Lenvatinib: First Global Approval
Lesley J. Scott1
ti Springer International Publishing Switzerland 2015
Abstract Lenvatinib (LenvimaTM) is a multitargeted
receptor kinase inhibitor that inhibits the kinase ac- tivities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor a, RET and KIT. In addition to their role in normal cellular function, these kinases have been implicated in patho- genic angiogenesis, tumour growth and cancer progres- sion. Lenvatinib is being developed by Eisai Co. Ltd for the treatment of solid tumours, primarily for differenti- ated thyroid cancer, and other malignancies. A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic, progres- sive, radioactive iodine-refractory differentiated thyroid cancer. Lenvatinib is in pre-registration for this indica- tion in the EU, Australia, Brazil, Canada, Japan, South Korea, Russia, Singapore and Switzerland, and is in phase 3 development in Argentina, Chile and Thailand. Lenvatinib has orphan designation in the EU and Japan for use in differentiated thyroid cancer. In addition, an ongoing global, phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma. This article summarizes the
this first approval in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.
1Introduction
Thyroid cancer is one of the most prevalent endocrine malignancies, with an age-standardized rate of 15.1 per 100,000 females in North America and 5.8 per 100,000 females in Western Europe [1–3]. Thyroid cancers are categorized into four major histological types consisting of papillary (80–85 % of cases), follicular (11 %), medullary (3–4 %) and anaplastic (1–2 %) [1–3]. Most patients with thyroid cancer have a very good prognosis [5-year overall survival (OS) rate of 98 %], with treatment involving surgery, thyroid-stimulating hormone-suppressive therapy and, in patients with differentiated (i.e. papillary plus fol- licular) thyroid cancer, radioactive iodine (RAI) ablation [1]. However, for patients with RAI-refractory thyroid cancer, treatment options are limited and the prognosis is poor [1, 2].
An improved understanding of molecular signalling pathways involved in normal physiological cellular functions and also implicated in the pathogenesis of tu-
This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.
& Lesley J. Scott [email protected]
mour growth and cancer progression, has led to the de- velopment of targeted therapies, including multikinase inhibitors for the treatment of RAI-refractory thyroid cancer (e.g. lenvatinib, pazopanib, sorafenib and vande- tanib [1–3]. Receptor tyrosine kinases (RTKs) located in the cell membrane play a central in the activation of signal transduction pathways involved in the normal
1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand
regulation of cellular processes, such as cell proliferation, migration, apoptosis and differentiation, and in
Features and properties of lenvatinib
Alternative names E 7080; E-7080; E7080; ER 20349200; ER-203492-00; lenvatinib mesylate; LenvimaTM
Class Amides, Chlorobenzenes, Cyclopropanes, Phenyl-ethers, Quinolines, Small-molecules, Urea-compounds
Mechanism of action Inhibits the kinase activities of vascular endothelial growth factor receptors 1–3,
fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor a, KIT and RET Route of administration Oral
Pharmacodynamics Inhibits multiple tyrosine kinases that have been implicated in pathogenic
angiogenesis, tumour growth and cancer progression, in addition to their normal cellular functions, including 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor a, KIT and RET
Pharmacokinetics Rapidly absorbed and slowly eliminated; metabolized by cytochrome
P450 3A and aldehyde oxidase Adverse reactions
Most frequent (incidence C30 % in SELECT trial)
Hypertension, diarrhoea, fatigue or asthenia, decreased appetite, bodyweight decreased, nausea, stomatitis, palmar-plantar erythrodysethaesia syndrome, proteinuria
ATC codes
WHO ATC code L01X-E (protein kinase inhibitors)
EphMRA ATC code L1X4 (antineoplastic protein kinase inhibitors)
Chemical name 4-[3-chloro-4-(3-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide
pathogenic angiogenesis, lymphogenesis, tumour growth and cancer progression. Key intracellular signalling pathways involved in the development of thyroid cancers include the mitogen-activated protein kinase (MAPK) pathway, the rat sarcoma (RAS)/B-type rapidly acceler- ated fibrosarcoma (BRAF)/mitogen-activated protein ki- nase (ERK)/extracellular signal-activated protein kinase (MEK) pathway and the phosphatidylinositol-3 kinase (P13K)/protein kinase B (AKT)/mammalian target of ra- pamycin (mTOR) pathway. The binding of specific li- gands to RTKs triggers these intracellular signal transduction pathways, with mutations at various steps in these pathways potentially associated with dysregulation of normal physiological function. RTKs involved in the MAPK, RAS/BRAF/ERK/MEK and P13K–AKTmTOR pathways include vascular endothelial-derived growth factor receptors (VEGFR; pivotal pro-angiogenic factor),
progressive, RAI-refractory differentiated thyroid cancer in the USA at an oral dosage of 24 mg once daily [4, 8]. Its approval in the USA in this indication was based on the phase 3, double-blind, multinational SELECT trial [9]. The drug is also in pre-registration for this indication in Aus- tralia, Brazil, South Korea, Japan, Switzerland, Canada, Singapore, Russia and Europe [10], and is in phase 3 de- velopment in Argentina, Chile and Thailand. Lenvatinib has orphan designation for use in differentiated thyroid cancer in the EU and Japan [11, 12]. In addition, an on- going global, phase 3 trial (NCT01761266) is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma, and global phase 2 and phase 1/2 trials are evaluating its use for several other malignancies, including melanoma, renal cell carcinoma and non-small cell lung cancer (NSCLC) [10].
