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.
At the time of data cutoff, estimated median progression-free survival (PFS) was 27.9 months; 8 patients (27%) had disease progression, 20 patients (67%) had stable disease and were alive at the time of analysis, and 2 patients had died at > 3 months after the final RECIST assessment (one of cardiac failure and one of colon cancer). On independent central review, 5 patients had a confirmed PR, 22 had stable disease, 1 patient had progressive disease, and 2 patients were not evaluable; the estimated median PFS was 34.7 months.
Primarily low-grade adverse events
Toxicity of vandetanib treatment was manageable in this phase II study. Adverse events were mostly grade 1 or 2, with the most frequent being diarrhea, rash, fatigue, and nausea (Table 1). The most common grade 3 adverse event was QTc prolongation (seven patients); next were diarrhea, nausea, and hypertension (three patients each). Two grade 4 adverse events were reported, consisting of azotemia and muscle weakness; neither one was considered to be related to vandetanib. Other notable adverse events included mild visual disturbances (grade 1) in 3 patients owing to vandetanib-related corneal changes, which were managed with a dose adjustment in vandetanib; hypophosphatemia in 3 patients (grade 2 in 2, grade 1 in 1); and increases in blood pressure > 30 mm Hg systolic in 23 patients, which did not lead to permanent discontinuation of treatment in any of the patients. Of the seven patients (23%) discontinuing vandetanib treatment because of adverse events, five patients had adverse events considered possibly related to vandetanib treatment, including hemorrhagic diarrhea, nausea, increased blood creatinine and blood urea nitrogen levels, acne, and asymptomatic QTc prolongation. Vandetanib dosing was reduced or interrupted in 24 patients (both in 21), with diarrhea being the most common reason (7 patients).