World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://wjon.elmerpub.com

Review

Volume 17, Number 5, October 2026, pages 599-613

Magnitude of Survival Benefit Associated With Tyrosine Kinase Inhibitors in Advanced Thyroid Carcinoma: A Systematic Review and Meta-Analysis Incorporating Updated Long-Term Evidence From SELECT (Lenvatinib) and COSMIC-311 (Cabozantinib) Trials

↓ Figure 1. PRISMA flow chart demonstrating search strategy for inclusion of studies reporting randomized controlled trials for tyrosine kinase inhibitors in thyroid carcinoma. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

↓ Figure 3. Forest plots of progression free survival (PFS). (a) Drug vs placebo. (b) Drug specific subgroup analysis. HR: hazard ratio; CI: confidence interval; MTC: medullary thyroid carcinoma; DTC: differentiated thyroid cancer.

↓ Figure 4. Forest plots of overall survival (OS). (a) Drug vs placebo. (b) Drug specific subgroup analysis. HR: hazard ratio; CI: confidence interval.

↓ **Table 1.** Baseline Characteristics of Placebo-Controlled Targeted Therapy Trials
Study	Registration ID	Malignancy	Phase	Number of patients	Sex of patients	Intervention vs comparator	OS HR (95% CI)	Median follow -up time^a	Median PFS in months (drug)	Median PFs in months (placebo)	PFS HR (95% CI)
^aD: drug; P: placebo. MTC: medullary thyroid carcinoma; RR-DTC: radioiodine-refractory differentiated thyroid cancer; BID: twice daily; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; DTC: differentiated thyroid cancer.
Wells et al, 2012 [37]	NCT00410761	MTC	III	331	Male: 58%/56%	Vandetanib 300 mg vs placebo	0.89 (0.48–1.65)	D (24)/P (24)	30.5	19.3	0.46 (0.31–0.69)
Leboulleux et al, 2012 [48]	NCT00537095	RR-DTC	II	145	Male: 54%/53%	Vandetanib 300 mg vs placebo	0.83 (0.52–1.33)	D (18.9)/P (19.5)	11.1	5.9	0.63 (0.43–0.92)
Elisei et al, 2013 [40]	NCT00704730	MTC	III	330	Male: 68.9%/63.1%	Cabozantinib 140 mg vs placebo	0.98 (0.63–1.52)	D (13.9)/P (13.9)	11.2	4	0.28 (0.19–0.40)
Brose et al, 2014 [39]	NCT00984282	RR-DTC	III	417	Male: 50.2%/45.2%	Sorafenib 400 mg BID vs placebo	0.80 (0.54–1.19)	D (16.2)/P (16.2)	10.8	5.8	0.59 (0.45–0.76)
Schlumberger et al, 2015 [25]	NCT01321554	RR-DTC	III	392	Male: 47.9%/57.3%	Lenvatinib 24 mg vs placebo	0.62 (0.40–1.00)	D (17.1)/P (17.4)	18.3	3.6	0.21 (0.14–0.31)
Schlumberger et al, 2017 [38]	NCT00704730	MTC	III	330	Male: 68.9%/63.1%	Cabozantinib 140 mg vs placebo	0.85 (0.64–1.12)	Not found	Not available	Not available	0.28 (0.19–0.40)
Li et al, 2021 [46]	NCT02586350	MTC	IIB	91	Male: 68%/62%	Anlotinib 12 mg vs placebo	0.92 (0.43–1.97)	D (25.8)/P (24.8)	20.7	11.1	0.53 (0.30–0.95)
Lin et al, 2022 [45]	NCT03048877	RR-DTC	III	92	Male: 41.3%/37.0%	Apatinib 500 mg vs placebo	0.42 (0.18–0.97)	D (18.1)/P (18.1)	20.2	4.5	0.26 (0.14–0.47)
Zheng et al, 2021 [47]	NCT02966093	RR-DTC	III	151	Male: 55.3%/43.8%	Lenvatinib 24 mg vs placebo	0.84 (0.39–1.83)	D (14.8)/P (15.6)	23.9	3.7	0.16 (0.10–0.26)
Brose et al, 2021 [42]	NCT03690388	RR-DTC	III	187	Male: 46%/45%	Cabozantinib 60 mg vs placebo	0.54 (0.27–1.11)	D (6.2)/P (6.2)	Not reached	1.9	0.22 (0.13–0.36)
Leboulleux et al, 2024 [33]	NCT01788982	RR-DTC + MTC	II	101	DTC male: 44.3%; MTC male: 74.2%	Nintedanib vs placebo	DTC: 1.00 (0.41–2.44); MTC: 0.88 (0.24–3.21)	DTC (D (26.3)/P (19.8)); MTC (D (48.4)/P (19.7))	DTC (3.7)/MTC (7)	DTC (2.9)/MTC (3.9)	DTC: 0.65 (0.34–1.25); MTC: 0.49 (0.16–1.53)