rearranged during transcription tyrosine kinase (RET) and fibroblast growth factor receptors (FGFR) [1–3]. Lenva- tinib (LenvimaTM) is a small molecule, multikinase in- hibitor that inhibits the kinase activities of VEGFR1 [also
H
N
H
N
known as fms-related tyrosine kinase 1 (FLT1)], VEGFR2 (or kinase insert domain receptor) and VEGFR3 (or
H
O
O
Cl
O
FLT4), FGFR 1–4, platelet-derived growth factor (PDGF) H
receptor a, KIT (or stem cell factor receptor or CD117)
N
and RET [4–7].
Lenvatinib is being developed by Eisai Co. Ltd as an
H
H
O
N
anticancer agent and was approved by the US FDA in February 2015 for locally recurrent or metastatic,
H
Chemical structure of lenvatinib
1.1Company Agreements
Eisai entered into a strategic collaboration agreement with Quintiles in October 2009 to develop six anticancer com- pounds [13]. Quintiles will conduct phase 1b/2 proof-of- concept studies for 11 tumour indications and Eisai will continue ongoing development for 18 other cancer indi- cations. Lenvatinib is one of the six anticancer compounds included in this collaboration [13].
In September 2011, Eisai entered into a collaborative development agreement with SFJ Pharma, a wholly-owned subsidiary of SFJ Pharmaceuticals Group, to help provide funding for phase 3 studies of lenvatinib in thyroid cancer [14]. Under this agreement, Eisai will conduct the studies and SFJ Pharma will wholly fund them. Eisai will make milestone payments to SFJ Pharma only if lenvatinib re- ceives regulatory approval. Commercial rights will remain with Eisai [14].
In February 2015, Eisai announced that Biologics Inc. was selected as a speciality pharmacy provider for lenva- tinib, within its limited distribution network, for the treat- ment of radioactive iodine-refractory thyroid cancer [15].
2Scientific Summary
2.1Pharmacodynamics
Based on x-ray crystallography and kinetic interaction studies, lenvatinib binds to the adenosine 50 -triphosphate binding site of VEGFR2 and to a neighbouring region via a cyclopropane ring and thereby inhibits tyrosine kinase ac- tivity and associated signalling pathways, with this binding differing from that of other VEGFR2 kinase inhibitors [16]. Lenvatinib bound with an equilibrium dissociation constant of 2.1 nmol/L (vs. 33 and 30 nmol/L with sorafenib and sunitinib) and had a residence time of 17 min (vs. 64 and \2.9 min, respectively) [16].
