Table 2.

Novel targeted therapies for thyroid cancer treatment.

Drug/ ClinicalTrials.gov ID/Reference	Mechanism of Action	Enrolled Patients *	Primary Outcome	Study Design	Results	Reported Adverse Events
Tyrosine Kinase Inhibitors
Anlotinib Sun et al. [83]	VEGFR, PDGFR, FGFR1	MTC: 58 (locally advanced or metastatic)	PFS	Phase II, single arm, open label	PR: 56.9% PFS at 48 weeks: 85.5% Drop of calcitonin and CEA > 50% in 78% of patients	Hand–foot syndrome, lipid profile abnormalities, fatigue, diarrhea, proteinuria
Anlotinib Li et al. [84]		MTC: 91 (no previous exposure to antiangiogenic agents)	PFS	Phase II/III, two arms, randomized, double blinded, placebo controlled (ALTER0103)	Median PFS: 20.67 months in Anlotinib arm vs. 11.07 months in placebo arm
Anlotinib NCT04309136		DTC/MTC (locally advanced thyroid cancer with/without distant metastasis)	ORR	Phase II, single arm, open label, recruiting	N/A Estimated End Date 6/2022 (clinicaltrials.gov)
Anlotinib NCT02586337		DTC (RAI refractory disease)	PFS	Phase II/III, two arms, randomized, double blinded, placebo controlled, active, not recruiting (ALTER01032)	N/A Estimated End Date 12/2019 (clinicaltrials.gov)
Apatinib NCT03048877	VEGFR	DTC (locally advanced or metastatic disease)	PFS	Phase III, two arms, Randomized, double blinded, placebo controlled, active, not recruiting	N/A Estimated End Date 6/2021 (clinicaltrials.gov)	Hypertension, hand–foot syndrome, proteinuria, fatigue
Apatinib NCT03167385		DTC (locally advanced or metastatic disease)	Disease control rate	Phase II, single arm, open label, recruiting	N/A Estimated End Date 12/2020 (clinicaltrials.gov)
Axitinib Cohen et al. [85]	VEGFR, PDGFR, KIT	DTC: 45 (resistant to or not appropriate for RAI) MTC: 11 ATC 11	ORR	Phase II, single arm, open label	ORR of 30% SD for ≥ 16 weeks: 38% PFS: 18.1 months	Fatigue, diarrhea, nausea, anorexia, hypertension, stomatitis
Axitinib Capdevila et al. [86]		DTC: 34 (RAI refractory) MTC: 13	ORR	Retrospective study, compassionate use program (CUP) in Spain	ORR for PTC: 29.4% PFS for PTC: 7.4 months ORR for MTC: 23.1% PFS for MTC: 9.4 months
Cabozantinib Elisei et al. [103]	VEGFR, RET, MET, FLT3, AXL	MTC: 219 (locally advanced, metastatic with radiographic progression in the past 14 months)	PFS	Phase III, randomized, double blinded, placebo controlled	PFS: 11.2 vs. 4.0 months for placebo (regardless of RET mutation status) PR: 28% (regardless of RET mutation status)	Diarrhea, hand–foot syndrome, weight loss, decreased appetite, nausea, fatigue
Cabozantinib NCT03690388		DTC (RAI disease that progressed after use of VEGFR–TKI therapy)	PFS ORR	Phase III, two arms, randomized, double blinded, placebo controlled, recruiting	N/A Estimated End Date 12/2022 (clinicaltrials.gov)
Cabozantinib NCT02041260		DTC (RAI refractory disease with radiographic progression in the past 14 months)	Number of AEs	Phase II, single arm, open label, active, not recruiting	N/A Estimated End Date 3/2021 (clinicaltrials.gov)
Donafenib NCT03602495	VEGFR	DTC (RAI refractory/resistant disease)	PFS	Phase III, two arms, randomized, double blinded, placebo controlled, recruiting	N/A Estimated End Date 3/2021 (clinicaltrials.gov)	Hand–foot syndrome, diarrhea, rash, hair loss, hypertension, tachycardia
Dovitinib Lim et al. [87]		DTC: 28 (RAI refractory or not appropriate) MTC: 12	ORR	Phase II, single arm, open label	ORR: 20.5% Median PFS: 5.4 months	Diarrhea, anorexia, nausea, vomiting, fatigue
