Cabozantinib in Prostate Cancer: The Beginning of a Precision Paradigm?

Abstract

The study reported in the article by Smith et al that accompanies this editorial presents data on a novel orally bioavailable tyrosine kinase inhibitor (TKI), cabozantinib, with activity against multiple targets including mesenchymal-epithelial transition factor (MET), also known as hepatocyte growth factor receptor, and the vascular endothelial growth factor receptor 2 (VEGFR2). The authors describe 171 men with castration-resistant prostate cancer (CRPC), a subgroup of patients from a larger phase II randomized discontinuation trial that included multiple tumor types treated with cabozantinib. The trial included a lead-in stage of open-label therapy with cabozantinib and a planned blinded random assignment to cabozantinib or placebo for patients who achieved stable disease at 12 weeks. As reported by the authors, the trial was suspended after 122 patients with CRPC were enrolled onto the open-label portion of the study because of improvements in bone scans and a decrease in pain. At the time the study was halted, a group of 31 patients had been randomly assigned. In this group, there was a marked improvement in the primary end point of progression-free survival (PFS) in the patients receiving cabozantinib compared with placebo (median, 23.9 v 5.9 weeks, respectively; hazard ratio, 0.12; P .001). Although impressive as a small phase II study, the completion of ongoing phase III studies will be critical to confirm the survival benefit. COMET-1, with a primary end point of overall survival, is a placebo-controlled trial of 960 men with CRPC and additional prior therapy randomly assigned to cabozantinib or prednisone (NCT01605227). COMET-2 is a placebo-controlled phase III trial evaluating cabozantinib versus mitoxantrone and prednisone in men with previously treated symptomatic CRPC (NCT01522443), with an emphasis on the effect of cabozantinib on pain and bone disease. Clearly, the results reported by Smith et al support the completion of these larger more definitive studies; perhaps just as important, however, is the need to understand these data as a direction toward more precise multitargeted therapy in prostate cancer. As one potential target in prostate cancer, the understanding of the role of MET, or MET in conjunction with VEGFR, is the subject of ongoing studies. Increased expression of MET protein in tumor cells compared with normal tissue has been associated with tumor grade. An evaluation of the MET ligand hepatocyte growth factor (HGF) in patients from a prior Cancer and Leukemia Group B 9480 study of suramin revealed a correlation between high plasma levels of HGF and decreased patient survival. Studies have also demonstrated that androgen receptor (AR) signaling represses the expression of MET, which supports future studies of targeting the combination of the AR and MET pathways. With the understanding that cabozantinib also inhibits the VEGF pathway, it is of interest that prior laboratory studies have supported the importance of angiogenesis in prostate cancer progression and provide a rationale for combined MET and VEGF pathway inhibition. Additional laboratory studies have demonstrated HGF-mediated angiogenesis through VEGF regulation and an association between VEGF regulation and the activation of c-MET signaling in prostate cancer. Clinical results of antiangiogenic agents alone in prostate cancer, however, have not been optimal, which supports the hypothesis that targeting multiple pathways in addition to VEGF need to be considered to fully influence the complex nature of the tumor microenvironment. In this regard, efforts to understand the effect of agents such as cabozantinib on the MET pathway with additional multitargeted effects such as VEGF inhibition are likely to be important. In fact, there are multiple agents targeting the MET pathway under investigation that have varying degrees of specificity for additional targets. In addition to MET and VEGFR2, cabozantinib has been shown in preclinical models to inhibit RET, KIT, AXL and FLT3 pathways. Cabozantinib has also been demonstrated to have distinct biologic effects on angiogenesis, invasiveness, and metastasis in animal models, as would be expected from these molecular targets. Other MET pathway–focused therapeutic approaches under investigation include antibodies against HGF such as rilotumumab (which is being evaluated in lung, gastric, and gynecologic malignancies) and antibodies against MET such as onartuzumab (which is being evaluated in a phase III trial in combination with erlotinib v erlotinib alone in patients with MET-positive non–small-cell lung carcinoma [NSCLC; NCT01456325]). Receptor TKIs targeting MET are under investigation and include nonselective TKIs such as cabozantinib (as studied in the clinical trial by Smith et al), crizotinib (which targets MET as well as ALK and is approved for the treatment of EML4-ALK positive NSCLC), and foretinib (which inhibits c-MET, VEGFR2, PDGFR, and KIT). More target-selective MET TKIs are also under investigation including agents such as tivantinib (ARQ197; Arqule, Woburn, MA), EMD 1214063 (EMD Serono, Darmstadt, Germany), EMD 1204831 (EMD Serono), AMG 337 (Amgen, Thousand Oaks, CA), and INCB028060 (Incyte, Wilmington, DE). JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 4 FEBRUARY 1 2013