Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions

Figures & data

Figure 1. Growth factor receptors and the MAPK/ERK pathway.

EGFR: EGF receptor; VEGFR: VEGF receptor.Adapted with permission from [95].

Table 1. Phase II trials of sorafenib in differentiated thyroid cancers.

Trial design	Patients (n)	Treatment	Efficacy results in DTC cohort	Grade ≥3 AEs in ≥5% of patients	NCT ID	Ref.
Two-stage single-arm trial; DTC, PD, medullary and anaplastic patients (first stage)	Total = 30; DTC = 27	Median duration of treatment = 27 weeks. Dose reduction (due to AEs) required in 47% of patients.	mPFS = 84 weeks	Hypertension, hand–foot syndrome, rash, weight loss, diarrhea, elevated LFTs^†	NCT00654238	[100]
Two-stage single-arm trial; DTC, PD, medullary and anaplastic patients (first and second stages)	Total = 55; DTC/PD = 50	Patients with progressing advanced, iodine-refractory differentiated or PD thyroid cancer	mPFS = 96 weeks; mOS 140.9 weeks; PR = 38%; SD = 57% and CBR = 95%	Rash, weight loss, hand–foot syndrome, diarrhea, hypertension	NCT00654238	[101]
Two-stage two-arm trial; Arm A – chemotherapy naive papillary TC with biopsy; Arm B – papillary vs non-papillary. Primary end point; ORR	Total = 56; DTC = 41 (arms A and B)	Dose reduction (due to AEs) required in 52% of patients	ORR = 15%; mPFS = 16 month; mOS = 23 month SD = 57% and DCR = 72%	Fatigue, hand–foot skin reaction, weight loss, skin rash, hypertension, diarrhea, stomatitis, tongue/tooth pain, abdominal/rectal pain, proximal myopathy, back pain, general pain, hand/foot pain, arthralgia, colon perforation	NCT00095683	[102]
Single-arm trial; primary end point: radiologic RR at 6 months	Total = 34; DTC = 19	Median duration = 16.5 months; dose reduction (due to AEs) required in 79% of patients	RR (6 month) = 16%; RR (12 month) = 18%;mPFS and mOS not reached at 19 months; 1-year OS = 79% and 1-year PFS = 68%	Hand–foot syndrome, other skin toxicities, diarrhea, alopecia	N/A	[103]
Single-arm two-stage design trial; primary end point: percentage of patients with reuptake of radioiodine at 26 weeks	Total = 32; DTC = 32	22 patients completed the 26-week therapy (21 evaluable for RaI uptake); dose reduction (due to AEs) was required in 56% of patients	Reinduction of RaI uptake not observed. mPFS = 58 weeks; SD = 34%; PR = 25% and DCR = 59%	Hand–foot skin reaction, hypertension, weight loss	NCT00887107	[104]

^†One patient developed grade 3/4 LFT abnormalities at 8 weeks and died of liver failure 12 weeks later.

AE: Adverse event; CBR: Clinical benefit rate; DCR: Disease control rate; DTC: Differentiated thyroid cancer; LFT: Liver function test; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Overall response rate; PD: Poorly differentiated; PR: Partial response; RR: Radiologic response rate; SD: Stable disease.

Table 2. Targeted therapeutic agents in late-stage clinical trials for differentiated thyroid cancer.

