Review
Copyright ©The Author(s) 2022.
World J Clin Oncol. Jan 24, 2022; 13(1): 9-27
Published online Jan 24, 2022. doi: 10.5306/wjco.v13.i1.9
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]; NCT00984282VEGFR1–3, PDGFR, RET, c-kit, BRAFIII400 mg orally twice daily20710.812.2Hand– foot skin reaction (76%), diarrhea (69%), alopecia (67%), rash (50%)Hand-foot skin reaction (20%), hypertension (10%), weight loss (6%)19%
Lenvatinib[7]; NCT01321554VEGFR1–3, FGFR1–4, PDGFR, RET, c-kitIII24 mg per d in 28-d cycles26163.2; 65 (4 complete response + 165 partial response)18.3Hypertension (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]; NCT01811212VEGFR2, MET, FLT3, RET, c-kitII60 mg/d orally254012.7Fatigue (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]; NCT00094055VEGFR, PDGFR, c-kitII5 mg twice daily603018.1Fatigue (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]; NCT00537095VEGFR2/3, EGFR, RETII300 mg/d728.311.1Diarrhea (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]; NCT00381641PDGFR, FLT3, c-kit, VEGFR, RETII37.5 mg/d orally353112.8Neutropenia (34%), leukopenia (31%), fatigue (26%), HFS (26%), diarrhea (26%)Neutropenia (34%), leukopenia (31%), diarrhea, hand/foot syndrome (17%), fatigue (11%)11%
Pazopanib[74]; NCT00625846VEGFR, PDGFR, c-kitII800 mg/d orally in 4-wk cycle374911.7Fatigue (78%), skin and hair hypopigmentation (75%), diarrhea (73%), nausea (73%)Raised alanine aminotransferase level (11%) 5%
Dovitinib[75]; NCT02964144FGFR, VEGFRII500 mg/d orally for five days, followed by a 2-d rest every week4020.55.4Diarrhea (54%), anorexia (36%), vomiting (26%), fatigue (23%), and nausea (21%)Neutropenia (13%)20%
Apatinib[31]; NCT03167385VEGFR2, c-Kit, c-SRCII750 mg/d orally (n = 10, group I) - 500 mg/d orally (n = 10, group II)2090 (I); 70 (II)18.4Hand– foot skin reaction (95%), proteinuria (90%) and hypertension (80%)
Lapatinib[76]; NCT01947023HER2/3I750 mg initial dose, escalated to 500 mg daily; + Dabrafenib 150 mg twice daily136015Lymphocytic toxicity (7%)
Vemurafenib[58]; NCT01286753BRAF V600EII960 mg orally twice daily51VEGFR naive: 39%; Previous VEGFR: 27% VEGFR naive: 18.8; Previous VEGFR: 8.9Rash (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]; NCT00880321BRAF V600EI150 mg twice daily132911.3Skin papillomas (57%), hyperkeratosis (36%), alopecia (29%)Elevated lipase, elevated amylase, fatigue, febrile neutropenia and squamous cell carcinoma (7%)0%
Selumetinib[66]; NCT00559949MEK-1/2, RAS, BRAF V600EII100 mg twice daily for 28-d cycles3938Rash (77%), fatigue (49%), diarrhea (49%), peripheral edema (36%)Rash (18%), fatigue (8%)15%
Larotrectinib[33]; NCT02122913NTRK fusionsII100 mg twice daily153129 (95%); 24 (16%) complete response 28.3Fatigue (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 fusionsII600 mg/d orally545010Dysgeusia (47%), fatigue, constipation (28%), diarrhea (27%), edema peripheral, dizziness (24%)Anemia (12%), weight gain (10%)4%
Everolimus[62]; NCT01118065mTORII10 mg/d orally33312.9Mucositis, acneiform rash, fatigue, coughFatigue (8%), weight loss, infection (6%)
Temsirolimus[63]; NCT01025453mTORIITemsirolimus (25 mg IV weekly) + sorafenib (200 mg twice daily) 362212Hyperglycemia (19%), fatigue (13%), anemia (11%), oral mucositis, alanine aminotransferase increased (8%)14%
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], 200827DTC 265919-HFS, 93%Hypertension, 13%
