title: 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.
authors.affiliation: Dept of Surgery, Washington University School of Medicine, Box 8109, 660 S Euclid Ave, St Louis, MO 63110, USA. wellss@wudosis.wustl.edu
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wells
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Gosnell
authors.forename: Robert F
authors.initials: RF
authors.lastname: Gagel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Moley
authors.forename: David
authors.initials: D
authors.lastname: Pfister
authors.forename: Julie A
authors.initials: JA
authors.lastname: Sosa
authors.forename: Michael
authors.initials: M
authors.lastname: Skinner
authors.forename: Annetta
authors.initials: A
authors.lastname: Krebs
authors.forename: James
authors.initials: J
authors.lastname: Vasselli
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood; D002116:Calcitonin / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; C000715470:MAS1 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib