• Rossella Elisei, Martin J Schlumberger, Stefan P Müller, Patrick Schöffski, Marcia S Brose, Manisha H Shah, Lisa Licitra, Barbara Jarzab, Viktor Medvedev, Michael C Kreissl, Bruno Niederle, Ezra E W Cohen, Lori J Wirth, Haythem Ali, Colin Hessel, Yifah Yaron, Douglas Ball, Barry Nelkin, and Steven I Sherman.
• Rossella Elisei, University of Pisa, Pisa; Lisa Licitra, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico-Istituto Nazionale dei Tumori, Milan, Italy; Martin J. Schlumberger, Institut Gustave Roussy, University Paris-Sud, Villejuif, France; Stefan P. Müller, Universitatsklinikum Essen, Essen; Michael C. Kreissl, Universitätsklinikum Würzburg, Würzburg, Germany; Patrick Schöffski, University Hospitals Leuven, Leuven, Belgium; Marcia S. Brose, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; Manisha H. Shah, Ohio State University Medical Center, Columbus, OH; Barbara Jarzab, Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Oddział w Gliwicach, Gliwice, Poland; Viktor Medvedev, Medical Radiological Research Centre of the Russian Academy of Medical Sciences, Obninsk, Russia; Bruno Niederle, Medizinische Universität Wien, Wien, Austria; Ezra E.W. Cohen, University of Chicago, Chicago, IL; Lori J. Wirth, Massachusetts General Hospital, Boston, MA; Haythem Ali, Henry Ford Health System, Detroit, MI; Colin Hessel and Yifah Yaron, Exelixis, South San Francisco, CA; Douglas Ball and Barry Nelkin, Johns Hopkins University School of Medicine, Baltimore, MD; and Steven I. Sherman, University of Texas MD Anderson Cancer Center, Houston, TX.
• J. Clin. Oncol. 2013 Oct 10; 31 (29): 3639-46.

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients And MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

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