Table 1.

In vivo studies on TC treated with different KIs.

Study	Indication	Main Results	Reference
An open-label phase II study enrolled 55 metastatic RAI-refractory TC patients (47% with PTC, 36% with FTC/Hürthle Cell, 9% with PDTC/ATC, and 8% with MTC) treated with sorafenib (400 mg orally bid).	Metastatic RAI-refractory TC	PFS was better in PTC/FTC patients with V600EBRAF mutation than in wild type (84 weeks vs. 54).	[49]
A phase II trial investigated sorafenib (400 mg twice daily) to reinduce RAI uptake in 31 patients treated for 26 weeks.	RAI-refractory DTC	The study reported partial response (PR) (25%), stable disease (SD) (34%), clinical response (59%), and progression-free survival (PFS) (58 weeks). No reinduction of RAI uptake was reported.	[50]
In a study, 13 patients with RAI-refractory PTC or FTC received sorafenib.	RAI-refractory PTC or FTC	The remission rate was 20%, with a durable response rate in 66% and a clinical benefit rate of 80%. Overall survival (OS) was 67% at 2 years with a PFS of 19 months.	[51]
In a UPCC 03305 phase II study, 55 patients with advanced TC (85% with DTC/PDTC, 9% with ATC, and 6% with MTC) were enrolled and treated with sorafenib (400 mg bid).	Advanced TC (85% with DTC/PDTC, 9% with ATC, and 6% with MTC)	DTC/PDTC patients had a higher PFS with respect to the other TCs (96 vs. 93.6 weeks); in addition, 38% of them had a PR, and 47% a SD.	[52]
In a phase II trial, 15 patients with aggressive MTC and 19 with RAI-refractory DTC were administered with sorafenib (400 mg twice daily).	Aggressive MTC and RAI-refractory DTC	The radiological response rate was 18%. A patient with a mutated BRAF exon 15 had an important response after 3 months.	[53]
In a phase II study, 31 RAI-refractory DTC patients received sorafenib (400 mg bid).	RAI-refractory DTC	The 31% of patients achieved a PR and 42% had a SD, after a median follow-up of 25 months. V600EBRAF did not correlate with the progression of the disease.	[54]
In a phase II trial, 20 ATC patients were treated with sorafenib (400 mg bid).	ATC	Patients reached a PR in 10% and SD in 25%. Only 20% of patients reached a survival of 1-year, suggesting the ineffectiveness of sorafenib in ATC patients.	[55]
In a double-blinded randomized phase III (DECISION) trial, 417 patients with RAI-refractory, locally advanced or metastatic DTC were enrolled, of which 207 received sorafenib and 210 received a placebo.	RAI-refractory, locally advanced or metastatic DTC	PFS was higher in patients treated with the drug than in those treated with placebo (10.8 vs. 5.8 months). PFS improved in all subgroups, with or without mutations. AEs occurred in 98.6% of sorafenib-treated patients.	[56]
Outside of clinical trials, 62 patients were treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%).	PTC, FTC, Hürthle cell, PDTC, MTC	Among the 39 sorafenib and 12 sunitinib treatments in DTC patients, partial response rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line therapy compared with first-line sorafenib or sunitinib therapy (6.7 vs. 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.	[57]
Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6–16 months).	Progressive radioiodine resistant metastatic TC	One patient showed a PR with tumor regression of −35% six months after the beginning of the treatment; five patients exhibited SD, and two patients had progressive disease (PD) and died.	[58]
A phase II trial investigated the effect of sorafenib in patients with aggressive ATC or MTC.	Aggressive ATC or MTC	The study reported, (a) in ATC, a median OS of 5.0 months and PFS of 2.8 months; and (b) in MTC, an objective response rate of 25% and disease control rate in 75%. It was concluded that sorafenib was effective in MTC, but not in ATC.	[59]
In a phase II study, sorafenib was administered to 36 patients with metastatic TC (i.e., PTC, Hürthle cell, FTC, or ATC) (200 mg twice daily per os., combined with intravenous temsirolimus (25 mg weekly)).	Metastatic TC (i.e., PTC, Hürthle cell, FTC, or ATC)	The study reported: 22% PR, 58% SD, and 3% PD.	[60]
A meta-analysis investigated the safety and efficacy of sorafenib in RAI-refractory DTC patients.	RAI-refractory DTC	Sorafenib improved PFS in comparison to placebo.	[61]
A study compared sorafenib or sunitinib in 28 RAI-refractory metastatic DTC patients (26 treated with sorafenib as first-line therapy (8 patients switched successively to sunitinib), and 2 with sunitinib).	RAI-refractory metastatic DTC	PR rate and mean PFS were 30.7% and 10.8 months, respectively, for sorafenib, and 37.5% and 6 months for sunitinib, as a second-line therapy.	[62]
In a phase I study, 184 terminal patients with inoperable solid tumors (carrying the V600EBRAF mutation) received dabrafenib (300 mg daily orally).	PTC	A total of 14/184 patients had PTC, and nine of these survived for all the duration of the study, showing PR in 33% of cases. However, as reported by many other clinical studies, BRAF-positive tumors exhibited resistance to dabrafenib in 6 to 7 months.	[63]
In a case report, two patients with V600EBRAF-positive ATC were administered with dabrafenib.	V600EBRAF ATC	BRAF inhibitor monotherapy appears to obtain only temporary clinical improvement in ATC.	[64]
A woman with an ATC with V600EBRAF mutation (treated with EBRT, and then with pazopanib when the metastatic disease progressed to the neck and lung, with no benefits) was treated with dabrafenib (150 mg bid) and trametinib (2 mg/day).	V600EBRAF ATC	The treatment led to a PR in 2 weeks. Then the disease progressed, and the patient died upon 6 months.	[65]
In a phase II open-label trial, patients with BRAF V600E-mutated ATC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death.	V600EBRAF ATC	Good clinical effect and a good tolerance; overall response rate of 69% (95% CI, 41–89%), with 7 ongoing responses.	[66]
Real-World Experience: ten patients (eight BRAF wild type and two V600EBRAF mutant tumors) were started on lenvatinib, and six with V600EBRAF-mutated tumors received a combination of dabrafenib plus trametinib.	ATC	In the entire cohort, 6/16 (38%) had a PR, 6/16 (38%) had SD, and 2/16 (12%) had PD. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months (CI 1.8–7.6) in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months (CI 1.8–7.6) for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib.	[67]
In a phase II Rare Oncology Agnostic Research (ROAR) basket study, thirty-six patients with ATC received dabrafenib (150 mg twice daily + trametinib 2 mg once) until disease progression, unacceptable toxicity, or death.	V600EBRAF ATC	The overall RR was 56%, including 3 complete responses; the 12-month duration of response rate was 50%. OS was 14.5 months, while PFS was 6.7. The OS at 12 months was 43.2%, and at 24 months, it was 31.5%.	[68]