Kloos et al[78], 200933PTC15571623Fatigue, 85%Fatigue, 16%
Hoftijzer et al[79], 200931DTC253414.5-HFS, 66%HFS, 18%
Cabanilas et al[59], 201013DTC206019HFS, 60%-
Keefe et al[80], 201147DTC/PD 38472232.4--
Ahmed et al[81], 201119DTC16---Dermatology (other than HFS), 88%HFS, 44%
Chen et al[82], 20119DTC334410.5-Alopecia, 100%-
Marotta et al[83], 201217DTC3041910HFS, 88%
Schneider et al[84], 201231DTC31421834.5HFS, 71%HFS, 22%
Capdevilla et al[85], 201216DTC195013.323.6HFS and diarrhea, 62%HFS, 23%
Brose et al[6], 2014207DTC124210.8.HFS, 73.6%HFS, 20.3%
Benekli et al[86], 201414DTC-4321.3--HFS, 22%
Dadu et al[87], 200851DTC---56--
Luo et al[88], 20148DTC50379.412.8Alopecia, 75%Hypocalcemia and serum amylase increased, 12.5%
Gallo et al[89], 201520DTC25408.228.4Fatigue, 95%Gastrointestinal symptoms, 15%
Kim et al[90], 201898DTC25379.7-HFS, 76%HFS, 41%
Jerkovich et al[12], 201918DTC117216.5-HFS, 67%HFS, 14%
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] 2015261251632318.3-Hypertension, 68%Hypertension, 42%
Berdelou et al[16], 201775680315110-Fatigue, 75%Hypertension 35%
Jasim et al[17], 2017253105028--Hypertension 64%Hypertension 40%
Sugino et al[18], 2018291306921--Hypertension 76%-
Locati et al[19], 201994640364110.823.8Fatigue, 13%Fatigue, 8%
Lee et al[20], 20195789038605.119.3General weakness 43%
Masaki et al[21], 201942100622413.8-Hypertension, 83%Proteinuria, 36%
Aydemirli et al[22], 20203977233379.718.3Hypertension and fatigue, 64%Hypertension, 28%
Jerkovich et al[23], 202022594323213.7-Hypertension, 64%Hypertension, 23%
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
NCT04554680Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Redifferentiation Therapy RecruitingDrug: Dabrafenib and trametinibStudy 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
NCT01709292Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid CancerActive, not recruitingDrug: 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 BPhase: Phase 2 Sex: AllStudy 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 UnknownDrug: Apatinib mesylateStudy type: Interventional Enrollment: n = 20 Age: 18 to 75 yrStudy start: March 22, 2017 Tianjin Medical University Cancer Institute and Hospital, Tianjin, Tianjin, China
Phase: Phase 2 Sex: AllStudy 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
NCT03753919Durvalumab Plus Tremelimumab for the Treatment of Patients With Progressive, Refractory Advanced Thyroid Carcinoma - The DUTHY TrialRecruitingDrug: Durvalumab Drug: TremelimumabStudy type: Interventional Enrollment: 46 Age: 18 yr and older Study start: April 2Instituto 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: AllStudy 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
NCT00537095Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer Active, not recruitingDrug: Vandetanib Other: PlaceboStudy 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: AllStudy 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
NCT03602495Donafenib in 131I-Refractory Differentiated Thyroid Cancer RecruitingDrug: Donafenib Drug: PlaceboStudy type: Interventional Enrollment: n = 204 Age: 18 yr and olderStudy start: August 29, 2018 Peking Union Medical College Hospital, Beijing, Beijing, China
Phase: Phase 3 Sex: AllStudy 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