↓ Table 1. Baseline Characteristics of Placebo-Controlled Targeted Therapy Trials

Study

Registration ID

Malignancy

Phase

Number of patients

Sex of patients

Intervention vs comparator

OS HR (95% CI)

Median follow -up time^a

Median PFS in months (drug)

Median PFs in months (placebo)

PFS HR (95% CI)

^aD: drug; P: placebo. MTC: medullary thyroid carcinoma; RR-DTC: radioiodine-refractory differentiated thyroid cancer; BID: twice daily; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval; DTC: differentiated thyroid cancer.

Wells et al, 2012 [37]

NCT00410761

MTC

III

331

Male: 58%/56%

Vandetanib 300 mg vs placebo

0.89 (0.48–1.65)

D (24)/P (24)

30.5

19.3

0.46 (0.31–0.69)

Leboulleux et al, 2012 [48]

NCT00537095

RR-DTC

145

Male: 54%/53%

Vandetanib 300 mg vs placebo

0.83 (0.52–1.33)

D (18.9)/P (19.5)

11.1

5.9

0.63 (0.43–0.92)

Elisei et al, 2013 [40]

NCT00704730

MTC

III

330

Male: 68.9%/63.1%

Cabozantinib 140 mg vs placebo

0.98 (0.63–1.52)

D (13.9)/P (13.9)

11.2

0.28 (0.19–0.40)

Brose et al, 2014 [39]

NCT00984282

RR-DTC

III

417

Male: 50.2%/45.2%

Sorafenib 400 mg BID vs placebo

0.80 (0.54–1.19)

D (16.2)/P (16.2)

10.8

5.8

0.59 (0.45–0.76)

Schlumberger et al, 2015 [25]

NCT01321554

RR-DTC

III

392

Male: 47.9%/57.3%

Lenvatinib 24 mg vs placebo

0.62 (0.40–1.00)

D (17.1)/P (17.4)

18.3

3.6

0.21 (0.14–0.31)

Schlumberger et al, 2017 [38]

NCT00704730

MTC

III

330

Male: 68.9%/63.1%

Cabozantinib 140 mg vs placebo

0.85 (0.64–1.12)

Not found

Not available

0.28 (0.19–0.40)

Li et al, 2021 [46]

NCT02586350

MTC

IIB

Male: 68%/62%

Anlotinib 12 mg vs placebo

0.92 (0.43–1.97)

D (25.8)/P (24.8)

20.7

11.1

0.53 (0.30–0.95)

Lin et al, 2022 [45]

NCT03048877

RR-DTC

III

Male: 41.3%/37.0%

Apatinib 500 mg vs placebo

0.42 (0.18–0.97)

D (18.1)/P (18.1)

20.2

4.5

0.26 (0.14–0.47)

Zheng et al, 2021 [47]

NCT02966093

RR-DTC

III

151

Male: 55.3%/43.8%

Lenvatinib 24 mg vs placebo

0.84 (0.39–1.83)

D (14.8)/P (15.6)

23.9

3.7

0.16 (0.10–0.26)

Brose et al, 2021 [42]

NCT03690388

RR-DTC

III

187

Male: 46%/45%

Cabozantinib 60 mg vs placebo

0.54 (0.27–1.11)

D (6.2)/P (6.2)

Not reached

1.9

0.22 (0.13–0.36)

Leboulleux et al, 2024 [33]

NCT01788982

RR-DTC + MTC

101

DTC male: 44.3%; MTC male: 74.2%

Nintedanib vs placebo

DTC: 1.00 (0.41–2.44); MTC: 0.88 (0.24–3.21)

DTC (D (26.3)/P (19.8)); MTC (D (48.4)/P (19.7))

DTC (3.7)/MTC (7)

DTC (2.9)/MTC (3.9)

DTC: 0.65 (0.34–1.25); MTC: 0.49 (0.16–1.53)

