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COMMUNITY TRANSLATIONS Vandetanib in advanced hereditary medullary thyroid cancer

Report prepared by Matt Stenger, MS

Medullary thyroid cancer (MTC), the third most common type of thyroid cancer, presents in a sporadic form in about 75% of cases and in a hereditary form in about 25%. Ten-year survival in MTC that has been treated early is between 70% and 80% but is less than 50% in patients with distant metastatic disease. Currently, there is no effective therapy for patients with distant metastases of MTC.

Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of sporadic MTC cases. Thyroid tumors are vascular, and increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.

Vandetanib (Caprelsa) is a oncedaily oral agent that targets RETdependent, VEGF receptor-dependent, and epidermal growth factor receptor-dependent signaling. In a recent open-label, single-arm, phase II study, vandetanib produced durable objective responses and disease control in patients with unresectable locally advanced or metastatic hereditary MTC.1

Objective responses and disease control
This study consisted of 30 patients (21 women), with a median age of 49 years and a mean time since MTC diagnosis of 16 years. They received vandetanib (300 mg/day) until disease progression, unacceptable toxicity, or withdrawal of consent. Twenty-nine patients had distant metastases, including metastasis to the liver (80%), lymph nodes (70%), and lungs (63%). Patients had a mean of 3.6 disease sites. All of the patients had undergone previous surgery, 37% had received radiation therapy, 20% had had chemotherapy, and 10% had received biologic therapy.

A total of 29 patients were assessable for investigator-judged response, with all 30 being included in the intent-to-treat analysis of efficacy and the safety analysis. At the time of data cutoff, after a median duration of vandetanib treatment of 18.8 months, 17 patients were still receiving vandetanib therapy, including 4 patients who had progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) but who were judged by their physician to be receiving clinical benefit from treatment. Among the remaining patients, seven discontinued treatment because of adverse events, four discontinued treatment because of disease progression, and two withdrew consent

On investigator assessment, a confirmed partial response (PR) was achieved in six patients (30%), with a median duration of response at data cutoff of 10.2 months (range, 1.9– 16.9 months); three patients subsequently developed progressive disease, at 10.6, 27.3, and 27.9 months. Stable disease for ≥ 24 weeks was observed in 16 patients (53%), yielding a disease  control (objective response plus stable disease) rate of 73%. Six patients had stable disease for ≥ 8 weeks but < 24 weeks, and one patient had progressive disease as best response. Overall, 25 patients (83%) had some reduction in tumor size during vandetanib treatment. In addition to the six patients with a confirmed PR, five had an unconfirmed PR; one had a single RECIST assessment indicating a PR but was found to have progressive disease at next assessment, and the PRs in the other four patients occurred at the final assessment before data cutoff. There was no apparent relationship between specific germline RET mutations and response to vandetanib treatment.