Lenvatinib Schlumberger et al. [81]		DTC: 261 (RAI refractory progressive disease)	PFS	Phase III, two arms, randomized, double blinded, placebo controlled	Median PFS: 18.3 vs. 3.6 for placebo ORR: 64.8% (CR 4/261 + PR 165/261)	Hypertension, diarrhea, fatigue, anorexia, weight loss, nausea
Lenvatinib Schlumberger et al. [88]	VEGFR, PDGFR, EGFR, RET, KIT	MTC: 59 (unresectable progressive disease)	ORR	Phase II, single arm, open label	PR 36%
Lenvatinib Tahara et al. [89]		Enrolled all types of thyroid cancer, but results reported one cohort for 17 patients with ATC	Serious/non-serious AE	Phase II, single arm, open label	Most frequent AE (Decreased appetite, 82%; HTN, 82%; Fatigue, 59%; Nausea, 59%; Proteinuria, 59%) Secondary Endpoints: ORR: 24% Median PFS: 7.4 months Median OS
Lenvatinib NCT03573960		DTC (locally recurrent or metastatic progressive RAI refractory disease)	-Grade 3 and higher TEAEs -Number of dose reductions -Time to 1st dose reduction	Phase IV, single arm, open label, recruiting	N/A Estimated End Date 12/2020 (clinicaltrials.gov)
Lenvatinib NCT03506048		DTC (progressive despite RAI in the past 12 months)	Time to progression	Phase II, single arm, open label, recruiting	N/A Estimated End Date 1/2021 (clinicaltrials.gov)
Lenvatinib NCT02702388		DTC (RAI refractory disease)	-PFS -TEAEs	Phase II, two arms, randomized, double blinded, evaluating the starting dose 18 mg vs. 24 mg, active, not recruiting	N/A Estimated End Date 9/2020 (clinicaltrials.gov)
Lenvatinib NCT02966093		DTC (RAI refractory disease in China)	PFS	Phase III, two arms, randomized, double blinded, placebo controlled, active, not recruiting	N/A Estimated End Date 4/2021 (clinicaltrials.gov)
Nintedanib NCT01788982	VEGFR, PDGFR, FGFR, RET, FLT,	DTC MTC (as second-line therapy if progressive disease after first-line therapy)	PFS	Phase II, two arms, randomized, double blinded, active not recruiting	N/A Estimated End Date 9/2019 (clinicaltrials.gov)	Diarrhea, nausea, vomiting, abdominal pain
Pazopanib Bible et al. [90]	VEGFR, FGFR, PDGFR, RET, KIT	DTC: 37 (progressive RAI refractory disease)	Tumor response rate	Phase II, two arms, open label	PR: 49%	Fatigue, skin and hair hypopigmentation, diarrhea, nausea
Pazopanib Bible et al. [91]		MTC: 35 (advanced or metastatic disease)	Tumor response rate	Phase II, two arms, open label	PR: 14.3% PFS: 9.4 months OS: 19.9 months
Pazopanib Bible et al. [92]		ATC: 15 (advanced or metastatic disease)	Tumor response rate	Phase II, two arms, open label	No response
Sorafenib Brose et al. [79]	VEGFR, PDGFR, RET, KIT, FLT	DTC: 209 (locally advanced or metastatic RAI refractory disease)	PFS	Phase III, two arms, randomized, double blinded, placebo controlled (decision trial)	PFS: 10.8 months vs. 5.8 for placebo (regardless of mutation status) PR: 12%	Hand–foot skin reaction, diarrhea, alopecia, skin rash or desquamation
Sorafenib Lam et al. [93]		MTC: 16 (locally advanced or metastatic, arm A—Hereditary MTC, arm B—Sporadic MTC)	ORR	Phase II, single arm, open label	PR: 6.3% SD: 87.5%
Sorafenib Capdevila et al. [94]		DTC: 16 MTC: 15 ATC: 3 (metastatic progressive unsuitable for surgery, RAI, or radiotherapy)	ORR	Retrospective, Spanish off-label-sorafenib-use program	DTC PR: 19% MTC PR: 47% ATC PR: 33%
Sunitinib Bikas et al. [95]	VEGFR, PDGFR, RET, KIT, FLT	DTC: 23 (metastatic, residual, recurrent, or progressive disease)	ORR	Phase II, single arm, open label, as adjunctive treatment	PR: 26% SD: 57%	Cytopenia, diarrhea, fatigue, hand–foot skin reaction, nausea, musculoskeletal pain, hypertension
