Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy

Abstract

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Keywords: differentiated thyroid cancer; multikinase inhibitor; progression-free survival; radioiodine refractory; vandetanib.

Figure 1

Study design and patient disposition. ^aInformed consent received. ^bAll randomized patients, regardless of whether they took study treatment. ^cPatients continued to receive randomized treatment until objective disease progression (RECIST version 1.1) or for as long as they received clinical benefit in the opinion of the investigator, unless any of the criteria for treatment discontinuation were met first. Patients who discontinued study treatment for reasons other than disease progression had to continue tumor assessments as per the Study Plan and until progression. ^dThe corresponding category in the electronic case report form was ‘Condition under investigation worsened’. ^eOnce PFS analysis had been performed, there was no longer a requirement for central confirmation of progression prior to open-label treatment. PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2

Kaplan–Meier curve of progression-free survival (efficacy analysis set).

Figure 3

Forest plot of progression-free survival by subgroup (efficacy analysis set). Hazard ratio (HR) and 95% CI. HR < 1 favors vandetanib 300 mg over placebo. Gray band represents the 95% CI for the overall (all patients) HR. Size of box is proportional to the number of events. HR and CI shown only for subgroups with ≥6 events. RECIST version 1.1. ECOG, Eastern Cooperative Oncology Group; PTC, papillary thyroid carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged during transfection; WHO, World Health Organization.

Figure 4

Waterfall plot of best percentage change in target lesion size from baseline (efficacy analysis set).

Figure 5

Kaplan–Meier curve for overall survival (efficacy analysis set). Circle indicates censored observation.