,20, 22).

Moreover, 24 mg once daily is also the recommended dose inJapanese patients with solid tumors, and no differences wereobserved in PK profiles between Japanese and non-Japanese

patients (18). Considering that lenvatinib is metabolized in theliver, and patients with HCC have impaired liver function, thelower MTD in CP-A and CP-B observed in this study of patientsfrom Japan with advanced HCC is likely explained by tumor typeand hepatic function, and not by ethnic differences.

The patient profile in this study was similar to that of previousreports of Japanese HCC patients, with the exception of a rela-tively higher rate of hepatitis B infection as a cause of HCC in thisstudy (28–30). There was no notable difference between patientswith and without prior exposure to sorafenib with respect to AEsand biomarkers. The preliminary evidence for efficacy and safetyof lenvatinib for patients with HCC aligned with that obtainedfrom previous studies on solid tumors. As reported earlier, thesafety profile of lenvatinib included the common toxicities ofVEGFR-TKIs, such as hypertension, diarrhea, anorexia, protein-uria, and PPES (18–20, 30). However, it is noteworthy thathepatic encephalopathy and hyperbilirubinemia have not been

Figure 1.Mean � standard deviation plasmaconcentration–time curves oflenvatinib after single dose (A) andmultiple doses (B) for HCC and solidtumor.

Ikeda et al.





reported in previous clinical trials of lenvatinib for solid tumors;such events could be expected due to the impaired liver functionof patients with advanced HCC.

The PK profile of 12-mg lenvatinib in patients with HCC andCP-A hepatic function might be different from that of patientswith solid tumors who received 12 and 25 mg lenvatinib in aprevious study. After administration of a single dose, the Cmax of12mg lenvatinib in the CP-A group was similar to that in patientswith solid tumors who received a 12 mg dose, but lower than inthose who received 25 mg. However, since lenvatinib oral clear-ance after administration of multiple doses in patients with HCCwas decreased in this study, the C24 h of 12 mg in the CP-A group

washigher than that in patientswith solid tumorswho received12mg lenvatinib, and was comparable to that of those who received25 mg. Shumaker and colleagues (31) showed that lenvatinibAUCs and oral clearance were similar for single-dose administra-tion between healthy subjects and those with mild (CP-A) ormoderate (CP-B) hepatic impairment. The reason for the discrep-ancy in PK outcomes related to hepatic impairment betweensubjects without HCC and patients with HCC is unknown, butmay result from differences in underlying hepatic etiology (32).The higher C24 h and different DLT profile observed in patientswith HCC may contribute to the lower MTD determined in thisstudy.

Figure 2.ToquantifyCECsandCEPs, a number ofCD34-positive andCD45-negative cellswere isolated, andCD133-negative cells andCD133-positive cellsweredetermined asCECs and CEPs, respectively. CECs and CEPs were divided into c-Kit–positive (c-Kitþ) and –negative (c-Kit�) subpopulations. C-Kitþ ratio (%) was calculatedas (c-Kitþ CEC or CEP)/(total CEC or CEP). The figure depicts change in the number of CEPs (A), number of CECs (B), and levels of biomarkers from predosebaseline to day 15 (C and D:). Data points for G-CSF, IL6, IL8, IL10, PDGF-BB, and VEGF of one subject, IL6 of a second subject on day 15, and PDGF-BB of athird subject were beyond the scale and are not shown in the plots, although they were included in the data analysis.






Figure 3.A, assessment of tumor response according to RECIST 1.1 using the waterfall plot displaying percentage change from baseline in sums of lesion diameters;B, Kaplan–Meier plot of time to progression (TTP) presented for individual patients of both hepatic function groups: Child–Pugh score 5,6 and Child–Pughscore 7, 8 þ censored observations. Computed tomographic image of a single patient at baseline (C) and posttreatment (D) with lenvatinib.

Ikeda et al.





Prognostic and predictive biomarker analyses can be useful inidentifying potential responders to treatment for various types ofcancers. A preclinical study by Matsui and colleagues (2008)showed that 1-week lenvatinib treatment increased CEC number,whereas a 3-week treatment reduced it to basal levels (16).Similarly, while there was no change in overall CEC numbers inour study, the number of CECs and CEPs negative for c-Kitexpression had increased and those positive had reduced frombaseline. c-Kit and its ligand SCF are expressed on activatedendothelial cell layers and play a key role in the survival anddifferentiation of cultured endothelial cell and inCEP recruitmentduring tumor growth and vascularization (20). Lenvatinib sup-pressed production of c-Kitþ CEPs, which might be caused byinhibition of recruitment of CEPs, thus normalizing tumor angio-genesis (16, 33).

Furthermore, there was an increase in levels of IL6, IL10, G-CSF,and VEGF PD biomarkers that are important mediators of angio-genesis. For example, elevations inG-CSF andVEGF plasma levelsimmediately after anticancer treatment are associated with mobi-lization of CEPs, which contributes to the regrowth of tumors(34). IL6 is a multifunctional cytokine that correlates with tumorsize and IL10 is an immunosuppressive factor that has beenimplicated in the disease prognosis of solid tumors. The inhib-itory effect of lenvatinib on VEGF signaling has been evaluated inpreclinical studies; VEGF-induced growth of human endothelialcells was suppressed by lenvatinib (35). The increase in VEGFlevels observed in this study suggests that lenvatinib inhibited theVEGF-signaling pathway. Changes in levels of various PDmarkersin this study suggested that multistep angiogenesis was inhibitedby administration of lenvatinib at the doses used in this study.