In preclinical in vitro studies in human cancer cell lines and in vivo studies involving a broad spectrum of human tumour xenograft models, including thyroid, melanoma and hepatocellular xenograft models and a RET gene fusion-driven tumour model (with RET gene fusions associated with thyroid and lung cancers), len- vatinib exhibited potent antitumour activity via inhibi- tion of tyrosine kinase activities of VEGFR 1–3 and other pro-angiogenic and oncogenic pathway-related RTKs [5–7, 17–20]. In an in vitro assay of angiogenesis, lenvatinib inhibited VEGFR- and FGFR-induced prolif- eration and tube formation of human umbilical vein endothelial cells [18]. Lenvatinib treatment also inhib- ited angiogenesis and FGFR and RET signalling
pathways in human differentiated, anaplastic and medullary thyroid cancer xenograft mouse models [17]. In cultured thyroid cancer cell lines, lenvatinib inhibited cell proliferation in 2 of 11 lines, and inhibited phos- phorylation of FGFR1 and its downstream effector FGFR substrate 2 (FRS2) [17]. Lenvatinib (typically at concentrations of 30–100 nmol/L) inhibited pro-onco- genic RET gene fusion signalling in human thyroid and lung cancer cell lines, including inhibition of anchorage- dependent and -independent growth and oncogenic ac- tivity of these RET gene transformed cell lines [19]. Lenvatinib also suppressed tumour growth and sig- nificantly decreased microvessel density in mouse RET gene fusion driven tumour models. In ex vivo analyses, lenvatinib treatment reduced phosphorylation of KIFB- RET and MAPK (also known as extracellular signal- regulated kinases; ERK) in mice with NIH3T3/KIF5B- RET tumours [19]. Lenvatinib also reduced microvessel density and inhibited angiogenesis in human sarcoma xenografts resistant to at least one or more clinically relevant reference drugs (doxorubicin, cisplatin or ifos- famide given at the maximum tolerated dose) [20]. Since lenvatinib inhibits both VEGFRs and FGFRs, the drug may provide a mechanism of overcoming resistance to drugs that only inhibit VEGF/VEGFR [2]
In phase 1 and 2 studies, oral lenvatinib exhibited an- titumour activity against a variety of tumour types [21–27], including unresectable advanced medullary thyroid cancer [22] and advanced hepatocellular carcinoma [26]. Results from these trials, most of which are ongoing, are discussed in Sect. 2.3. In phase 1 dose-escalation study in patients with advanced solid tumours, oral lenvatinib was associ- ated with tumour shrinkage and changes in plasma angio- genic proteins (potential biomarkers for lenvatinib-induced antitumour activity), including increasing plasma VEGF and stromal cell-derived factor 1a (SDF1a) levels and decreasing plasma levels of soluble VEGFR2 [28]. These changes occurred in a dose-dependent manner, with max- imum tumour shrinkage correlated with increases in plas- ma SDF1a levels [28].
In a thorough QT study, lenvatinib (single 32 mg dose; i.e. 1.39 recommended daily dose) had no clinically rele- vant effect on the corrected QT interval in healthy volun- teers [29]. However, QT interval prolongation was observed in the phase 3 SELECT trial in patients with RAI- refractory thyroid cancer [4], as discussed in Sect. 2.4.
2.2Pharmacokinetics
In patients with solid tumours, exposure to lenvatinib was dose-proportional after single and multiple doses across a dose range of 3.2–32 mg, with a medium accumulation
index of 0.96 (20 mg dose) to 1.54 (6.4 mg dose) [4]. Maximum plasma concentrations (Cmax) were typically attained 1–4 h postdose. In vitro, lenvatinib was highly protein bound (98–99 %) and the blood-plasma ratio ran- ged from 0.59 to 0.61 [4]. In healthy volunteers, the pharmacokinetics of lenvatinib did not differ to a clinically relevant extent between the fasted and fed state [30]. Lenvatinib is primarily metabolized in humans via enzy- matic [primarily cytochrome P450 (CYP) 3A4; also alde- hyde oxidase] and non-enzymatic processes [4]. Plasma levels of lenvatinib decline bi-exponentially after Cmax is attained, with a terminal elimination half-life (tti ) of *28 h [4]. In patients with solid tumours, *64 % of ra- dioactive lenvatinib was eliminated in the faeces and *25 % in the urine [4, 31].
