Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer

Abstract

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).

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Best radiologic response in patients with medullary thyroid cancer (MTC) with one or more postbaseline scans (n = 34). Scan data available for 34 patients with MTC with measurable disease and at least one postbaseline scan. Two patients had nonmeasurable disease, and one patient had no postbaseline scan. (*) Confirmed partial response per Response Evaluation Criteria in Solid Tumors (RECIST). (†) Patient with MTC and G469A BRAF mutation. (‡) Germline RET mutation. (B) Best radiologic response in all patients with one or more postbaseline scan (n = 70). Scan data available for all patients with measurable disease and with at least one postbaseline scan. Eight patients had nonmeasurable disease and are not represented in this graph. An additional seven patients had no postbaseline scan and are also not represented in this graph. HCC, hepatocellular; CA, carcinoma; H&N, head and neck; RCC, renal cell carcinoma; GE, gastroesophageal.

Fig 2.

Relationship between maximal tumor shrinkage and maximal decrease in calcitonin and/or carcinoembryonic antigen (CEA) in patients with medullary thyroid cancer (MTC; n = 30). Lack of correlation between maximal tumor shrinkage and maximal change in calcitonin and/or CEA in patients with MTC with complete calcitonin and CEA measurements and with measurable disease. (*) Bars represent a patient with MTC who had a BRAF mutation but no known RET mutation and progressed rapidly. This patient did not demonstrate a decrease in calcitonin or CEA from baseline values.

Fig A1.

Analysis of selected exploratory biomarkers ([A] vascular endothelial growth factor A [VEGF-A], [B] erythropoietin [EPO], [C] soluble VEGF receptor 2 [sVEGFR2], [D] soluble MET [sMET], [E] placental growth factor [PlGF]) in plasma samples from patients enrolled at the maximum-tolerated dose of 175 mg per day (cohorts 12 and 99; n = 34). Changes in plasma levels during treatment with cabozantinib were normalized to baseline level at day 1. Blue lines indicate patients with medullary thyroid cancer (n = 28); gray lines indicate patients with other solid tumors (n = 6; colon, follicular thyroid, hepatocellular, pancreatic, papillary thyroid, and rectal cancers). D1, day 1; D29, day 29.

Fig A2.

Immunohistochemistry analysis of cabozantinib targets MET and RET in serial skin biopsies from a patient dosed at the maximum-tolerated dose of 175 mg once daily. Representative images of each sample with 4',6-diamidino-2-phenylindole counterstain are shown at 200× magnification (zoom). Significant changes in total (nonphosphorylated) MET and RET were not observed (data not shown).