Sunitinib Carr et al. [96]		DTC: 28 (RAI refractory disease, FDG–PET avid disease) MTC: 7 (FDG–PET avid disease)	ORR	Phase II, Single Arm, Open Label	DTC ORR: 28% MTC ORR: 50%
Sunitinib Ravaud et al. [97]		DTC: 41 (RAI resistant) MTC: 26 ATC: 4 (sunitinib as a first-line anti-angiogenic therapy)	ORR	Phase II, single arm, open label	DTC PR: 22% MTC PR: 38.5% ATC: no response
Vandetanib Wells et al. [104]	VEGFR, EGFR, RET, KIT	MTC: 231 (unresectable locally advanced or metastatic disease)	PFS	Phase III, two arms, randomized, double blinded, placebo controlled	PFS HR 0.46 compared to placebo (predicted median PFS 30.5 vs. 19.3 months for placebo) PR 45%	Diarrhea, rash, nausea, hypertension, headache
Vandetanib Leboulleux et al. [98]		DTC: 72 (locally advanced or metastatic disease)	PFS	Phase II, randomized, double blind, placebo controlled	PFS 11.1 vs. 5.9 months for placebo
Vandetanib NCT01876784		DTC: 119 (locally advanced or metastatic RAI refractory or unsuitable disease)	PFS	Phase III, two arms, randomized, double blind, placebo controlled	PFS (no statistically significant difference—10.0 months vs. 5.7 months with p value 0.080)
Selective Ret Inhibitors
LOXO-292 (Selpercatinib) NCT03157128	RET	MTC (among multiple RET-fusion and RET-activation-positive solid tumors)	Phase I: maximum tolerated dose (MTD), recommended phase II dose Phase II: ORR	Phase I/II, single arm, open label (LIBRETTO-001 trial), recruiting	N/A Estimated End Date 3/2022 (clinicaltrials.gov)	Fatigue, dyspnea, joint pain, insomnia, abnormal liver enzymes (from proof-of-concept study)
LOXO-292 (Selpercatinib) NCT03899792		MTC PTC (among multiple RET-altered solid and CNS tumors in pediatrics)	Phase I: safety Phase II: ORR	Phase I/II, single arm, open label (LIBRETTO-121), recruiting	N/A Estimated End Date 10/2022 (clinicaltrials.gov)
BLU-667 (Pralsetinib) NCT03037385	RET	MTC: 49 RET mutant PTC: 5 RET mutant (among multiple RET-altered solid tumors)	Phase I: maximum tolerated dose, number of patients with TEAEs Phase II: ORR, number of patients with TEAEs	Phase I/II, seven groups in Phase II, open label (ARROW TRIAL), recruiting	MTC ORR: 47% MTC PR: 21/49 MTC CR: 2/49 MTC SD: 25/49 Rapid reduction of calcitonin and CEA levels PTC PR 2 of 4 evaluable Estimated End Date 2/2024 (clinicaltrials.gov)	Constipation, elevated liver enzymes, diarrhea, fatigue, elevated serum creatinine, WBC count decrease, hypertension
BRAF Inhibitors
Dabrafenib Falchook et al. [99]	BRAFV600E	DTC: 13 (BRAFV600E mutant disease)	ORR	Subset of phase I study	PR: 29%	Skin papilloma hyperkeratosis, alopecia, fatigue, fever, diarrhea
Vemurafenib Brose et al. [100]	BRAFV600E	DTC: 51 (unresectable and metastatic RAI refractory BRAFV600E mutant disease)	ORR	Phase II, parallel assignment, open label	PR 38.5% (VEGFR multikinase inhibitor naïve cohort) PR 27% (prior treatment with VEGFR multikinase inhibitors)	Rash, fatigue, arthralgia
Vemurafenib Hytman et al. [105]		ATC: 7 (multiple BRAFV600E mutant tumors)	ORR	Phase II, basket trial	PR: 14% CR: 14%
BRAF/MEK Inhibitor Combination
Dabrafenib and Trametinib Subbiah et al. [106]	Dabrafenib: BRAFV600E Trametinib: MEK1, MEK2	ATC: 16 locally advanced or metastatic BRAFV600E mutant disease	ORR	Phase II, single arm, open label	PR: 63% CR: 6%	See Dabrafenib See Trametinib