Lenvatinib has a low potential for drug–drug interactions, based on clinical [32, 33] and in vitro studies [4]. In vitro studies indicated that lenvatinib is a substrate for P-glyco- protein (P-gp) and breast cancer resistant protein (BCRP), but not for organic anion transporters (OAT1 and OAT3), organic anion transporting polypeptides (OATP1B1 and OAT1B3), organic cation transporters (OCT1 and OCT2) or the bile salt export pump [4]. No dosage adjustments are required when lenvatinib is coadministered with CYP3A4 (e.g. ketoconazole [32]), P-gp (e.g. rifampicin [33]) and BCRP inhibitors, and CYP3A4 and P-gp inducers (e.g. ri- fampicin [33]) [4].
In patients with severe hepatic impairment, exposure to lenvatinib (single 5 mg dose) was increased by 170 % and tti was prolonged (37 vs. 23 h in healthy volunteers) [34]; thus, in patients with severe hepatic impairment, the rec- ommended dosage is 14 mg once daily [4]. No dosage adjustments are required in patients with mild or moderate hepatic or renal impairment [4]. After a single 24 mg dose, exposure to lenvatinib was similar in patients with renal impairment to that in healthy volunteers; patients with end- stage renal disease were not studied [4]. In patients with severe renal impairment, the recommended dosage is 14 mg once daily [4].
2.2.3Therapeutic Trials
2.2.3.1Thyroid Cancer
In SELECT, patients with RAI-refractory thyroid cancer and confirmed radiographical evidence of disease progression within the previous 13 months were randomized to oral len- vatinib 24 mg once daily (n = 261) or placebo (n = 131) in 28-day cycles, with treatment continuing until the occurrence of unacceptable disease progression. Incremental dosage re- ductions were permitted based on tolerability. Eligible pa- tients were stratified according to age, geographic region, and whether or not they had previously received tyrosine kinase
inhibitor (TKI) therapy. Placebo recipients with radio- graphical evidence of disease progression could elect to enter the open-label lenvatinib phase. The primary endpoint was progression-free survival (PFS), based on Kaplan–Meier methods, with the primary analysis conducted after at least 214progressioneventsordeathshadoccurred(220events had occurred at the time of the primary analysis) [9].
Lenvatinib treatment significantly prolonged median PFS compared with placebo at the time of the primary analysis [18.3 vs. 3.6 months; hazard ratio (HR) for pro- gression or death 0.21; 95 % CI 0.14–0.31; p \ 0.001] [9]. Sensitivity analyses showed that median PFS was pro- longed in all prespecified subgroups, including based on age, sex, race, prior or no prior treatment with a TKI, geographic region, histological findings (papillary, poorly differentiated, follicular and Hu¨rthle-cell) and baseline thyrotropin level. Overall response rates were significantly higher in the lenvatinib group than in the placebo group (64.8 vs. 1.5 %; odds ratio 28.87; 95 % CI 12.46–66.86; p \ 0.001), with 1.5 % and no patients achieving a com- plete response, 63.2 and 1.5 % achieving a partial response and 23.0 and 54.2 % having stable disease. The median OS time had not been reached in either treatment group at the time of this primary analysis. In evaluable patients who entered the open-label phase, median PFS was 10.1 months and the overall response rate was 52.3 %, including one complete response and 56 partial responses [9].
In a phase II trial, response rates based on an indepen- dent imaging review and investigator assessments were 36 % (95 % CI 24–49) and 49 % (95 % CI 36–62), re- spectively, in patients receiving lenvatinib 24 mg once daily [22]. This study enrolled patients with unresectable advanced medullary thyroid cancer who had disease pro- gression in the previous 12 months (n = 59) [22].
2.2.3.2Hepatocellular Cancer
In a phase 1/2 study conducted in Japan and Korea in patients with advanced hepatocellular cancer and Child- Pugh class A liver function (n = 42 evaluable), 14 patients treated with lenvatinib (initial dosage 12 mg once daily) had confirmed partial responses, as assessed by investiga- tors in an initial analysis [26]. In a subsequent analysis (n = 46), the median time-to-progression was 12.8 months and median OS time was 18.7 months [35].
Based on results from this phase 1/2 study, an open-label, multinational, phase 3 trial (NCT01761266) will evaluate the noninferiority or superiority of lenvatinib to sorafenib as first-line treatment in patients with unresectable hepatocel- lular cancer (estimated enrolment of 940 patients) [35]. Pa- tients will be randomized to oral lenvatinib 8 or 12 mg once daily (based on bodyweight) or sorafenib 400 mg twice daily. The primary endpoint is median OS [35].
