Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer

作者：Kurzrock, Razelle^*; Sherman, Steven I.; Ball, Douglas W.; Forastiere, Arlene A.; Cohen, Roger B.; Mehra, Ranee; Pfister, David G.; Cohen, Ezra E. W.; Janisch, Linda; Nauling, Forlisa; Hong, David S.; Ng, Chaan S.; Ye, Lei; Gagel, Robert F.; Frye, John; Mueller, Thomas; Ratain, Mark J.; Salgia, Ravi

来源：Journal of Clinical Oncology, 2011, 29(19): 2660-2666.

DOI：10.1200/JCO.2010.32.4145

• RET PROTOONCOGENE MUTATIONS
• GROWTH-FACTOR RECEPTOR
• PHASE-II
• C-MET
• EXPRESSION
• CARCINOMA
• VEGF
• GLIOBLASTOMA
• CHEMOTHERAPY
• METASTASIS

Purpose @@@ XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. @@@ Patients and Methods @@@ A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. @@@ Results @@@ Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. @@@ Conclusion @@@ Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605). J Clin Oncol 29:2660-2666.

• 出版日期2011-7-1
• 单位上海交通大学