New approaches for patients with advanced radioiodine-refractory thyroid cancer

Table 1 Available agents studied in the treatment of radioiodine refractory-differentiated thyroid carcinoma

Agent and national clinical trial number1	Molecular target	Phase	Dosage	Enrolled patients (n)	PR (%)	mPFS (mo)	Common AEs	Serious AEs (grade ≥ 3)	Withdrawal due to AEs
Sorafenib[6]; NCT00984282	VEGFR1–3, PDGFR, RET, c-kit, BRAF	III	400 mg orally twice daily	207	10.8	12.2	Hand– foot skin reaction (76%), diarrhea (69%), alopecia (67%), rash (50%)	Hand-foot skin reaction (20%), hypertension (10%), weight loss (6%)	19%
Lenvatinib[7]; NCT01321554	VEGFR1–3, FGFR1–4, PDGFR, RET, c-kit	III	24 mg per d in 28-d cycles	261	63.2; 65 (4 complete response + 165 partial response)	18.3	Hypertension (68%), diarrhea (59%), fatigue (59%), decreased appetite (50%), decreased weight (46%), nausea (41%)	Hypertension (42%), proteinuria (10%), decreased weight (10%), fatigue (9%), diarrhea (8%)	14%
Cabozantinib[28]; NCT01811212	VEGFR2, MET, FLT3, RET, c-kit	II	60 mg/d orally	25	40	12.7	Fatigue (44%), weight loss (36%), diarrhea (36%), hand– foot skin reaction (32%), hypertension (24%)	Hypophosphatemia (16%), lipase/amylase increase, neutropenia, fatigue, weight loss (12%)
Axitinib[71]; NCT00094055	VEGFR, PDGFR, c-kit	II	5 mg twice daily	60	30	18.1	Fatigue (50%), diarrhea (48%), nausea (33%), anorexia (30%), hypertension (28%), stomatitis (25%), weight loss (25%), and headache (22%)	Hypertension (12%), proteinuria (5%), fatigue (5%)
Vandetanib[72]; NCT00537095	VEGFR2/3, EGFR, RET	II	300 mg/d	72	8.3	11.1	Diarrhea (74%), hypertension (34%), acne (27%), asthenia, anorexia (26%), nausea, rash (25%), fatigue, QTc prolongation (23%)	QTc prolongation (14%), diarrhea (10%), asthenia (7%), fatigue (5%)	33%
Sunitinib[73]; NCT00381641	PDGFR, FLT3, c-kit, VEGFR, RET	II	37.5 mg/d orally	35	31	12.8	Neutropenia (34%), leukopenia (31%), fatigue (26%), HFS (26%), diarrhea (26%)	Neutropenia (34%), leukopenia (31%), diarrhea, hand/foot syndrome (17%), fatigue (11%)	11%
Pazopanib[74]; NCT00625846	VEGFR, PDGFR, c-kit	II	800 mg/d orally in 4-wk cycle	37	49	11.7	Fatigue (78%), skin and hair hypopigmentation (75%), diarrhea (73%), nausea (73%)	Raised alanine aminotransferase level (11%)	5%
Dovitinib[75]; NCT02964144	FGFR, VEGFR	II	500 mg/d orally for five days, followed by a 2-d rest every week	40	20.5	5.4	Diarrhea (54%), anorexia (36%), vomiting (26%), fatigue (23%), and nausea (21%)	Neutropenia (13%)	20%
Apatinib[31]; NCT03167385	VEGFR2, c-Kit, c-SRC	II	750 mg/d orally (n = 10, group I) - 500 mg/d orally (n = 10, group II)	20	90 (I); 70 (II)	18.4	Hand– foot skin reaction (95%), proteinuria (90%) and hypertension (80%)
Lapatinib[76]; NCT01947023	HER2/3	I	750 mg initial dose, escalated to 500 mg daily; + Dabrafenib 150 mg twice daily	13	60	15		Lymphocytic toxicity (7%)
Vemurafenib[58]; NCT01286753	BRAF V600E	II	960 mg orally twice daily	51	VEGFR naive: 39%; Previous VEGFR: 27%	VEGFR naive: 18.8; Previous VEGFR: 8.9	Rash (73%), fatigue (69%), alopecia, dysgeusia (54%), creatinine increase, weight decrease (50%), arthralgia, anorexia, nausea, skin papilloma (46%)	Skin squamous cell carcinoma (23.5%), lymphopenia, and increased γ-glutamyl-transferase (8%)	27%
Dabrafenib[57]; NCT00880321	BRAF V600E	I	150 mg twice daily	13	29	11.3	Skin papillomas (57%), hyperkeratosis (36%), alopecia (29%)	Elevated lipase, elevated amylase, fatigue, febrile neutropenia and squamous cell carcinoma (7%)	0%
Selumetinib[66]; NCT00559949	MEK-1/2, RAS, BRAF V600E	II	100 mg twice daily for 28-d cycles	39	3	8	Rash (77%), fatigue (49%), diarrhea (49%), peripheral edema (36%)	Rash (18%), fatigue (8%)	15%
Larotrectinib[33]; NCT02122913	NTRK fusions	II	100 mg twice daily	153	129 (95%); 24 (16%) complete response	28.3	Fatigue (30%), cough, constipation (27%), dizziness, alanine aminotransferase increase (25%)	Anemia (10%), decreased neutrophil count (5%)	2%
Entrectinib[36]; NCT02097810 (STARTRK-1) NCT02568267 (STARTRK-2)	NTRK fusions	II	600 mg/d orally	54	50	10	Dysgeusia (47%), fatigue, constipation (28%), diarrhea (27%), edema peripheral, dizziness (24%)	Anemia (12%), weight gain (10%)	4%
Everolimus[62]; NCT01118065	mTOR	II	10 mg/d orally	33	3	12.9	Mucositis, acneiform rash, fatigue, cough	Fatigue (8%), weight loss, infection (6%)
Temsirolimus[63]; NCT01025453	mTOR	II	Temsirolimus (25 mg IV weekly) + sorafenib (200 mg twice daily)	36	22	12		Hyperglycemia (19%), fatigue (13%), anemia (11%), oral mucositis, alanine aminotransferase increased (8%)	14%