2.2.3.3Other Cancers
Lenvatinib has also been evaluated in multicentre (typically multinational), phase 1 or 2 trials (n = 20–135) in patients with advance solid tumours [27, 36], advanced NSCLC [23, 37], metastatic renal cell carcinoma [21], stage III and/or IV melanoma (NCT01133977 [38, 39]; NCT01136967 [24, 40]), or advanced or recurrent en- dometrial cancer [25]. Based on results from these trials, further studies are warranted to investigate the efficacy of lenvatinib in these patient populations.
In an ongoing, double-blind, phase II study in patients with nonsquamous NSCLC who had failed at least two prior treatments, median OS with lenvatinib plus best supportive care (BSC; n = 89) was 38.4 weeks compared with 24.1 weeks in the placebo plus BSC group (n = 46) (primary endpoint) [23]. Median PFS was significantly prolonged in lenvatinib versus placebo recipients (20.9 vs. 7.9 weeks; p \ 0.001), with no between-group difference in the objective response rate (10.1 vs. 2.1 %). This interim analysis was conducted after 90 deaths had occurred [23].
As first-line treatment in patients with stage IV me- lanoma (n = 78), median PFS was significantly prolonged in the lenvatinib plus dacarbazine group compared with the dacarbazine group in a phase II study (19.1 vs.
7.0 weeks; HR 0.4; 95 % CI 0.23–0.75; p = 0.0033), as assessed by independent review (primary endpoint) [38]. In this ongoing study (NCT01133977), patients received lenvatinib 20 mg once daily plus dacarbazine 1000 mg/m2 once every 21 days combination therapy or dacarbazine 1000 mg/m2 once every 21 days [38]. In a cohort of patients with stage III unresectable or stage IV BRAF wild-type melanoma who had received at least one prior treatments (n = 93), eight lenvatinib recipients achieved a partial response in an ongoing, phase II trial (primary endpoint; assessed by independent review; NCT01136967) [24]. The median PFS and OS were 3.7 and 9.5 months, with a clinical benefit rate (complete plus partial responses plus durable stable disease of C23 weeks) of 32 %. In this study, which also evaluated a cohort of patients who were BRAF mutant advanced melanoma (data not reported), patients received lenva- tinib 24 mg once daily [24].
In an ongoing, open-label, phase II trial in patients with metastatic or recurrent endometrial cancer (n = 133), the independent review and investigator assessed overall ob- jective response rates with lenvatinib 24 mg once daily were 14.3 and 28.1 %, respectively (primary endpoint) [25]. The median PFS was 5.4 months and the median OS was 10.6 months [25].
Key clinical trials of lenvatinib (Eisai Inc./Eisai Co. Ltd)
Drugs(s) Indication Phase Status Location(s) Identifier
LEN vs.
PL
Radioactive iodine-refractory
differentiated thyroid cancer
3 Ongoing; primary analysis completed
Multinational SELECT; NCT01321554;
Eudra CT2010-023783-41
LEN
Radioactive iodine-refractory
differentiated thyroid cancer
EXP Ongoing
USA NCT02211222
LEN
Radioactive iodine-refractory
differentiated thyroid cancer
2
Completed
Multinational NCT00784303
LEN
Radioactive iodine-refractory
differentiated thyroid cancer
2
Recruiting
Japan
NCT01728623
LEN vs.
SOR
Unresectable hepatocellular cancer
3
Recruiting
Multinational NCT01761266; Eudra
CT2012-002992-33
LEN Advanced hepatocellular carcinoma 2 Ongoing Japan NCT00946153
LEN Advanced endometrial cancer 2 Ongoing Multinational NCT01111461
LEN Unresectable stage III or IV melanoma 2 Ongoing Multinational NCT01136967
LEN ?
DAC
Stage IV melanoma 1/2
Ongoing
Multinational NCT01133977
LEN ?
E7050
Recurrent glioblastoma/unresectable
stage III or IV melanoma
2 ? expansion cohort
Ongoing
USA
NCT01433991
LEN ±
EVE
Unresectable advanced or metastatic
renal cell carcinoma
1/2
Ongoing
Multinational NCT01136733
LEN
KIF5B-RET-positive lung
adenocarcinoma
2
Recruiting
Multinational NCT01877083
LEN ?
