Table 1. Summary of Phase 3 Clinical Trials of Vandetanib and Cabozantinib versus Placebo in Patients with Advanced Medullary Thyroid Carcinoma.

Variable	Vandetanib	Cabozantinib
Targets	VEGFR, RET, EGFR	VEGFR, RET, c-MET
Clinical trial	ZETA study	EXAM study
No. of patients	331	330
Randomization (drug vs. placebo)	2:1, crossover allowed	2:1, crossover not allowed
Radiologic progression before enrolment	Not requested	Yes (within 14 mo)
Previous treatment, %	40	38
Previous TKIs, %	Unknown	20
Distant metastasis, %	94	95
Hereditary disease, %	10	6
RET mutation positive, %	38	45
RET 918, %	Not available	35
Follow-up duration, mo	24	14
Results
Median progression-free survival, mo	30.5 vs. 19.3 (HR, 0.46; P<0.001)	11.2 vs. 4.0 (HR, 0.28; P<0.001)
Objective response rate, %	45 vs. 13	28 vs. 0
Complete response rate, %	0	0
Stable disease, %	Not available	48.1 vs. 50
Survival, mo	Not available	27 vs. 21
Biochemical response, %	69 vs. 3	45 vs. 0
Safety
Toxic effects (≥grade 3), %	55 (24)	69 (33)
Most common adverse events at least grade 3	Diarrhea, hypertension, QTc prolongation, fatigue	Diarrhea, palmar-plantar erythrodysesthesia, fatigue
Deaths, %	2 vs. 2 (placebo)	5.6 vs. 2.8 (placebo)

VEGFR, vascular endothelial growth factor receptor; RET, rearranged during transfection; EGFR, epidermal growth factor receptor; c-MET, hepatocyte growth factor receptor; ZETA, Zactima Efficacy in Thyroid Cancer Assessment; EXAM, Efficacy of XL184 (cabozantinib) in Advanced Medullary Thyroid Cancer; TKI, tyrosine kinase inhibitor; HR, hazard ratio; QTc, corrected QT.