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

Abstract

A B S T R A C TPurpose 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 MethodsA 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. ResultsEighty-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. ConclusionCabozantinib 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).

Novel targeted therapeutics for MEN2

“…Cabozantinib received FDA approval in 2012 and EMA approval in 2014 for the treatment of patients with progressive metastatic MTC. The activity of cabozantinib was firstly assessed in a phase I study on 87 patients with different solid tumors, including 37 MTC patients (Kurzrock et al 2010). In the MTC subgroup 29% of cases achieved a PR and 41% had a SD for at least 6 months.…”

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

“…They are seen in 43% to 71% of sporadic cases, with the most common mutation being RET M918T (5)(6)(7)(8). Of note, germline mutations of RET are a hallmark of multiple endocrine neoplasia (MEN), including type 2A, 2B, and familial medullary thyroid carcinoma, with all three subtypes being associated with a high risk of developing a medullary thyroid carcinoma (70%-100% risk by age 70 years; ref.…”

“…However, none of these inhibitors are FDA approved on the basis of targeting RET aberrations. Meanwhile, there are a series of reports suggesting that matched therapies against RET aberrations can yield significant responses (8,15,(21)(22)(23)(24)(25)(26)(27). Further clinical trials with a focus on RET-aberrant advanced cancer are being conducted to determine impact on outcome (Supplementary Table S1).…”

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

“…There have also been preclinical reports of acquired resistance to MET targeting TKIs via receptor mutation (17). Although molecules such as XL184, ARQ197, and crizotinib have all showed varying degrees of efficacy in MET positive patients, it is difficult to apportion this solely to their inhibition of a MET phenotype due to their broader inhibitory profile against other kinases (18)(19)(20)(21)(22). Anti-HGF antibodies, such as AMG102, bind circulating ligand and although they may benefit a subset of patients they cannot impact HGF-independent receptor activation (23,24).…”