Tropomyosin Receptor Kinase Inhibitor
Larotrectinib Drilon et al. [107]	TRKI: TRKA, TRKB, TRKC	NTRK harboring solid tumors in pediatrics and adults (thyroid cancer: 5 patients)	ORR	NCT02122913 (Phase I adults, open label) NCT02637687 (Phase I/II, pediatrics, open label) NCT02576431 (Phase II pediatrics and adults, basket study)	PR: 100% (5/5)	Elevated ALT and AST, fatigue, nausea, vomiting, dizziness
Entrectinib Doebele et al. [108]	TRKI: TRKA, TRKB, TRKC ALK, ROS1	Locally advanced and metastatic NTRK-fusion solid tumors (thyroid cancer: 4 patients)	ORR Median duration of response	(STARTRK-1): NCT02097810 Phase I (STARTRK-2): NCT02568267 Phase II (ALKA-372-001): EudraCT 2012-000148-88 Phase I	Thyroid cancer PR 50% (2/4)	Dysgeusia, dizziness, constipation, diarrhea, weight gain
Radioactive Iodine Restoration Treatments
Selumetinib Ho et al. [109]	MEK1, MEK2	DTC: 20 (RAI refractory disease—9 BRAF mutation, 5 NRAS mutation)	The percentage of patients with selumetinib-induced increases in iodine uptake in the index tumor	Open label, single arm, treatment with selumetinib, then evaluate by RAI uptake study	Increased I-124 uptake in 12/20 (4/9 with BRAF mutations) (5 of 5 with NRAS mutations) (8/12 reached dosimetry threshold for RAI treatment)	Fatigue, maculopapular rash, elevated liver enzymes, acneiform rash
Selumetinib ISRCTN17468602 (UK)		Locally advanced and metastatic RAI refractory DTC	PFS	Phase II, single arm, treatment with selumetinib, then evaluate by RAI uptake study (SEL-I-METRY Trial)	N/A
Trametinib with RAI NCT02152995	MEK1, MEK2	DTC: RAS mutant or RAS/RAF wild-type RAI-refractory recurrent and/or metastatic disease	PFS	Phase II, single arm, open label, recruiting	N/A Estimated End Date 12/2020 (clinicaltrials.gov)	Acneiform rash
Trametinib OR Dabrafenib NCT03244956		DTC RAI refractory with RAS (trametinib) or BRAFV600E (dabrafenib) mutation	ORR	Phase II, two arms, open label, recruiting	N/A Estimated End Date 12/2022	See Trametinib See Dabrafenib
Trametinib/ combination Dabrafenib and Trametinib or Vemurafenib and Cobimetinib Irvani et al. [110]	Trametinib (see above), Dabrafenib (see above), Vemurafenib (see above), Cobimetinib: MEK1, MEK2	DTC: 6 (3 BRAFV600E positive treated with combination, 3 NRAS-positive treated with trametinib)	Restoration of RAI uptake	Retrospective, cohort study	RAI uptake restoration: BRAFV600E (3/3), NRAS (1/3) with median follow-up 16.6 months	See Trametinib See Dabrafenib See Vemurafenib Cobimetinib: diarrhea, pyrexia, photosensitivity reaction, abnormal LFT, hyponatremia
Peptide Receptor Radionuclide Therapy
PRRT 90Y-DOTATATE or 177Lu-DOTATATE Budiawan et al. [111]		DTC: 7 MTC: 8 Mixed DTC and MTC: 1 (non-RAI avid and RAI refractory thyroid cancer)	Treatment response Treatment related toxicity	Phase II trial, single arm, open label	PR 18.2% SD 36.4% Median PFS 25 months Mean survival 4.2 years	Mild hematological toxicity, abnormal liver enzymes, mild nephrotoxicity
PRRT (90)Y-DOTATOC Versari et al. [112]		DTC: 41 (RAI negative enrolled in the study 11/41 patients were treated with PRRT)	Treatment response	Phase II trial, single arm, open label	ORR 63% (PR 2/11, SD 4/11)
PRRT 177Lu-DOTATATE or 90Y-DOTATOC Lapa et al. [113]		DTC: 8 (progressive RAI refractory) MTC: 4	Assess tumor heterogenicity in predicting PFS and OS	Phase II trial, single arm, open label	Mean PFS 221 days Mean OS 450 days
mTOR Inhibitors
