Vandetanib confers clinical benefit for certain patients with medullary thyroid cancer
Vandetanib extended PFS among patients with symptomatic and progressive medullary thyroid cancer, according to results of a post hoc analysis of a randomized phase 3 study published in Journal of Clinical Oncology.
“Medullary thyroid cancer is a rare neuroendocrine malignancy that derives from parafollicular cells of the thyroid gland that secrete the polypeptide hormone calcitonin,” Michael C. Kreissl, MD, clinical investigator at University Hospital of Magdeburg in Germany, and colleagues wrote. “It accounts for almost 5% of all thyroid cancers and occurs in either a hereditary (25%) or a sporadic (75%) pattern.”
Hereditary medullary thyroid cancer (MTC) is a component of multiple endocrine neoplasia (MEN) types 2A and 2B. The vast majority of patients with MEN 2A and MEN 2B have germline mutations in the RET proto-oncogene. Many patients with sporadic MTC have somatic RET mutations at diagnosis. Because of this, targeting RET-positive MTC may be a feasible therapeutic strategy, researchers noted. RAS mutations are the only other point-driver mutations in MTC.
Vandetanib (Caprelsa, Sanofi Genzyme), an oral tyrosine kinase inhibitor that targets cell receptors involved in RET, VEGFR2 and EGFR signaling, is approved for treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease.
The phase 3 ZETA trial included 331 patients with unresectable locally advanced or metastatic MTC randomly assigned to oral vandetanib at a starting dose of 300 mg daily (n = 231) or placebo (n = 100). Treatment continued until disease progression.
For the post hoc analysis, Kreissl and colleagues divided eligible patients into four disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline.
PFS, determined from objective tumor measurements, served as the primary objective of the analysis. OS, time to worsening pain and objective response rate served as secondary outcomes.
Among the 184 patients (55.6%) with symptomatic and progressive disease at baseline, results appeared similar in magnitude to those observed in the overall trial for PFS (HR = 0.43; 95% CI, 0.28-0.64), OS (HR = 1.08; 95% CI, 0.72-1.61) and time to worsening pain (HR = 0.67; 95% CI, 0.43-1.04).
Researchers observed an ORR of 37% among patients in this subgroup who received vandetanib compared with 2% of patients who received placebo.
A greater number of patients who received vandetanib vs. placebo required dose reductions (n = 83 vs. 3). Adverse events with vandetanib appeared consistent with the agent’s known safety profile. Ninety-eight percent of patients in the vandetanib group reported at least one adverse event vs. 91.9% in the placebo group.
The small sample size served as a limitation to this study.
“Vandetanib showed statistically significant prolonged median PFS in both the progression and symptoms subgroup and the symptoms-only subgroup, compared with placebo, but not in the progression-only and no symptoms/no progression subgroups,” Kreissl and colleagues wrote. “This post hoc analysis of the vandetanib pivotal trial in MTC demonstrates clinical benefit in patients with symptomatic and progressive disease.”