↓ **Table 2.** Baseline Characteristics of Active-Comparator (Dose vs Dose) Targeted Therapy Trials
Study	Registration ID	Malignancy	Phase	Number of patients	Sex of patients	Intervention vs comparator	OS HR (95% CI)	Median follow -up time^a	Median PFS in months (drug)	Median PFs in months (drug)	PFS HR (95% CI)
^aD: drug; P: placebo. MTC: medullary thyroid carcinoma; RR-DTC: radioiodine-refractory differentiated thyroid cancer; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval.
Brose et al, 2022 [35]	NCT02702388	RR-DTC	II	152	Male: 54.7%/48.1%	Lenvatinib 24 mg vs lenvatinib 18 mg	Not reported	D (12.8)/D (11.2)	24 mg (not reached)	18 mg (24.4)	1.44 (0.76–2.74)
Capdevila et al, 2022 [36]	NCT01896479	MTC	IV	247	Male: 73%/60%	Cabozantinib 60 mg vs 140 mg	1.12 (0.77–1.63)	D (30)/D (30)	60 mg (11)	140 mg (13.9)	1.24 (0.90–1.70)
Lin et al, 2021 [32]	NCT02870569/CTR20160220	RR-DTC	II	35	Not clearly extracted	Donafenib 300 mg vs 200 mg	Not reported	Not reported	300 mg (14.98)	200 mg (9.44)	0.678 (0.298–1.547)

↓ Table 2. Baseline Characteristics of Active-Comparator (Dose vs Dose) Targeted Therapy Trials

Study

Registration ID

Malignancy

Phase

Number of patients

Sex of patients

Intervention vs comparator

OS HR (95% CI)

Median follow -up time^a

Median PFS in months (drug)

Median PFs in months (drug)

PFS HR (95% CI)

^aD: drug; P: placebo. MTC: medullary thyroid carcinoma; RR-DTC: radioiodine-refractory differentiated thyroid cancer; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; CI: confidence interval.

Brose et al, 2022 [35]

NCT02702388

RR-DTC

152

Male: 54.7%/48.1%

Lenvatinib 24 mg vs lenvatinib 18 mg

Not reported

D (12.8)/D (11.2)

24 mg (not reached)

18 mg (24.4)

1.44 (0.76–2.74)

Capdevila et al, 2022 [36]

NCT01896479

MTC

247

Male: 73%/60%

Cabozantinib 60 mg vs 140 mg

1.12 (0.77–1.63)

D (30)/D (30)

60 mg (11)

140 mg (13.9)

1.24 (0.90–1.70)

Lin et al, 2021 [32]

NCT02870569/CTR20160220

RR-DTC

Not clearly extracted

Donafenib 300 mg vs 200 mg

Not reported

300 mg (14.98)

200 mg (9.44)

0.678 (0.298–1.547)

↓ **Table 3.** Updated Analysis of SELECT (Lenvatinib) and COSMIC-311 (Cabozantinib) Trials With Key Outcomes
Study	Trial number	Experimental vs comparator	Subgroup/analysis type	PFS findings: drug vs placebo	Key outcome reported
NQ: not quantifiable; PFS: progression-free survival; DTC: differentiated thyroid cancer; RR-DTC: radioiodine-refractory differentiated thyroid cancer; RAI: radioactive iodine; TKI: tyrosine kinase inhibitor; HR: hazard ratio; CI: confidence interval.
Kiyota et al, 2017 [43]	NCT01321554	Lenvatinib 24 mg/day vs placebo	No RAI uptake: 275 patients	NQ vs 3.7 months	Treatment outcomes were comparable regardless of the RR-DTC definition used, suggesting that different diagnostic criteria identify clinically similar patient populations.
			Disease progression despite RAI avidity: 235 patients	16.5 vs 3.7 months
			Extensive RAI exposure: 73 patients	18.7 vs 3.6 months
Gianoukakis et al, 2018 [44]	NCT01321554	Lenvatinib 24 mg/day vs placebo	Overall updated SELECT analysis	19.4 vs 3.7 months; HR 0.24; 99% CI, 0.17–0.35	The updated SELECT analysis confirmed sustained PFS benefit with lenvatinib, with responders showing significantly longer PFS than non-responders.
			Responders vs non-responders	Responders: 33.1 months vs 7.9 months in non-responders
Brose et al, 2022 [34]	NCT03690388	Cabozantinib 60 mg/day vs placebo	Overall updated COSMIC: 311 analyses	11.0 vs 1.9 months; HR 0.22; 96% CI, 0.15–0.32	Long-term follow-up supported the sustained efficacy of cabozantinib in previously treated RAIR-DTC, while maintaining a consistent safety profile.
Capdevila et al, 2024 [41]	NCT03690388	Cabozantinib 60 mg/day vs placebo	Prior sorafenib only	16.6 vs 3.2 months; HR 0.13; 95% CI, 0.06–0.26	Cabozantinib consistently improved PFS across all treatment history and histological subgroups, indicating that its therapeutic benefit is maintained regardless of prior TKI exposure or differentiated thyroid carcinoma subtype.
			Prior lenvatinib only	5.8 vs 1.9 months; HR 0.28; 95% CI, 0.16–0.48
			Prior sorafenib + lenvatinib	7.6 vs 1.9 months; HR 0.27; 95% CI, 0.13–0.54
			Papillary DTC	9.2 vs 1.9 months; HR 0.27; 95% CI, 0.17–0.43
			Follicular DTC	11.2 vs 2.5 months; HR 0.18; 95% CI, 0.10–0.31
			Oncocytic DTC	11.2 vs 2.5 months; HR 0.06; 95% CI, 0.02–0.21
			Poorly differentiated DTC	7.4 vs 1.8 months; HR 0.18; 95% CI, 0.08–0.43