Everolimus Lim et al. [101]	mTOR	Thyroid cancer (all subtypes): 38	Disease control rate (PR + SD > 12 weeks)	Phase II, single arm, open label	PR: 5% (2/38, one PTC patient and one FTC) SD: 76%	Mucositis, anorexia, abnormal liver enzymes, acneiform rash
Everolimus Hanna et al. [102]		DTC: 33 MTC: 10 ATC: 7	PFS	Phase II, single arm, open label	DTC: Median PFS 12.9 months, PR 1/38 MTC: Median PFS 13.1 months, PR 1/10 ATC: Median PFS 2.2 months, PR 1/7
Immunotherapy
Pembrolizumab Mehnert et al. [114]	PD-1 receptor	DTC: 22 (Refractory to standard therapy, with PD-L1 expression)	ORR	Phase 1b, single arm, open label (KEYNOTE-28 Trial)	ORR: 9% PR: 2/22 (9%) SD: 13/22 (59%) Median PFS (PR+SD): 7 months	Diarrhea, fatigue, pruritis, rash, colitis (grade 3 in one patient)
Combination Therapies Under Investigation
Cabozantinib and Atezolizumab NCT03170960	Cabozantinib (see above), Atezolizumab: PD-L1	Multiple tumors, including DTC that is locally advanced or metastatic	Dose escalation: maximum tolerated Dose Expansion: ORR	Phase I/II, dose escalation/expansion, open label, recruiting	Estimated End Date 12/2021 (clinicaltrials.gov)	N/A
Cabozantinib, Nivolumab, and Ipilimumab NCT03914300	Cabozantinib (see above), Nivolumab: PD-1, Ipilimumab: CTLA-4	DTC (RAI refractory progressive after one prior VEGFR therapy)	ORR	Phase II, single group assignment, open label, recruiting	Estimated End Date 1/2021 (clinicaltrials.gov)	N/A
Cediranib Maleate with or without Lenalidomide NCT01208051	Cediranib: VEGFR, Lenalidomide: CRL4CRBN E3 ubiquitin ligase	DTC (unresectable progressive RAI refractory disease)	Phase I: Maximum tolerated dose Phase II: PFS	Phase I/II, parallel assignment, randomized, open label, active, not recruiting	Estimated End Date 2/2020 (clinicaltrials.gov)	N/A
Lenvatinib and Denosumab NCT03732495	Lenvatinib (see above), Denosumab: RANKL	DTC (RAI resistant with bone metastasis)	Skeletal-related event-free (multiple)	Phase II, single group assignment, open label, recruiting	Estimated End Date 6/2022 (clinicaltrials.gov)	N/A
Lenvatinib and Pembrolizumab (PD-1 Inhibitor) NCT02973997	Lenvatinib (see above), Pembrolizumab: (see above)	DTC (progressive RAI refractory disease)	ORR	Phase II, single group assignment, open label, active not recruiting	Estimated End Date 9/2022 (clinicaltrials.gov)	N/A

Abbreviations: AE, adverse event; ATC, anaplastic thyroid cancer; CEA, carcinoembryonic antigen; CR, complete response; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DCR, disease control rate; DTC, differentiated thyroid cancer; ECG, electrocardiogram; FDA, US Food and Drug Administration; FTC, follicular thyroid cancer; FGFR, fibroblast growth factor receptor; FTL-3, FMS-like receptor tyrosine kinase-3; HR, hazard ratio; MTC, medullary thyroid cancer; MTD, maximum tolerated dose; N/A, not available; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor PD; PFS, progression-free survival; PR, partial response; PRRT, peptide receptor radionuclide therapy; PTC, papillary thyroid cancer; RAI, radioactive iodine; SD, stable disease; SSTR, somatostatin receptor; TEAEs, treatment emergent adverse events; TKI, tyrosine kinase inhibitor; TRKI, tropomyosin receptor kinase inhibitor; RANK, receptor activator of nuclear factor kappa-Β ligand; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor. * For placebo-controlled studies, only the number for patients enrolled under the treatment arm is mentioned.