TABLE 1.

Summary of selected studies

No.	References	Study design	Population	Mean age and sample size	Intervention, number of patients and mean follow‐up duration	Control, number of patients and mean follow‐up duration	Findings
1	Kiyota 2017	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63.0 years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients 17.1 months	Oral placebo once daily, continuously until toxicity or disease progression 131 patients 17.4 months	‐Patients were stratified into 3 categories for comparison: ‘No radioactive iodine (RAI) uptake’, ‘Disease progression despite RAI avidity’ and ‘Extensive RAI exposure’ ‐Median progression‐free survival (PFS) in ‘No RAI uptake’ group was not reached (NR, 95% CI 14.8 to NR) and 3 months (95% CI 2.5‐5.3) in the lenvatinib and placebo arms, respectively. ‐Median PFS in ‘Disease progression despite RAI avidity’ was 16.5 months (95% CI 12.8 to NR) and 3.7 months (95% CI, 1.9‐5.4) in the lenvatinib and placebo arms, respectively ‐Median PFS in ‘Extensive RAI exposure’ group was 18.7 months (95% CI 10.7 to NR) and 3.6 months (95% CI 1.9‐5.5) in lenvatinib and placebo arms, respectively ‐The hazard ratio for progression of death compared with placebo arms was 0.21 (95% CI 0.15‐0.29; P < .001), 0.24 (95% CI 0.16‐0.36; P < .001) and 0.22 (95% CI, 0.10‐0.48; P < .001) ‐Overall response rates (ORRs) are 71.8%, 60.0% and 56.0% in patients receiving lenvatinib in the ‘no RAI uptake’, ‘disease progression despite RAI activity’ and ‘extensive RAI exposure’ groups, respectively. ORRs are 2.0%, 1.3% and 0% in the placebo arms of the above categories, respectively ‐Treatment‐related adverse events (of all grades) were experienced in more than 96% of patients receiving lenvatinib. 50% of patients experienced adverse events in placebo group ‐Incidence of treatment‐related adverse events (grade 3 or above) was experienced in more than 70% of patients receiving lenvatinib in 3 categories. The incidence rate is 0% to 10% in placebo arms of the 3 categories
2	Schlumberger 2015	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63.0 years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients 17.1 months (95% CI, 16.0 to 17.6; IQR, 14.4 to 20.4)	Oral placebo once daily, continuously until toxicity or disease progression 131 patients 17.4 months (95% CI, 15.9 to 19.0; IQR, 0.27; 14.8 to 20.4)	‐Median progression‐free survival was 18.3 months (95% CI, 15.1 to not estimable) in lenvatinib group; the placebo group was 3.6 months (95% CI, 2.2 to 3.7). Hazard ratio for progression or death compared to placebo group, 0.21 99% CI 0.14 to 0.31; P < .001 ‐6‐month progression‐free survival rates were 77.5% and 25.4% in lenvatinib and placebo groups, respectively ‐Subgroup analysis of lenvatinib group, median progression‐free survival for patients without prior tyrosine kinase inhibitor (TKI) and with prior TKI was 18.7 months and 15.1 months, respectively ‐Progression‐free survival benefit maintained regardless of BRAF or RAS mutation status in patients ‐Significant improvement response rate in lenvatinib group (64.8%) vs placebo group (1.5%); odd ratio 28.87 (95% CI, 12.46 to 66.86; P < .001) ‐Overall survival (OS) was not significant (hazard ratio for death 0.73; 95% CI, 0.50 to 1.07, P = .10) ‐Treatment‐related adverse events (of all grades) in lenvatinib group were 97.3% and 59.5% in placebo group ‐Incidences of treatment‐related adverse events of grade 3 or higher were 75.9% and 9.9% in lenvatinib and placebo group, respectively