BSC
Advanced or metastatic non-squamous
NSCLC
2
Ongoing
Multinational NCT01529112; Eudra
CT2011-002347-10
BSC best supportive care, DAC dacarbazine, EVE everolimus, EXP expanded access, LEN lenvatinib, NSCLC non-small cell lung cancer, PL placebo, RI radioactive iodine, SELECT Study of (E7080) LEnvatinib in differentiated Cancer of the Thyroid, SOR sorafenib
2.4Adverse Events
Oral lenvatinib had a manageable safety and tolerability profile in clinical trials. In patients with RAI-refractory differentiated thyroid cancer participating in SELECT, treatment-related adverse events (TRAE) of any grade occurred in 97.3 % of lenvatinib recipients and 59.5 % of placebo recipients, with TRAEs of grade 3 or higher oc- curring in 75.9 and 9.9 % of patients [9]. Serious TRAEs occurred in 30.3 and 6.1 % of lenvatinib and placebo re- cipients. Treatment-emergent adverse events that lead to death occurred in 7.7 % of lenvatinib recipients and 4.6 % of placebo recipients, with 2.3 % of those occurring in the lenvatinib group considered to be treatment-related [9].
The most common (incidence C30 %) TRAEs of any grade occurring in lenvatinib recipients were hypertension (67.8 vs. 9.2 % in the placebo group), diarrhoea (59.4 vs. 8.4 %), fatigue or asthenia (59.0 vs. 27.5 %), decreased appetite (50.2 vs. 11.5 %), decreased bodyweight (46.4 vs. 9.2 %), nausea (41.0 vs. 13.7 %), stomatitis (35.6 vs. 3.8 %), palmar-plantar erythrodysethaesia syndrome (31.8 vs. 8.0 %) and proteinuria (31.0 vs. 1.5 %) [9]. TRAEs led to discontinuation of the study drug in 14.2 % of lenvatinib recipients and 2.3 % of placebo recipients, with the most frequent of these being asthenia and hypertension (each of which occurred in 1.1 % of lenvatinib recipients). Dosage reductions (67.8 vs. 4.6 %) or interruptions (82.4 vs. 18.3 %) occurred more frequently in the lenvatinib than in the placebo group. The most common adverse effects as- sociated with dosage discontinuations or interruptions of lenvatinib were diarrhoea (22.6 %), hypertension (19.9 %), proteinuria (18.8 %) and decreased appetite (18.0 %).
TRAEs that occurred in clinical trials and for which there is a warning/precaution in US manufacturer’s pre- scribing information were hypertension, cardiac dysfunc- tion (decreased left or right ventricular function, cardiac failure or pulmonary oedema), arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure and im- pairment, gastrointestinal perforation and fistula formation (incidence in SELECT: 2 % in the lenvatinib group vs. 0.8 % in the placebo group), QT interval prolongation, hypocalcaemia, reversible posterior leucoencephalopathy syndrome (three cases across clinical studies; n = 1108 lenvatinib recipients), haemorrhagic events and impairment of thyroid stimulating hormone (TSH) suppression [4]. In SELECT, the incidences of these adverse events that were of grade 3 or higher in the lenvatinib and placebo groups were: hypertension (*44 vs. 4 %), cardiac dysfunction (2 vs. 0 %), arterial thromboembolic events (3 vs. 1 %), hepatotoxicity (4 vs. 0 % for an increase in alanine aminotransferase level; 5 vs. 0 % for an increase in as- partate aminotransferase level), proteinuria (11 vs. 0 %),
renal failure or impairment (3 vs. 1 %), QT interval pro- longation (2 vs. 0 %), hypocalcaemia (9 vs. 2 %) and haemorrhagic events (2 vs. 3 %). In patients who had normal TSH levels (B0.5 mU/mL) at baseline in SELECT, 57 % of lenvatinib recipients and 14 % of placebo re- cipients had elevations in TSH level of [0.5 mU/mL [4].
Based on the mechanism of action of lenvatinib and results from animal reproduction studies, which showed embryotoxicity, foetotoxicity and teratogenicity at lenva- tinib doses below the recommended dose in humans, fe- males of reproductive potential should be advised to use effective contraception during treatment and for at least 2 weeks following completion of therapy [4].
2.5Ongoing Clinical Trials
The pivotal phase 3 SELECT trial, which is evaluating the efficacy of lenvatinib treatment in patients with RAI-re- fractory thyroid cancer, is ongoing (NCT01321554; Eudra CT2010-023783-41); the primary analysis has been com- pleted [9]. In addition, a US expanded access study is ongoing in patients with RAI-refractory thyroid cancer (NCT02211222), with a Japanese phase 2 study in this setting currently recruiting patients (NCT01728623).
A multinational phase 3 trial (NCT01761266; Eudra CT-2012-002992-33) and a Japanese phase 2 trial (NCT00946153) are currently recruiting patients with un- resectable hepatocellular cancer. The phase 3 trial will evaluate the noninferiority or superiority of lenvatinib to sorafenib as first-line treatment in patients with unre- sectable hepatocellular cancer.
The efficacy of lenvatinib is also being evaluated in ongoing, multinational, phase 2 trials in patients with ad- vanced endometrial cancer (NCT01111461), unresectable stage III or IV melanoma with or without V600E BRAF mutations (NCT01136967), or advanced or metastatic non- squamous NSCLC (NCT01529112; Eudra CT2011- 002347-10). A multinational phase 2 trial in patients with KIF5B-RET-postive lung adenocarcinoma is currently re- cruiting patients to evaluate the efficacy of lenvatinib in this setting (NCT01877083). An ongoing, multinational, phase 1/2 trial is evaluating combination lenvatinib plus everolimus therapy in patients with unresectable or ad- vanced renal cell carcinoma (NCT01136733). An ongoing, multinational, phase 1/2 trial is evaluating the efficacy of lenvatinib plus dacarbazine versus dacarbazine mono- therapy as first-line treatment in patients with stage IV melanoma (NCT01133977). A US phase 2 and expansion cohort study is evaluating the efficacy of E7050 plus len- vatinib in patients with recurrent glioblastoma or unre- sectable stage III or IV melanoma after prior systemic therapy (NCT0143399).
3Current Status
Lenvatinib received its first global approval on 13 Fe- bruary 2015 in the USA for the treatment of locally re- current or metastatic, progressive, RIA differentiated thyroid cancer.
Disclosure The preparation of this review was not supported by any external funding. During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. L. J. Scott is a salaried employee of Adis, Springer SBM.
References
1.Stjepanovic N, Capdevila J. Multikinase inhibitors in the treat- ment of thyroid cancer: specific role of lenvatinib. Biologics. 2014;8:129–39.
2.Jasmin S, Ozsari L, Habra MA. Multikinase inhibitors use in differentiated thyroid carcinoma. Biol Targ Ther. 2014;8:281–91.
3.Alonso-Gordoa T, Diez JJ, Duran M, et al. Advances in thyroid cancer treatment: latest evidence and clinical potential. Ther Adv Med Oncol. 2015;7(1):22–38.
4.Eisai Inc. Lenvima (lenvatinib) capsules, for oral use: US pre- scribing information. 2015. http://www.fda.gov. Accessed 24 February 2015.
5.Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel in- hibitor that targets multiple kinases, has potent antitumor ac- tivities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122(3):664–71.
6.Glen H, Mason S, Patel H, et al. E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer. 2011;11:309.
7.Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459–65.
8.US FDA. FDA approves lenvima for a type of thyroid cancer (media release). http://www.fda.gov/newsevents/newsroom/
pressannouncements/ucm434288.htm. Accessed 13 February 2015.
9.Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621–30.
10.Eisai Co Ltd. U.S. FDA approves anticancer agent LenvimaTM (lenvatinib mesylate) as treatment for radioactive iodine-refrac- tory differentiated thyroid cancer. 2015. http://www.eisai.com. Accessed 24 February 2015.
11.European Medicines Agency. Public summary opinion on orphan designation: lenvatinib for the treatment of follicular thyroid cancer. 2013. http://www.ema.europa.eu. Accessed 24 February 2015.
12.European Medicines Agency. Public summary opinion on orphan designation: lenvatinib for the treatment of papillary thyroid cancer. 2013. http://www.ema.europa.eu. Accessed 24 February 2015.