¹from ClinicalTrials.gov.

PR: Partial response; AE: Adverse event; VEGFR: Vascular endothelial growth factor receptor; NTRK: Neurotrophic tropomyosin receptor kinase.

Table 2 Summary of the efficacy and safety of sorafenib in patients with thyroid cancer reported by clinical trials

Ref.	n	Type	PR, %	SD, %	Median	Median	Most frequent AE	Most frequent grade 3-4 AE
					PFS (mo)	OS (mo)
Gupta-Abramson et al[77], 2008	27	DTC	26	59	19	-	HFS, 93%	Hypertension, 13%
Kloos et al[78], 2009	33	PTC	15	57	16	23	Fatigue, 85%	Fatigue, 16%
Hoftijzer et al[79], 2009	31	DTC	25	34	14.5	-	HFS, 66%	HFS, 18%
Cabanilas et al[59], 2010	13	DTC	20	60	19		HFS, 60%	-
Keefe et al[80], 2011	47	DTC/PD	38	47	22	32.4	-	-
Ahmed et al[81], 2011	19	DTC	16	-	-	-	Dermatology (other than HFS), 88%	HFS, 44%
Chen et al[82], 2011	9	DTC	33	44	10.5	-	Alopecia, 100%	-
Marotta et al[83], 2012	17	DTC	30	41	9	10	HFS, 88%
Schneider et al[84], 2012	31	DTC	31	42	18	34.5	HFS, 71%	HFS, 22%
Capdevilla et al[85], 2012	16	DTC	19	50	13.3	23.6	HFS and diarrhea, 62%	HFS, 23%
Brose et al[6], 2014	207	DTC	12	42	10.8	.	HFS, 73.6%	HFS, 20.3%
Benekli et al[86], 2014	14	DTC	-	43	21.3	-	-	HFS, 22%
Dadu et al[87], 2008	51	DTC	-	-	-	56	-	-
Luo et al[88], 2014	8	DTC	50	37	9.4	12.8	Alopecia, 75%	Hypocalcemia and serum amylase increased, 12.5%
Gallo et al[89], 2015	20	DTC	25	40	8.2	28.4	Fatigue, 95%	Gastrointestinal symptoms, 15%
Kim et al[90], 2018	98	DTC	25	37	9.7	-	HFS, 76%	HFS, 41%
Jerkovich et al[12], 2019	18	DTC	11	72	16.5	-	HFS, 67%	HFS, 14%

DTC: Differentiated thyroid carcinoma. PR: Partial response; PFS: Progression free survival; SD: Stable disease; OS: Overall survival; AE: Adverse event.

Table 3 Summary of the efficacy and safety of lenvatinib in patients with thyroid cancer reported by phase III clinical trial and real-life studies

Ref.	n	Patients with prior TKIs %	CR %	PR %	SD %	Median	Median	Most frequent AE	Most frequent grade 3-4 AE
						PFS (mo)	OS (mo)
Schlumberger et al[7] 2015	261	25	1	63	23	18.3	-	Hypertension, 68%	Hypertension, 42%
Berdelou et al[16], 2017	75	68	0	31	51	10	-	Fatigue, 75%	Hypertension 35%
Jasim et al[17], 2017	25	31	0	50	28	-	-	Hypertension 64%	Hypertension 40%
Sugino et al[18], 2018	29	13	0	69	21	-	-	Hypertension 76%	-
Locati et al[19], 2019	94	64	0	36	41	10.8	23.8	Fatigue, 13%	Fatigue, 8%
Lee et al[20], 2019	57	89	0	38	60	5.1	19.3	General weakness 43%
Masaki et al[21], 2019	42	10	0	62	24	13.8	-	Hypertension, 83%	Proteinuria, 36%
Aydemirli et al[22], 2020	39	77	2	33	37	9.7	18.3	Hypertension and fatigue, 64%	Hypertension, 28%
Jerkovich et al[23], 2020	22	59	4	32	32	13.7	-	Hypertension, 64%	Hypertension, 23%

TKIs: Tyrosine kinase inhibitors; CR: Complete response; PR: Partial response; SD: Stable disease; PFS: Progression free survival; OS: Overall survival; AE: Adverse event.

Table 4 Some relevant ongoing clinical trials for the treatment of advanced radioiodine refractory-differentiated thyroid carcinoma (thru March 11, 2021, from clinicaltrials.gov)

NCT number	Title	Status	Interventions	Characteristics	Population	Dates	Locations
NCT04554680	Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Redifferentiation Therapy	Recruiting	Drug: Dabrafenib and trametinib	Study type: Interventional	Enrollment: n = 5	Study start: December 30, 2020	National University Hospital, Singapore, Singapore
				Phase: Phase 2	Age: 21-99 yr	Study completion: April 2022
				Study design: Allocation: N/A; Intervention model: Single group assignment; Masking: None (open label); Primary purpose: Treatment outcome; Measures: The proportion of participants attaining at least one tumor lesion with lesional dosimetry of ≥ 2000 cGy with I-131 dose of =	Sex: All
NCT01709292	Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid Cancer	Active, not recruiting	Drug: Vemurafenib (all groups)	Study type: Interventional	Enrollment: n = 24 Age: 18 yr and older	Study start: November 7, 2012	University of Texas MD Anderson Cancer Center, Houston, Texas, United States
			Drug: Vemurafenib (Post Surgery) - Group A + C Other: Post Surgery - Group B	Phase: Phase 2	Sex: All	Study completion: November 30, 2020
				Study design: Allocation: NonRandomized intervention; Model: Parallel assignment; Masking: None (open label); Primary purpose: Treatment outcome; Measures: Percent change in ERK (extracellular-signal regulated kinase) phosphorylation and tumor size, objective response rate
NCT03167385	Phase 2 Trial of Apatinib Mesylate in Locally Advanced/ Metastatic Differentiated Thyroid Carcinoma	Unknown	Drug: Apatinib mesylate	Study type: Interventional	Enrollment: n = 20 Age: 18 to 75 yr	Study start: March 22, 2017	Tianjin Medical University Cancer Institute and Hospital, Tianjin, Tianjin, China
				Phase: Phase 2	Sex: All	Study completion: December 31, 2020
				Study design: Allocation: N/A; Intervention model: Single group; assignment; Masking: None (open label); Primary purpose: Treatment outcome; Measures: Disease control rate, progression free survival, overall survival, objective response rate
NCT03753919	Durvalumab Plus Tremelimumab for the Treatment of Patients With Progressive, Refractory Advanced Thyroid Carcinoma - The DUTHY Trial	Recruiting	Drug: Durvalumab Drug: Tremelimumab	Study type: Interventional	Enrollment: 46 Age: 18 yr and older	Study start: April 2	Instituto Catalán de Oncología de Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain; Hospital Provincial de Castellón, Castelló, Valencia, Spain; Hospital Clínic Barcelona, Barcelona, Spain; Hospital Universitari Vall d'Hebron, Barcelona, Spain; MD Anderson Cancer Center, Madrid, Spain; Hospital Clínico San Carlos, Madrid, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Universitario HM Sanchinarro, Madrid, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; and 5 more
				Phase: Phase 2 study	Sex: All	Study completion: July 2021
				Design: Allocation: N/A; Intervention model: Single group assignment; Masking: None (open label); Primary purpose: Treatment outcome; Measures: Progression-free survival rate at 6 mo, overall survival rate at 6 mo, overall response rate, duration of response, median progression-free survival, incidence of treatment, emergent adverse events (safety and tolerability), median overall survival, response status after start of study treatment
NCT00537095	Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer	Active, not recruiting	Drug: Vandetanib Other: Placebo	Study type: Interventional	Enrollment: n = 165 Age: 18 yr and older	Study start: September 29, 2007	Research Site, Brussels, Belgium; Research Site, Odense, Denmark; Research Site, Angers Cedex 9, France Research Site, Angers Cedex, France; Research Site, Bordeaux Cedex, France; Research Site, Caen Cedex 5, France; Research Site, Caen Cedex, France; Research Site, Lyon Cedex, France; Research Site, Lyon, France; Research Site, Marseille Cedex 9, France; and 12 more
				Phase: Phase 2	Sex: All	Study completion: December 2021
				Study design: Allocation: Randomized; Intervention model: Parallel assignment; Masking: Double (participant, investigator); Primary purpose: Treatment outcome; Measures: Time to tumor progression, disease control rate at 6 mo, objective response rate, time to death
NCT03602495	Donafenib in 131I-Refractory Differentiated Thyroid Cancer	Recruiting	Drug: Donafenib Drug: Placebo	Study type: Interventional	Enrollment: n = 204 Age: 18 yr and older	Study start: August 29, 2018	Peking Union Medical College Hospital, Beijing, Beijing, China
				Phase: Phase 3	Sex: All	Study completion: December 2021
				Study design: Allocation: Randomized; Intervention model: Parallel assignment; Masking: Double (participant, investigator); Primary purpose: Treatment outcome; Measures: Progression-free survival, overall survival, objective response rate, disease control rate, time to disease progression