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.