13.Eisai Co Ltd. Eisai and Quintiles enter into a strategic col- laboration to develop Eisai’s anticancer compounds (media re- lease). http://www.eisai.co.jp. Accessed 30 October 2009.
14.Eisai Co Ltd. Eisai to accelerate late-stage clinical development of new drugs by effectively leveraging external resources (media release). http://www.eisai.com. Accessed 7 September 2011.
15.Biologics Inc. LenvimaTM (lenvatinib) approved for radioactive iodine-refractory differentiated thyroid cancer, available through Biologics Inc (media release). http://www.biologicsinc.com. Accessed 13 February 2015.
16.Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2015;6(1):89–94.
17.Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (E7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014. doi:10.1155/2014/638747.
18.Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014; 6:18.
19.Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340(1):97–103.
20.Bruheim S, Kristian A, Uenaka T, et al. Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts. Int J Cancer. 2011;129(3):742–50.
21.Molina AM, Hutson TE, Larkin J, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014;73 (1):181–9.
22.Schlumberger M, Jarzab B, Cabanillas ME, et al. A phase II trial of the multi-targeted kinase inhibitor lenvatinib (E7080) in ad- vanced medullary thyroid cancer (MTC) (abstract no. IS8-4). Ann Oncol. 2012;23(8 suppl 11):xi35–xi6.
23.Havel L, Lee JS, Lee KH, et al. E7080 (lenvatinib) in addition to best supportive care (BSC) versus BSC alone in third-line or greater nonsquamous, non-small cell lung cancer (NSCLC) (ab- stract no. 8043). J Clin Oncol. 2014;32(15 suppl 1).
24.O’Day S, Gonzalez R, Kim K, et al. A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with ad- vanced BRAF wild-type melanoma (abstract no. 9026). J Clin Oncol. 2013;31(15 suppl 1).
25.Vergote I, Teneriello M, Powell MA, et al. A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: angiopoietin-2 as a predictive marker for clinical out- comes (abstract no. 5520). J Clin Oncol. 2013;31(15 suppl 1).
26.Okita K, Kumada H, Ikeda K, et al. Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): initial assessment of response rate (abstract no. 320). J Clin Oncol. 2012;30(4 suppl 1).
27.Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106(10):1598–604.
28.Koyama N, Saito K, Nishioka Y, et al. Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer. 2014;14:530.
29.Shumaker RC, Zhou M, Ren M, et al. Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers. Cancer Chemother Pharmacol. 2014;73(6): 1109–17.
30.Shumaker R, Aluri J, Fan J, et al. Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52(4):284–91.
31.Dubbelman AC, Rosing H, Nijenhuis C, et al. Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas. Invest New Drugs. 2015;33(1):233–40.
32.Shumaker R, Aluri J, Fan J, et al. Effect of ketoconazole coad- ministration on lenvatinib (E7080) exposure in healthy volunteers. Clinical study. 2012; 24th EORTC-NCI-AACR international conference on molecular targets and cancer therapeutics.
33.Shumaker RC, Aluri J, Fan J, et al. Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. Clin Drug In- vestig. 2014;34(9):651–9.
34.Shumaker R, Aluri J, Fan J, et al. Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral ad- ministration. J Clin Pharmacol. 2014.
35.Finn RS, Cheng AL, Ikeda K, et al. A multicenter, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) versus sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma (abstract no. TPS4153). J Clin Oncol. 2014;32(15 suppl 1).
36.Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-esca- lation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17(8):2528–37.
37.Nishio M, Horai T, Horiike A, et al. Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non- small-cell lung cancer. Br J Cancer. 2013;109(3):538–44.
38.Maio M, Hassel JC, Del Vecchio M, et al. Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma (abstract no. 9027). J Clin Oncol. 2013;31(15 suppl 1).
39.Calvo E, Becerra C, Maio M, et al. A Phase Ib/II study of len- vatinib (E7080), a VEGFR and FGFR tyrosine kinase inhibitor (TKI), in combination with dacarbazine (DTIC) versus DTIC alone as first-line therapy in patients with stage IV melanoma: Phase Ib safety and efficacy results (abstract no. SMR-P43). Pigment Cell Melanoma Res. 2011;24(5):1035.
40.Sachdev P, Hamid O, Kim K, et al. Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma (abstract no. 9058). J Clin Oncol. 2013;31(15 suppl 1).