Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial

被引：1067

作者：

Wells, Samuel A., Jr. ^{[1
]}

Robinson, Bruce G. ^{[2
]}

Gagel, Robert F. ^{[3
]}

Dralle, Henning ^{[4
]}

Fagin, James A. ^{[5
]}

Santoro, Massimo ^{[6
]}

Baudin, Eric ^{[7
]}

Elisei, Rossella ^{[8
]}

Jarzab, Barbara ^{[9
]}

Vasselli, James R.

Read, Jessica ^{[11
]}

Langmuir, Peter ^{[10
]}

Ryan, Anderson J. ^{[12
]}

Schlumberger, Martin J. ^{[7
]}

机构：

[1] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA

[2] Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia

[3] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[4] Univ Halle Wittenberg, Halle, Germany

[5] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

[6] Univ Naples Federico II, Naples, Italy

[7] Inst Gustave Roussy, Villejuif, France

[8] Univ Pisa, Pisa, Italy

[9] Maria Sklodowska Curie Mem Canc Ctr, Gliwice, Poland

[10] AstraZeneca, Wilmington, DE USA

[11] AstraZeneca, Macclesfield, Cheshire, England

[12] Univ Oxford, Oxford, England

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2012年 / 30卷 / 02期

关键词：

ENDOCRINE NEOPLASIA SYNDROMES; RET PROTOONCOGENE; CARCINOMA; MUTATIONS; ZD6474; GUIDELINES; SURVIVAL; EFFICACY; THERAPY; KINASES;

D O I：

10.1200/JCO.2011.35.5040

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients and Methods Patients with advanced MTC were randomly assigned in a 2: 1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Results Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P < .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Conclusion Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761). J Clin Oncol 30:134-141. (C) 2011 by American Society of Clinical Oncology

引用

页码：134 / 141

页数：8

共 30 条

[1]

Carlomagno F, 2002, CANCER RES, V62, P7284

[2] BAY 43-9006 inhibition of oncogenic RET mutants [J].

Carlomagno, F ;

Anaganti, S ;

Guida, T ;

Salvatore, G ;

Troncone, G ;

Wilhelm, SM ;

Santoro, M .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (05) :326-334

[3] SINGLE MISSENSE MUTATION IN THE TYROSINE KINASE CATALYTIC DOMAIN OF THE RET PROTOONCOGENE IS ASSOCIATED WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B [J].

CARLSON, KM ;

DOU, SS ;

CHI, D ;

SCAVARDA, N ;

TOSHIMA, K ;

JACKSON, CE ;

WELLS, SA ;

GOODFELLOW, PJ ;

DONISKELLER, H .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (04) :1579-1583

[4] Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study [J].

Cohen, Ezra E. W. ;

Rosen, Lee S. ;

Vokes, Everett E. ;

Kies, Merrill S. ;

Forastiere, Arlene A. ;

Worden, Francis P. ;

Kane, Madeleine A. ;

Sherman, Eric ;

Kim, Sinil ;

Bycott, Paul ;

Tortorici, Michael ;

Shalinsky, David R. ;

Liau, Katherine F. ;

Cohen, Roger B. .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (29) :4708-4713

[5]

COX DR, 1972, J R STAT SOC B, V34, P187

[6] A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma [J].

de Groot, J. W. B. ;

Zonnenberg, B. A. ;

van Ufford-Mannesse, P. Quarles ;

de Vries, M. M. ;

Links, T. P. ;

Lips, C. J. M. ;

Voest, E. E. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2007, 92 (09) :3466-3469

[7] MUTATIONS IN THE RET PROTOONCOGENE ARE ASSOCIATED WITH MEN 2A AND FMTC [J].

DONISKELLER, H ;

DOU, SS ;

CHI, D ;

CARLSON, KM ;

TOSHIMA, K ;

LAIRMORE, TC ;

HOWE, JR ;

MOLEY, JF ;

GOODFELLOW, P ;

WELLS, SA .

HUMAN MOLECULAR GENETICS, 1993, 2 (07) :851-856

[8] Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer:: A 10-year follow-up study [J].

Elisei, Rossella ;

Cosci, Barbara ;

Romei, Cristina ;

Bottici, Valeria ;

Renzini, Giulia ;

Molinaro, Eleonora ;

Agate, Laura ;

Vivaldi, Agnese ;

Faviana, Pinuccia ;

Basolo, Fulvio ;

Miccoli, Paolo ;

Berti, Piero ;

Pacini, Furio ;

Pinchera, Aldo .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (03) :682-687

[9] Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma [J].

Frank-Raue, Karin ;

Fabel, Michael ;

Delorme, Stefan ;

Haberkorn, Uwe ;

Raue, Friedhelm .

EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2007, 157 (02) :215-220

[10] Phase II trial of sorafenib in advanced thyroid cancer [J].

Gupta-Abramson, Vandana ;

Troxel, Andrea B. ;

Nellore, Anoma ;

Puttaswamy, Kanchan ;

Redlinger, Maryann ;

Ransone, Kathy ;

Mandel, Susan J. ;

Flaherty, Keith T. ;

Loevner, Laurie A. ;

O'Dwyer, Peter J. ;

Brose, Marcia S. .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (29) :4714-4719

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