3	Brose 2017	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	62.0 years 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients 17.1 months	Oral placebo once daily, continuously until toxicity or disease progression 131 patients 17.1 months	‐In patients younger than 65 years, median PFS was 20.2 months and 3.2 months in lenvatinib and placebo group, respectively (hazard ratio 0.19; 95% CI 0.13 to 0.27, P < .001) ‐In patients older than 65 years, median PFS was 16.7 months and 3.7 months in lenvatinib and placebo group, respectively (hazard ratio 0.27; 95% CI, 0.17 to 0.43; P < .001) ‐Median OS achieved in older placebo‐treated patients was 18.4 months; 95% CI 13.3 to 20.3 ‐Within lenvatinib group, longer OS was observed in patients less than 65 years, compared with those older (hazard ratio 0.53; 95% CI 0.31 to 0.9; P = .02) ‐Better ORR in lenvatinib group, compared with placebo group regardless of age (younger patients; odd ratio 45.7; 95% CI 14.8 to 141.0, P < .001 vs older patients, odd ratio 16.8, 95% CI 4.7 to 60.0, P < .001) ‐Among patients younger than 65 years, change of tumour size was −40.3% in lenvatinib group, compared with + 5.5% in placebo group ‐Among patients older than 65 years, change of tumour size was −41.5% in lenvatinib group, compared with + 0.6% in placebo group
4	Gianoukakis 2018	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	Average age unreported and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients 58 months	Oral placebo once daily, continuously until toxicity or disease progression 131 patients 36 months	‐Median PFS was 19.4 months in lenvatinib group, compared with 3.7 months in placebo group (hazard ratio 0.24, 99% CI 0.17‐0.35; P < .001) ‐Median PFS was 33.1 months (95% CI, 27.8 to 44.6) in lenvatinib responders, compared with 7.9 months (95% CI 5.8‐10.7) in poor responders ‐ORR was 60.2% (95% CI, 54.2 to 66.1) for lenvatinib‐treated patients, compared with 2.3% (95% CI 0.0 to 4.9) for placebo‐treated patients ‐Median duration of response (DOR) was shorter in patients with heavier disease burden (tumour size less than 35 nm: 44.3 months; tumour size 35‐60 nm: 27.5 months; tumour size 60‐92 nm: 18.0 months; tumour size more than 92 nm: 15.7 months), patients with liver metastasis (yes: 15.7 months; no: 30.5 months) and patients with brain metastasis (yes: 9.3 months; no: 30.5 months)
5	Kiyota 2015	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	65.4 years and 40 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 30 patients	Oral placebo once daily, continuously until toxicity or disease progression 10 patients	‐Median progression‐free survival in lenvatinib group is 16.5 months (95% CI, 7.4‐not estimable), compared with 3.7 months (95% CI, 1.6‐9.1) in placebo group. Hazard ratio is 0.39 (99% CI, 0.10‐1.57, P = .067) ‐Median DOR is 16.6 months (95% CI 14.6‐NE) ‐Higher ORR in lenvatinib group (63.3%) compared with 0% for placebo (odd ratio 11.64; 95% CI 1.68‐80.82, P < .001) ‐83.3% clinical benefit rate in lenvatinib group, compared to 30.0% for placebo (OR, 5.68; 95% CI, 0.90‐35.92, P = .002)
6	Robinson 2016	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	Age unreported and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients	Oral placebo once daily, continuously until toxicity or disease progression 131 patients	‐Mean percentage change of tumour size is −45.9% for lenvatinib group vs 2.7% for placebo group (P < .001) in patients with lung metastasis ‐Mean percentage change of tumour size is −35.6% for lenvatinib group vs 5.1% for placebo group (P < .001) in patients with liver metastasis Mean percentage change of tumour size is −10.7% for lenvatinib group vs 6.5% for placebo group (P < .01) in patients with bone metastasis ‐Median maximum percentage change in tumour size was −42.9% for all patients receiving lenvatinib ‐Median time to first objective response was 2.0 months (95% CI 1.9‐3.5) ‐Responders to lenvatinib reduced median target lesion size by −51.9% (range, −100 to −30.3). ‐Non‐responders achieved median target lesion reduction by −20.3% (range, −37.8 to 65.6 ‐Lenvatinib‐induced tumour reduction was in two phases: phase one change of median average tumour size by −25.0% by 8 weeks, followed by phase two an average rate of reduction by 1.3% monthly ‐Median tumour size change was −22.1% by week 8, −29.6% at week 16 and greater than 50% by week 88
