Vandetanib for the Treatment of Patients With Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer

Abstract

Purpose There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. Methods Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at ≥ 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). Conclusion In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…Moreover, recent phase II/III clinical trials have confirmed an important clinical activity of ZD6474 in both NSCLC [8,11] and on RET-mutated MTC [12,13]. However, all these new small molecules demonstrated a higher activity when administered in combinations with chemotherapeutic drugs [14,15].…”

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

“…1 Recently, overall survival benefits gained from small molecule tyrosine kinase inhibitors (TKI) directed against the VEGF receptor (VEGFR) have been observed in several randomized clinical trials (RCTs) among variety of solid tumors. [2][3][4][5][6][7][8][9][10] In addition, the United States Food and Drug Administration (FDA) has approved four VEGF TKIs, sunitinib (Sutent, Pfizer, New York, NY), sorafenib (Nexavar, Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Richmond, CA), pazopanib (Votrient, GlaxoSmithKline, Middlesex, UK), and vandetanib (Caprelsa, AstraZeneca, London, UK), for use in cancer therapy. 11 As a result, the use of VEGFR-TKIs is expected to increase in the near future, and an appreciation for the differences in toxicity profiles between traditional cytotoxic agents and targeted agents is therefore urgently needed.…”

Development of molecular targeted drugs for advanced thyroid cancer in Japan [Review]

“…Because expression of angiogenesis factors, including vascular endothelial growth factor (VEGF), is increased in thyroid cancer [7], inhibition of signal transduction is expected to have an antitumor effect, and clinical trials of various molecular targeted drugs as a treatment for advanced thyroid cancer have been conducted. Table 1 shows a summary of those trials [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. All of molecular targeted drugs are low-molecular-weight compounds that inhibit multiple kinases, including the VEGF receptor.…”

“…Wells et al reported the results of a phase 2 trial in which vandetanib was administered at a dose of 300 mg QD to patients with hereditary MTC (familial MTC, MEN2A, MEN2B) who had unresectable locally advanced disease or distant metastasis [13]. The primary endpoint, the response rate, was 20% (6/30 patients).…”