Spotlight on lenvatinib in the treatment of thyroid cancer: patient selection and perspectives

Figures & data

Table 1 Kinase inhibitors studied and not yet US FDA approved in radioactive iodine-refractory thyroid tumors of follicular origin

Drug	Histology (descending order in frequency)	Study phase (n)	ORR (%)	PFS (months)	Toxicity common all-grade AEs (descending order in frequency)
Sunitinib^Citation92	PTC, FTC, Hürthle cell carcinoma, and MTC	II (35)	31	12.8	Neutropenia, leukopenia, fatigue, diarrhea, HFS
Axitinib^Citation93	PTC, FTC, medullary, anaplastic	II (60)	30	18.1	Fatigue, diarrhea, nausea, anorexia, hypertension, stomatitis, weight loss, and headache
Pazopanib^Citation94	FTC, PTC, and Hürthle cell carcinoma	II (37)	49	11.7	Fatigue, hair and skin hypopigmentation, diarrhea, nausea, vomiting, anorexia, hypertension, and AST/ALT elevations
Motesanib^Citation95	PTC, Hürthle cell carcinoma, and FTC	II (93)	14	10	Diarrhea, hypertension, fatigue, weight loss, abdominal pain, nausea, anorexia, headache, dry mouth, and hypothyroidism
Cabozantinib^Citation96	FTC, PTC, and Hürthle cell carcinoma	I (15)	53	Not reached for median follow-up of 12.2 months	Diarrhea, hypertension, decreased appetite, and fatigue
Vandetanib^Citation97	PTC, FTC, and poorly differentiated carcinoma	II (145)	8	11.1	Diarrhea, hypertension, acne, asthenia, decreased appetite, rash, QTc prolongation
Vemurafenib^Citation98	PTC only#	II (51)	35–26##	15.6–6.8##	Rash, fatigue, weight loss, and increased bilirubin
Dabrafenib^Citation99	Well differentiated (not specified), poorly differentiated carcinoma, FTC, oncocytic, and Hürthle cell features#	II (14)	29	11.3	Skin papillomas, hyperkeratosis, alopecia, arthralgia, hair texture abnormality, pyrexia, seborrheic keratosis, and skin hypertrophy
Selumetinib^Citation100	PTC and poorly differentiated carcinoma	II (20)	25*	35% of patients had disease controlled for at least 6 months**	Fatigue, maculopapular rash, acneiform rash, AST and ALT elevations

Notes:

* In 60% of patients, iodine¹²⁴ uptake increased after selumetinib therapy; partial responses were observed in 20% (5/20) of patients treated with both iodine¹²⁴ and selumetinib;

** 35% (7/20) of the patients who received both therapeutic iodine and selumetinib had sustained partial and stable disease for at least 6 months;

# all BRAF-mutated tumors;

## best results were seen in the TKI-naïve patient group compared to the TKI-exposed group.

Abbreviations: FDA, Food and Drug Administration; ORR, overall response rate; PFS, progression-free survival; AEs, adverse events; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma; HFS, hand–foot syndrome; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TKI, tyrosine kinase inhibitor; QTc,; PET-CT,.

Table 2 Kinase inhibitors studied in radioiodine-refractory PTC and FTC and their targets

TKI	Targets
	VEGFR	RET	c-KIT	PDGFR	FGFR	BRAF	EGFR	MET	FLT3	MEK1	MEK2
Lenvatinib^Citation32,Citation33,Citation36	✓	✓	✓	✓	✓
Sorafenib^Citation25,Citation26	✓	✓		✓		✓			✓
Sunitinib^Citation101	✓		✓	✓
Axitinib^Citation102	✓		✓	✓
Pazopanib^Citation103,Citation104	✓		✓	✓
Motesanib^Citation105	✓	✓	✓	✓
Cabozantinib^Citation106,Citation107	✓	✓	✓					✓	✓
Vandetinib^Citation108,Citation109	✓	✓					✓
Dabrafenib^Citation110						✓
Selumetinib^Citation111										✓	✓
Vemurafenib^Citation112						✓

Abbreviations: PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor; FLT3, FMS-like tyrosine kinase 3.

Table 3 Lenvatinib Phase II and III trials toxicities profile

	Phase II and III studies
	SELECT trial*^Citation47	Phase II*^Citation45	Phase II*^Citation46
n	392	58	59
Cohort	Radioiodine-refractory thyroid cancer of follicular origin	Radioiodine-refractory thyroid cancer of follicular origin	Refractory medullary thyroid
Common clinical AEs**	Hypertension, diarrhea, fatigue, decreased appetite, nausea, vomiting, weight loss	Weight loss, hypertension, diarrhea, fatigue, dehydration, arthralgia	Diarrhea, hypertension, decreased appetite, fatigue
Grade ≥3	75%	72%	61%
Discontinuation of medication due to AEs	14%	26%	24%
Dose reduction due to AEs	67%	66%	59%
Dose delay due to AEs	82%	74%	75%
Number of deaths on study	6	2	3
Cause of death	Three unspecified, one pulmonary embolism, one hemorrhagic stroke, one health deterioration	One cardiac arrest, one arterial hemorrhage	Two respiratory failures (one not specified), one paraneoplastic syndrome

Notes:

* Lenvatinib was administered at 24 mg po daily in 28-day treatment cycles.