7	Tahara 2017	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	61.9 years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients	Oral placebo once daily, continuously until toxicity or disease progression 131 patients	‐Lenvatinib PFS benefits observed in all subgroups regardless of tumour BRAF or RAS mutation status ‐BRAF mutation was associated with PFS in both univariate (P = .031) and multivariate (P = .0083) analyses in the placebo arm ‐Baseline Ang2 levels correlated with PFS (P = .0067) in the placebo arm and with maximum tumour shrinkage (MTS), ORR and PFS in the lenvatinib arm (P < .001 for each) ‐Baseline VEGF levels correlated significantly with MTS, ORR and PFS in the placebo in arm (P = .044, P = .038 and P = .037, respectively) and with MTS (P = .0082) and with ORR (P = .0009) in the lenvatinib group ‐High baseline thyroglobulin level may be a prognostic factor for poorer PFS in radioiodine‐refractory differentiated thyroid cancer ‐Thyroglobulin level decreased significantly in patients treated with lenvatinib, but increased in placebo patients at each treatment cycle
8	Tahara 2018	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63.2 years and 261 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression, but with dose interruption less than 0 134 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression, but with dose interruption more than 10%. 127 patients	‐Median PFS for the shorter lenvatinib dose‐interruption group (less than 10%) was not yet reached, while the median PFS for the longer lenvatinib dose‐interruption group (more than 10%) was 12.8 months ‐Hazard ratio for mortality risk was 0.14 (95% CI 0.09‐0.20) in shorter lenvatinib dose‐interruption group, compared with placebo ‐Hazard ratio for mortality risk was 0.31 (95% CI 0.22‐0.43) in longer lenvatinib dose‐interruption group, compared with placebo ‐Patients in the shorter dose‐interruption group had a better objective response rate (ORR; 76.1%) than those in the longer dose‐interruption group (52.8%)
9	Wirth 2018	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63.0 years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients	Oral placebo once daily, continuously until toxicity or disease progression 131 patients	‐47% lenvatinib‐based patients experienced their first occurrence of treatment‐emergent hypertension (TE‐HTN) during cycle 1 of treatment compared with 6% of placebo‐treated patients ‐The first occurrence of worst‐grade TE‐HTN was also primarily in cycle 1 for both treatment groups (lenvatinib, 36%; placebo, 5%) ‐No difference in PFS improvement with lenvatinib between patients with and without baseline HTN (HR, 1.10; 95% CI, 0.75‐1.61; P = .6290) ‐Within lenvatinib group, PFS advantage was shown in patients with TE‐HTN than those without TE‐HTN (hazard ratio, 0.59; 95% CI, 0.39‐0.88, P = .0085) ‐Median PFS for lenvatinib‐treated patients was 18.8 months (95% CI, 16.5 months to not estimable) and 12.9 months (7.4 months to not estimable) in placebo (hazard ratio 0.59; 95% CI, 0.39 = 0.88; P = .0085) ‐Lenvatinib‐treated patients with TE‐HTN showed OS advantage compared with those without TE‐HTN (HR, 0.43, 95% CI, 0.27 to 0.69; P < .001) ‐ORR was 69% for lenvatinib‐treated patients with TE‐HTN and 56% for those without TE‐HTN (odds ratio, 1.72; 95% CI, 0.98‐3.01) ‐Within lenvatinib group, median change of tumour size for patients with TE‐HTN and without TE‐HTN is −45% and −40%, respectively
