Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

Abstract

Purpose Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and Methods Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. Results One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Conclusion Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Bone remodeling markers and bone metastases: From cancer research to clinical implications

“…Indeed, by the RECIST criteria, BM is usually not a measurable disease, unless there is a soft tissue mass component evaluable by CT scan or MRI. 79 There is also a need for a more adequate assessment of the ongoing risk for bone complications after 2 years of BTAs in long-term survivors. In this setting, together with the clinical information, the level of bone remodeling markers could add significant input to decide whether there is a need to continue BTAs, change the treatment regimen or simply stop the BTAs until new relevant information appears.…”

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

“…In addition, a phase II trial with cabozantinib (XL-184) in castration-resistant prostate cancer (CRPC) patients showed promising results [80]. These results included regression of soft tissue tumors in 72% of patients and improved bone scans in 68% of evaluable patients, of which there was complete resolution of bone metastasis in 12% of patients after treatment with cabozantinib.…”

“…Many of these studies involve drugs that are in phase I clinical trials, in which the overall goal is to overcome acquired resistance. Phase II trials are also being conducted to improve PFS in various types of cancers [79][80][81]. Interesting results were obtained in a phase I clinical trial investigating the efficacy of a combinatorial therapy using tivantinib and sorafenib, a VEGF receptor inhibitor [82], in hepatocellular carcinoma (HCC) patients.…”

“…After 12 weeks of the study, a 5% ORR and SD in 75% of cabozantinib treated patients were also observed. In addition, median PFS was 23.9 weeks with cabozantinib treatment, compared to 5.9 weeks with only placebo treatment [80]. Other tumor types, such as ovarian cancer, are also currently being investigated in this clinical trial (NCT00940225) ( Table 1).…”

Yhhu3813 is a novel selective inhibitor of c-Met Kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells

“…Therefore, the inhibition of increased c-Met signaling could have a significant potential in the treatment of human cancers in which the c-Met pathway is aberrantly activated. In fact, recent clinical trials of c-Met pathway-targeted agents have yielded convincing evidence to support the potential utility of this class of agents in treating various human cancers [25][26][27][28] . In this study, we assessed the antitumor efficacy of Yhhu3813, an orally bioavailable, selective, small-molecule inhibitor of the catalytic activity of the c-Met kinase.…”