- © 2012 by American Society of Clinical Oncology
Cabozantinib in Prostate Cancer: The Beginning of a Precision Paradigm?
- The Cancer Institute of New Jersey; and University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, New Brunswick, NJ
- Corresponding author: Robert S. DiPaola, MD, Department of Medicine, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, 195 Little Albany St, New Brunswick, NJ 08901; e-mail: dipaolrs{at}umdnj.edu.
The study reported in the article by Smith et al1 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 al1 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.2 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.3 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.4 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.5–7 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.8,9 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.10 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.11,12 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 al1), 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).
Giving us a potential clue to the biologic effects of cabozantinib in clinical studies, Smith et al1 also reported a reduction in uptake on bone scan with improvement in 68% of men (79 of 116) with bone metastasis and complete resolution in 14 patients. Of additional interest, bone pain decreased in correlation with bone scan improvement, and bone markers improved in an exploratory analysis. Although clearly hypothesis generating with additional insight to be gained from the ongoing COMET-2 trial, these data support further evaluation of targeted therapies on both tumor and the bone microenvironment. Prior preclinical studies support this hypothesis by demonstrating the effect of the HGF/MET pathway on BMP-2 and osteopontin expression in osteoblasts, suggesting an effect in the bone microenvironment, and providing a rationale for bone-specific clinical effects.13,14 These data, however, are preliminary but support additional assessment of effects on bone metastasis in ongoing studies.
Studies to understand the potential for stratification of patients to optimize effects, and to validate the target effect in tumor, although not addressed in the trial by Smith et al,1 should also be considered in targeted therapy development. MET activation has been shown to be the result of protein overexpression from transcriptional upregulation, oncogenic gene fusion, gene amplification, and rarely activating mutations. Although the assessment for MET signaling dysregulation may lead to future targeted and individual approaches, few studies of MET-targeted therapies have begun to assess biomarkers—for example, the analysis of expression levels or receptor phosphorylation that could stratify patients on the basis of MET pathway activity.11 In a study of patients with NSCLC with an antibody to MET (onartuzumab) combined with erlotinib, there was a correlation between MET expression status and clinical outcome, including progression- free and overall survival, which supports the design of the phase III study in NSCLC using MET expression as an entry criteria (NCT01456325).15 A study reported in a previous issue of the Journal treated patients with medullary thyroid carcinoma with cabozantinib and assessed clinical effect, pharmacodynamics, RET mutational status, and MET in an effort to validate biologic effects within this pathway.16 In this study, one patient with sequential skin biopsies experienced decreased phosphorylation of MET and RET, at least demonstrating the feasibility of the types of assessments that could potentially lead to validation of target effect.
Taken together, efforts to optimally stratify patients on the basis of validated genetic or molecular abnormalities as biomarkers, with an effort toward optimization of multitargeted therapy, are the future of a more precise and effective approach, or a precision paradigm. Studies that now attempt treatment stratification in advanced malignancies often include specific gene mutation assessments, whole-genome sequencing, targeted whole-exome sequencing, and transcriptome sequencing.17,18 In prostate cancer, clues to potential biomarkers to stratify patients for a more precise therapeutic approach are just beginning to emerge. For example, data demonstrating a correlation of TMPRSS2:ERG fusion and sensitivity to DNA-damaging agents supports additional studies to determine the importance of stratification of patients with such fusions for treatment with PARP inhibitors.19 Data demonstrating SPINK1-positive prostate cancer, which occurs in approximately 10% of advanced prostate cancers, are sensitive to antibodies to SPINK1 and epidermal growth factor receptor suggest that SPINK1 could potentially stratify patients to appropriate inhibitors.20 Data demonstrating that gene amplification of AURKA and MYCN occurs commonly in neuroendocrine prostate cancer and enhanced sensitivity to aurora kinase inhibitor therapy supports the study of additional biomarkers that might effectively stratify appropriate patients.21
The study reported by Smith et al1 is therefore an important contribution supporting additional, more definitive studies of cabozantinib in prostate cancer on the basis of the improvement of multiple measures of clinical activity, including measurements of soft-tissue and bone metastasis, and is an example of an important targetable pathway in prostate cancer. Clearly, much work needs to be done to determine the usefulness of MET and other biomarkers in predicting drug combination effect. Despite these challenges, however, the hope to more effectively target and treat advanced prostate cancer and other advanced malignancies to a more remarkable level of response will require a continued investment in the study of a precision-based paradigm. Importantly, we have now entered an area of study to develop and optimize specific targeted therapies in prostate cancer as well as other tumor types.5,22 Coupled with the success of targeting the AR pathway and overall efforts to discover and validate biomarkers that effectively stratify patients, we now have a strategic plan toward designing a multitargeted approach with greater therapeutic impact.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Administrative support: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