** Grade ≥3 proteinuria was present in 10% of patients in two of the trials described in the table and AEs are presented in descending order of frequency.

Abbreviation: AEs, adverse events.

Figure 1 Proposed algorithm for initiation of lenvatinib therapy in patients with DTC.

Note: *Individualized decision making is necessary.
Abbreviations: DTC, Differentiated thyroid cancer; TKI, Tyrosine kinase inhibitor.

CarrLLMankoffDAGoulartBHPhase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlationClin Cancer Res201016215260526820847059

 PubMed Web of Science ®Google Scholar

CohenEERosenLSVokesEEAxitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II studyJ Clin Oncol200826294708471318541897

 PubMed Web of Science ®Google Scholar

BibleKCSumanVJMolinaJREfficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium studyLancet Oncol2010111096297220851682

 PubMed Web of Science ®Google Scholar

ShermanSIWirthLJDrozJPMotesanib diphosphate in progressive differentiated thyroid cancerN Engl J Med20083591314218596272

 PubMed Web of Science ®Google Scholar

CabanillasMEBroseMSHollandJFergusonKCShermanSIA phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancerThyroid201424101508151425102375

 PubMed Web of Science ®Google Scholar

LeboulleuxSBastholtLKrauseTVandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trialLancet Oncol201213989790522898678

 PubMed Web of Science ®Google Scholar

BroseMS CMCohenEEWWirthLAn open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to radioactive iodineEur J Cancer201349E177119

 PubMed Web of Science ®Google Scholar

FalchookGSMillwardMHongDBRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancerThyroid2015251717725285888

 PubMed Web of Science ®Google Scholar

HoALGrewalRKLeboeufRSelumetinib-enhanced radioiodine uptake in advanced thyroid cancerN Engl J Med2013368762363223406027

 PubMed Web of Science ®Google Scholar

MatsuiJFunahashiYUenakaTWatanabeTTsuruokaAAsadaMMulti-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 kinaseClin Cancer Res200814175459546518765537

 PubMed Web of Science ®Google Scholar

MatsuiJYamamotoYFunahashiYE7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibitionInt J Cancer2008122366467117943726

 PubMed Web of Science ®Google Scholar

TohyamaOMatsuiJKodamaKAntitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer modelsJ Thyroid Res2014201463874725295214

 PubMedGoogle Scholar

WilhelmSMCarterCTangLBAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesisCancer Res200464197099710915466206

 PubMed Web of Science ®Google Scholar

CarlomagnoFAnagantiSGuidaTBAY 43-9006 inhibition of oncogenic RET mutantsJ Natl Cancer Inst200698532633416507829

 PubMed Web of Science ®Google Scholar

ChowLQEckhardtSGSunitinib: from rational design to clinical efficacyJ Clin Oncol200725788489617327610

 PubMed Web of Science ®Google Scholar

Hu-LoweDHallinMFeeleyRCharacterization of potency and activity of the VEGF/PDGF receptor tyrosine kinase inhibitor AG013736Am Assoc Cancer Ress2002435357

 Google Scholar

KumarRKnickVBRudolphSKPharmacokinetic- pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activityMol Cancer Ther2007672012202117620431

 PubMed Web of Science ®Google Scholar

HurwitzHIDowlatiASainiSPhase I trial of pazopanib in patients with advanced cancerClin Cancer Res200915124220422719509175

 PubMed Web of Science ®Google Scholar

PolverinoACoxonAStarnesCAMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenograftsCancer Res200666178715872116951187

 PubMed Web of Science ®Google Scholar

YakesFMChenJTanJCabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growthMol Cancer Ther201110122298230821926191

 PubMed Web of Science ®Google Scholar

FallahiPFerrariSMDi BariFCabozantinib in thyroid cancerRecent Pat Anticancer Drug Discov201510325926926152149

 PubMed Web of Science ®Google Scholar

WedgeSROgilvieDJDukesMZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administrationCancer Res200262164645465512183421

 PubMed Web of Science ®Google Scholar

CarlomagnoFVitaglianoDGuidaTZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinasesCancer Res200262247284729012499271

 PubMed Web of Science ®Google Scholar

SalernoPDe FalcoVTamburrinoACytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cellsJ Clin Endocrinol Metab201095145045519880792

 PubMed Web of Science ®Google Scholar

BanerjiUCamidgeDRVerheulHMThe first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancerClin Cancer Res20101651613162320179232

 PubMed Web of Science ®Google Scholar

BollagGHirthPTsaiJClinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanomaNature2010467731559659920823850

 PubMed Web of Science ®Google Scholar

SchlumbergerMTaharaMWirthLJLenvatinib versus placebo in radioiodine-refractory thyroid cancerN Engl J Med2015372762163025671254

 PubMed Web of Science ®Google Scholar

CabanillasMESchlumbergerMJarzabBA phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: a clinical outcomes and biomarker assessmentCancer2015121162749275625913680

 PubMed Web of Science ®Google Scholar

SchlumbergerMJarzabBCabanillasMEA phase 2 trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer (MTC)Clin Cancer Res2016221445326311725

 PubMed Web of Science ®Google Scholar