Vandetanib Does Not Meet PFS End Point for Advanced RAI-Refractory DTC

Phase 3 results show that treatment with vandetanib had no statistically significant improvement in PFS and more adverse effects than placebo.

Investigators found that vandetanib (Caprelsa), used for treatment in tyrosine kinase inhibitor–naïve patients with locally advanced or metastatic radioiodine (RAI)-refractory differentiated thyroid cancer (DTC), did not meet the primary end point of progression-free survival (PFS), according to results from the phase 3 VERIFY trial (NCT01876784) published in Endocrine-Related Cancer.

Data showed a median PFS of 10.0 months (95% CI, 6.0-11.1) in the vandetanib group and 5.7 months (95% CI, 5.5-8.4) in the placebo arm. Although subset analysis demonstrated that PFS was favorable in the vandetanib group, PFS was not significantly improved in the vandetanib arm vs the placebo arm as assessed by local review (HR, 0.75; 95% CI, 0.55-1.03; P = 0.080) and independent central review (HR, 0.75; 95% CI, 0.55-1.02; P = 0.065).

PFS in the vandetanib arm at 6, 12, and 18 months was 60.0% (95% CI, 50.1%-68.5%), 31.1% (95% CI, 21.0%-41.7%), and 16.9% (95% CI, 7.9%-28.9%), respectively. For patients who received placebo, the rates were 48.5% (95% CI, 39.1%-57.3%), 23.6% (95% CI, 15.3%-33.0%), and 9.8% (3.3%-20.6%), respectively.

Additional findings revealed greater incidence of adverse effects (AEs) and death in those treated with vandetanib over placebo. Furthermore, overall survival (OS) was not significantly different between either arm.

Of 235 patients, 97.4% in the vandetanib arm and 89.8% in the placebo arm experienced 1 or more AEs, with 18.8% in the vandetanib arm discontinuing treatment due to AEs vs 14.4% in the placebo arm. Serious AEs (SAEs) were reported in 29.9% of vandetanib-treated patients vs 16.9% of patients who received placebo. Furthermore, deaths were reported in 28.2% of the vandetanib arm vs 13.6% in the placebo arm.

Patients (n = 238) were randomly assigned to receive vandetanib (n = 119) or placebo (n = 119). Three patients did not receive treatment, as 2 withdrew from the study and 1 no longer met eligibility criteria, leaving 117 patients in the 300-mg vandetanib group and 118 patients receiving placebo. Metastases were present in 98.3% of patients.

The primary end point was PFS. Secondary end points included best objective response rate (ORR), OS, safety, and tolerability. Patients continued randomized treatment until disease progression.

Patients in neither arm had a complete response, and only 5.0% of the vandetanib cohort had a partial response. Stable disease at 12 or more weeks was observed in 62.2% of the vandetanib arm and 64.4% of the placebo arm. Disease progression occurred in 28.6% of the vandetanib arm and 33.1% of the placebo arm, resulting in death for 2.5% and 5.1% of patients, respectively.

Any AE of grade 3 or greater occurred in 55.6% of the vandetanib arm and 25.4% of the placebo arm, with 37.6% and 5.9% causally related to study treatment, respectively. Additionally, SAEs casually related to study treatment occurred in 14.5% of the vandetanib arm and 2.5% of the placebo arm. Furthermore, AEs leading to treatment discontinuation that were causally related to therapy occurred in 12.0% and 0.8% of each arm, respectively.

Common any-grade AEs occurring in 20% or more of the vandetanib arm included diarrhea (68.4%), hypertension (41.0%), rash (31.6%), and prolonged electrocardiogram QT (30.8%).

“In conclusion, VERIFY did not reach its primary end point. This result does not confirm the preliminary findings from the previous randomized phase [2 ZACTHYF] study [NCT00537095], perhaps due to sample size or the potential effect of thyroid-stimulating hormone [TSH] on DTC growth during treatment with vandetanib. Furthermore, no new safety concerns were reported,” the authors of the study concluded.

Reference

Brose MS, Capdevila J, Elisei R, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy. Endocr Relat Cancer. 2024;31(8):e230354. doi:10.1530/ERC-23-0354