↓ Table 3. Updated Analysis of SELECT (Lenvatinib) and COSMIC-311 (Cabozantinib) Trials With Key Outcomes

Study

Trial number

Experimental vs comparator

Subgroup/analysis type

PFS findings: drug vs placebo

Key outcome reported

NQ: not quantifiable; PFS: progression-free survival; DTC: differentiated thyroid cancer; RR-DTC: radioiodine-refractory differentiated thyroid cancer; RAI: radioactive iodine; TKI: tyrosine kinase inhibitor; HR: hazard ratio; CI: confidence interval.

Kiyota et al, 2017 [43]

NCT01321554

Lenvatinib 24 mg/day vs placebo

No RAI uptake: 275 patients

NQ vs 3.7 months

Treatment outcomes were comparable regardless of the RR-DTC definition used, suggesting that different diagnostic criteria identify clinically similar patient populations.

Disease progression despite RAI avidity: 235 patients

16.5 vs 3.7 months

Extensive RAI exposure: 73 patients

18.7 vs 3.6 months

Gianoukakis et al, 2018 [44]

NCT01321554

Lenvatinib 24 mg/day vs placebo

Overall updated SELECT analysis

19.4 vs 3.7 months; HR 0.24; 99% CI, 0.17–0.35

The updated SELECT analysis confirmed sustained PFS benefit with lenvatinib, with responders showing significantly longer PFS than non-responders.

Responders vs non-responders

Responders: 33.1 months vs 7.9 months in non-responders

Brose et al, 2022 [34]

NCT03690388

Cabozantinib 60 mg/day vs placebo

Overall updated COSMIC: 311 analyses

11.0 vs 1.9 months; HR 0.22; 96% CI, 0.15–0.32

Long-term follow-up supported the sustained efficacy of cabozantinib in previously treated RAIR-DTC, while maintaining a consistent safety profile.

Capdevila et al, 2024 [41]

NCT03690388

Cabozantinib 60 mg/day vs placebo

Prior sorafenib only

16.6 vs 3.2 months; HR 0.13; 95% CI, 0.06–0.26

Cabozantinib consistently improved PFS across all treatment history and histological subgroups, indicating that its therapeutic benefit is maintained regardless of prior TKI exposure or differentiated thyroid carcinoma subtype.

Prior lenvatinib only

5.8 vs 1.9 months; HR 0.28; 95% CI, 0.16–0.48

Prior sorafenib + lenvatinib

7.6 vs 1.9 months; HR 0.27; 95% CI, 0.13–0.54

Papillary DTC

9.2 vs 1.9 months; HR 0.27; 95% CI, 0.17–0.43

Follicular DTC

11.2 vs 2.5 months; HR 0.18; 95% CI, 0.10–0.31

Oncocytic DTC

11.2 vs 2.5 months; HR 0.06; 95% CI, 0.02–0.21

Poorly differentiated DTC

7.4 vs 1.8 months; HR 0.18; 95% CI, 0.08–0.43