Vandetanib for the Treatment of Symptomatic or Progressive Medullary Thyroid Cancer in Patients with Unresectable Locally Advanced or Metastatic Disease: U.S. Food and Drug Administration Drug Approval Summary

Abstract

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n ¼ 231), or to placebo (n ¼ 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio ¼ 0.35; 95% confidence interval, 0.24-0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease.

Influence of RET mutations on the expression of tyrosine kinases in medullary thyroid carcinoma

“…In this study, we used a large retrospective series of well-characterized MTC patients to define the expression of TKI target proteins in relation to specific clinical and tumor characteristics to provide data that could be used for rational selection of patients for TKI treatment. So far, vandetanib and cabozantinib, which have markedly improved the progression-free survival of MTC patients (Schoffski et al 2013, Thornton et al 2012, are the only agents that have been approved for the treatment of this disease, but a wide variety of additional multitargeted kinase inhibitors have entered clinical trials and several have shown clinical benefit in MTC patients. Promising results have been obtained with agents that primarily target angiogenesis and inhibit VEGF receptors at nanomolar concentrations.…”

Autophagy and thyroid carcinogenesis: genetic and epigenetic links

“…Molecular therapy with inhibitors of mitogenic kinases has been disappointing, because it has not substantially improved the survival of patients with aggressive thyroid cancers, while showing an adverse sideeffect profile (Gild et al 2011). For instance, the multikinase inhibitor vandetanib, which has been approved for the treatment of inoperable or metastatic MTC (Thornton et al 2012), has shown a modest efficacy toward MTC progression, but an extremely toxic profile that includes gastrointestinal, cardiovascular, and neurological disorders (Chau & Haddad 2013). Similarly, the results of a phase II clinical trials on the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus for the treatment of locally advanced or metastatic thyroid cancer have been disappointing (Lim et al 2013).…”

Vascular normalization window: A positive prognostic foresight for head and neck cancer

“…[8] Adverse effects: Diarrhea, colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and QT interval prolongation. [31] Sunitinib Sunitinib inhibits receptor tyrosine kinase which is responsible for the proliferation and angiogenesis of the cells of the tumor. It has multiple targets, and its inhibiting mechanism involves VEGFR-1, 2, and 3, PDGFR-a and -b, stem cell factor receptor (Kit), and fms-like tyrosine kinase Flowchart 2: Possible advantages and mechanisms using antiangiogenic therapies to enhance tumor response to radiation.…”