We also demonstrated antitumor activity of lenvatinib that wassimilar in both the CP-A and CP-B groups. Tumor shrinkage wasobserved in 14 patients (7 each in the CP-A and CP-B groups).Confirmed PR and DCR in the CP-A group were 22.2% (2patients) and 66.7% (6 patients), respectively, with the medianTTPof 5.40months in theCP-A group.Of the 3 patientswith PR, 2had prior exposure to sorafenib. These efficacy findings are com-parable to those in a phase III study (28) and a Japanese phase Istudy of sorafenib in HCC (10).

In conclusion, MTDs in patients with HCC were determined inthe present phase I study; this study demonstrated favorable safetyand tolerability, and preliminary antitumor activity of lenvatinibin patients with advanced HCC. Considering the DLT profile, ourfindings provide preliminary recommendations for the use of 12-mg once-daily and 8-mg once-daily regimens in future studies inpatients with advanced HCC (CP-A or CP-B class, respectively).Further studies to evaluate the efficacy, includingOS, of lenvatinibin patients with HCC, enrolling larger numbers of patients andwith longer follow-up periods, are needed to confirm ourfindings.

Disclosure of Potential Conflicts of InterestT. Okusaka reports receiving commercial research grants from AstraZeneca

K.K, Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Dainippon

Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K.,KowaCompany, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Serono Co., Ltd.,Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Onco Ther-apy Science, Inc., Ono Pharmaceutical Co., Ltd., Otsuka PharmaceuicalCo., Ltd., Pfizer Japan Inc., Sceti Medical Labo K.K., Shizuoka Industry,Taiho Pharmaceutical Co., Ltd., Takeda Bio Development Center Limited,and Yakult Honsha Co., Ltd.; speakers bureau honoraria from BayerYakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Dainippon SumitomoPharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Merck SeronoCo., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., and Taiho PharmaceuticalCo., Ltd.; and is a consultant/advisory board member for Amgen, ChugaiPharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eli LillyJapan K.K., Nano Carrier Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd.,Nobelpharma Co., Ltd., Novartis Pharma K.K., Onco Therapy Science, Inc.,Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., YakultHonsha Co., Ltd., and Zeria Pharmaceutical Co., Ltd. S. Mitsunaga reportsreceiving commercial research grants from Eisai. H. Uneo reports receivingspeakers bureau honoraria from Taiho Pharmaceutical Co., Ltd., andYakult Honsha Co., Ltd. T. Kadowaki has ownership interest (includingpatents) in Eisai Co Ltd. K. Okita is a consultant/advisory board member forEisai Co., Ltd., and Kowa Co., Ltd. H. Kumada reports receiving speakersbureau honoraria from Bristol-Myers Squibb, GlaxoSmithKline, JANSSEN,and MSD. No potential conflicts of interest were disclosed by the otherauthors.

Authors' ContributionsConception and design:M. Ikeda, T. Okusaka, T. Suzuki, K. Okita, H. KumadaDevelopment of methodology: M. Ikeda, T. Okusaka, T. Tamai, T. Suzuki,Seiichi Hayato, Tadashi Kadowaki, Kiwamu Okita, Hiromitsu KumadaAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): M. Ikeda, T. Okusaka, S. Mitsunaga, H. UenoAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis):M. Ikeda, T. Okusaka, T. Tamai, T. Suzuki, S. Hayato,T. Kadowaki, K. Okita, H. Kumada, Shuichi Mitsunaga, Hideki UenoWriting, review, and/or revision of the manuscript: M. Ikeda, T. Okusaka,S.Mitsunaga,H.Ueno, T. Tamai, T. Suzuki, K.Okita,H.Kumada, SeiichiHayato,Tadashi KadowakiAdministrative, technical, or material support (i.e., reporting or organizingdata, constructing databases):M. Ikeda, T. Okusaka, T. Tamai, Takuya Suzuki,Seiichi Hayato, Tadashi KadowakiStudy supervision: T. Tamai, K. Okita, H. Kumada, Takuya Suzuki

AcknowledgmentsThe authors thank all the patients who participated and their families, as well

as the investigators, physicians, nurses, and clinical research coordinators whohelped with this study; the Efficacy and Safety Evaluation Committee: Drs. J.Furuse (Kyorin University School of Medicine), K. Koike (The University ofTokyo) and S. Arii (Hamamatsu Rosai Hospital). Medical writing services wereprovided by Cactus Communications (funded by Eisai Co., Ltd.). All authorsretained full control over the manuscript content.

Grant SupportThe study was funded by Eisai Co., Ltd., Japan.The costs of publication of this article were defrayed in part by the

payment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received June 9, 2015; revised September 21, 2015; accepted October 13,2015; published OnlineFirst October 23, 2015.

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Ikeda et al.




2016;22:1385-1394. Published OnlineFirst October 23, 2015.Clin Cancer Res Masafumi Ikeda, Takuji Okusaka, Shuichi Mitsunaga, et al. Advanced Hepatocellular CarcinomaSafety and Pharmacokinetics of Lenvatinib in Patients with

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