10	Haddad 2017	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	? years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients	Oral placebo once daily, continuously until toxicity or disease progression 131 patients	‐Grade 3 treatment‐emergent adverse events (TEAEs) occurred in 72% of lenvatinib‐treated patients and 22% of placebo‐treated patients ‐Grade 4 TEAEs occurred in 12% in lenvatinib‐treated patients and 8% of placebo‐treated patients ‐Following hypertension, the most common TEAEs in lenvatinib‐treated patients vs placebo‐treated patients included diarrhoea (67% vs 17%), fatigue/asthenia/malaise (67% vs 35%), proteinuria (32% vs 3%), rash (23% vs 5%) and Palmar‐plantar erythrodysesthesia syndrome (PPES; 33% vs 1%) ‐Median time to first onset of any‐grade TEAEs was 12.1 weeks (IQR: 4.1‐23.7 weeks); for diarrhoea, 3.0 weeks (IQR 1.1‐7.0 weeks); for fatigue/asthenia/malaise, 6.1 weeks (IQR: 2.9‐16.3 weeks); for rash 7.3 weeks (IQR: 2.9‐16.3 weeks) and 5.9 weeks for PPES in lenvatinib‐treated patients
11	Nair 2015	Phase 3, double‐blind, multicentre randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63 years and 392 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 261 patients	Oral placebo once daily, continuously until toxicity or disease progression 131 patients	‐Median PFS was 18.3 months (95% CI, 15.1‐not reached) in lenvatinib group, and it was 3.6 months (95% CI 2.2‐3.7). Hazard ratio 0.21 (95% CI 0.16‐0.28, P < .001) ‐Median OS was not reached (95% CI, 22.1‐not reached) in lenvatinib group, and it was not reached (95% CI, 20.3‐not reached) in placebo group. Hazard ratio 0.73 (95% CI, 0.50‐1.07, P = .10) ‐The ORRs in lenvatinib group and placebo group were 65% (95% CI, 59‐71) and 2% (95% CI, 0‐4). p‐value <.001.
12	Cabanillas 2015	Phase 2, open‐labelled, multicentre single arm clinical trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	63 years and 58 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 58 patients	No control	‐The ORR was 50% (95% CI, 37%‐63%) ‐ORR was similar in patients who had received VEGFR‐targeted therapy and those without. ‐The median PFS was 12.6 months (95% CI, 9.9‐16.1 months) ‐The 6‐month PFS rate was 78% (95% CI, 64%‐87%, and the 12‐month PFS rate was 55% (95% CI, 40%‐67%)
13	Schlumberger 2016	Phase 2, open‐labelled, multicentre single arm clinical trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	51.6 years and 59 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression 59 patients	No control	‐The ORR was 50% (95% CI, 37%‐63%) ‐The median duration of response for patients who had received prior VEGFR treatment and responded to lenvatinib therapy was 5.7 months (95% CI, 4.5‐not reached) and was not reached for lenvatinib responders without prior VEGFR treatment ‐The median PFS was 7.3 months (95% CI, 4.0‐not reached) in patients with prior VEGFR therapy and 12.9 months (95% CI, 7.1‐not reached) for patients without prior VEGFR therapy. ‐The median OS for patients with prior VEGFR therapy was 16.6 months (95% CI, not reached to not reached). Median OS was not reached for patients without prior VEGFR therapy ‐The disease control rate was 80% (95% CI, 67 to 89) ‐The 6‐month PFS rate was 67% (95% CI, 52%‐78%); the 12 month PFS rate was 46% (95% CI, 31%‐60%)
14	Takahashi 2019	Phase 2, open‐labelled, multicentre non‐randomized controlled trial	Pathologically confirmed thyroid carcinoma with evidence of radioiodine‐refractory disease	61.0 years and 51 patients	Lenvatinib 24 mg once daily continuously until toxicity or disease progression, but with dose interruption less than 10% 51 patients	No control	‐Patients were classified into subtype for further investigations: radioiodine‐refractory differentiated thyroid cancer (RR‐DTC), medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC) ‐The median PFS in patients with RR‐DTC, MTC and ATC was 25.8 months (95% CI: 18.4‐not reached), 9.2 months (95% CI: 1.8‐NR) and 7.4 months (95% CI: 1.7‐12.9) ‐The median OS in patients with RR‐DTC, MTC and ATC is 31.8 months (95% CI 31.8‐not reached), 12.1 months (95% CI: 3.8‐not reached) and 10.6 months (95% CI: 3.8‐19.8) ‐The objective response rate (ORR) in patients with RR‐DTC, MTC and ATC was 68%, 22% and 24% ‐The disease control rate in patients with RR‐DTC, MTC and ATC was 100%, 100% and 94%, respectively ‐The clinical benefit rate in patients with RR‐DTC, MTC and ATC was 84%, 78% and 71%, respectively