Agent	Patients (n)	Molecular targets	Description of study	NCT ID	Trial phase	Estimated completion date
Monotherapy
Sunitinib	66	VEGFRs, PDGFRs, kit	Nonrandomized, open-label trial of sunitinib in locally advanced or metastatic anaplastic, differentiated or medullary thyroid cancer	NCT00510640	II	Febuary 2011
Gefitinib	38	EGFR	Nonrandomized, open-label trial of gefitinib in advanced thyroid cancer	NCT00095836	II	March 2011
Motesanib	184	VEGFRs, PDGFR, kit	Nonrandomized, open-label trial of motesanib in locally advanced or metastatic thyroid cancer	NCT00121628	II	August 2011
Lenvatinib	104	VEGFRs, FGFRs, RET, kit, PDGFb	Multicenter, open-label, single-arm trial of oral lenvatinib in medullary and RAI-refractory, unresectable DTCs	NCT00784303	II	October 2011
Sorafenib	419	VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf	Double-blind, randomized trial of sorafenib in locally advanced/metastatic RAI-refractory DTC	NCT00984282	III	November 2011
Panobinostat	33	HDAC inhibitor	Nonrandomized, open-label trial of panobinostat in metastatic medullary thyroid cancer and RAI-resistant DTC	NCT01013597	II	January 2012
Pazopanib	188	VEGFRs, PDGFRs, kit	Open-label trial of pazopanib in advanced thyroid cancer	NCT00625846	II	May 2012
Everolimus	42	mTOR inhibitor	Open-label trial of everolimus in unresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinomas	NCT01118065	II	May 2012
Everolimus	33	mTOR inhibitor	Nonrandomized, open-label trial of everolimus in RAI-refractory thyroid cancer	NCT00936858	II	June 2012
Vandetanib^†	145	VEGFR-2, EGFR, RET	Multicenter, randomized, double-blind, placebo-controlled trial of vandetanib in locally advanced or metastatic papillary or follicular thyroid carcinoma	NCT00537095	II	December 2012
Sorafenib	419	VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf	Double-blind, randomized trial of sorafenib in locally advanced/metastatic RAI-refractory DTC	NCT00984282	III	March 2013
Cabozantinib	315	MET, VEGFR-2	International, randomized, double-blind trial of cabozantinib in unresectable, locally advanced or metastatic medullary thyroid cancer	NCT00704730	III	March 2013
Everolimus	32	mTOR inhibitor	Multicenter, open-label trial of everolimus in advanced thyroid cancer	NCT01164176	II	March 2013
Lenvatinib	360	VEGFRs, FGFRs, RET, kit, PDGFb	Multicenter, randomized, double-blind, placebo-controlled trial in RAI-refractory DTC	NCT01321554	III	July 2013
Axitinib	52	VEGFRs	Nonrandomized, open-label trial of axitinib in RAI-refractory thyroid cancer	NCT00389441	II	August 2013
Sunitinib	46	VEGFRs, PDGFRs, kit	Nonrandomized, open-label trial of sunitinib in DTC	NCT00668811	II	December 2013
Everolimus	30	mTOR inhibitor	Randomized, open-label trial of pasireotide and everolimus in RAI-refractory DTCs and medullary thyroid cancers	NCT01270321	II	June 2014
Vemurafenib	40	(V600E) BRAF inhibitor	Nonrandomized, open-label, multicenter trial of vemurafenib in metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to RAI	NCT01286753	II	June 2014
Valproic acid	25	HDAC inhibitor	Nonrandomized, open-label trial of valproic acid in advanced thyroid cancers of follicular origin	NCT01182285	II	September 2014
Axitinib	100	VEGFRs	Nonrandomized, open-label trial of axitinib in patients previously receiving axitinib in clinical trials	NCT00828919	II	December 2015
Combination therapy
Sorafenib plus everolimus	38	Sorafenib: VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf Everolimus: mTOR inhibitor	Nonrandomized, open-label of the combination of everolimus and sorafenib in RAI-refractory thyroid cancer	NCT01141309	II	June 2012
Sorafenib plus temsirolimus	40	Sorafenib: VEGFRs, PDGFR, Flt-3, RET, c-kit, and Raf Temsirolimus: mTOR inhibitor	Open-label of the combination of temsirolimus and sorafenib in RAI-refractory thyroid cancer	NCT01025453	II	December 2012
Cediranib plus lenalidomide	30	Cediranib: VEGFRsLenalidomide: immunomodulator	Randomized, open-label of cediranib with or without lenalideomide in thyroid cancer	NCT01208051	II	September 2013
Everolimus plus pasireotide	30	Everolimus: mTOR inhibitor Pasireotide: somatostatin analogue	Randomized, open-label of pasireotide and everolimus in RAI-refractory differentiated and medullary thyroid cancer	NCT01270321	II	October 2013

Phase II trials for agents in Phase III are not listed.

^†Approved by the US FDA for medullary cancer.

DTC: Differentiated thyroid cancer; EGFR: EGFR receptor; FGFR: FGF receptor; PDGFR: PDGF receptor; RAI: Radioactive iodine; VEGFR: VEGF receptor.

Data taken from [203].

Table 3. Key terms and outcome measures for clinical trials of targeted therapies in patients with differentiated thyroid cancer.

Term	Definition/criteria
Target lesion	To assess the burden of disease and identify objective tumor responses, it is important to be able to estimate the overall tumor burden at baselineTarget lesions are those with the longest diameters that lend themselves to reproducible repeated measurementsTarget lesions should be selected to be representative of all involved organs and should include all lesions up to a maximum of five
Stable disease	Neither sufficient increase nor decrease in the size of target lesions considered to be meaningful
Progressive disease	A 20% or greater increase in the sum of diameters of the target lesions
Partial response	At least a 30% decrease in the sum of diameters of target lesions
Complete response	Disappearance of all target lesions. Any pathologic lymph nodes must have a reduction in their short axis to <10 mm

Adapted with permission from [39].

Deshpande HA, Gettinger SN, Sosa JA. Targeted therapy for thyroid cancer: an updated review of investigational agents. Curr. Opin. Investig. Drugs 11(6), 661–668 (2010).

 PubMedGoogle Scholar

Gupta-Abramson V, Troxel AB, Nellore A et al. Phase II trial of sorafenib in advanced thyroid cancer. J. Clin. Oncol. 26(29), 4714–4719 (2008).

 PubMed Web of Science ®Google Scholar

Keefe SM, Troxel AB, Rhee S et al. Phase II trial of sorafenib in patients with advanced thyroid cancer J. Clin. Oncol. 29(Suppl. 15), abstract 5562 (2011).

 Google Scholar

Kloos RT, Ringel MD, Knopp MV et al. Phase II trial of sorafenib in metastatic thyroid cancer. J. Clin. Oncol. 27(10), 1675–1684 (2009).

 PubMed Web of Science ®Google Scholar

Ahmed M, Barbachano Y, Riddell A et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a Phase II study in a UK based population. Eur. J. Endocrinol. 165(2), 315–322 (2011).

 PubMed Web of Science ®Google Scholar

Hoftijzer H, Heemstra KA, Morreau H et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur. J. Endocrinol. 161(6), 923–931 (2009).

 PubMed Web of Science ®Google Scholar

Clinical Trials.gov. (2011). Trial of E7080 in 131-I-refractory differentiated thyroid cancer. http://clinicaltrials.gov/ct2/show/NCT01136733 (Accessed 2 November 2011)

 Google Scholar

Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45(2), 228–247 (2009).

 PubMed Web of Science ®Google Scholar