Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial
University of Michigan1, Harvard University2, University of Texas MD Anderson Cancer Center3, University of California, San Francisco4, Pinnacle Financial Partners5, Wayne State University6, University of Pennsylvania7, University of California, Davis8, National Taiwan University9, Stanford University10, Katholieke Universiteit Leuven11, Exelixis12
01 Feb 2013-Journal of Clinical Oncology (American Society of Clinical Oncology)-Vol. 31, Iss: 4, pp 412-419
TL;DR: Cabozantinib has clinical activity in men with castration-resistant prostate cancer, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
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%).
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TL;DR: The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.
Abstract: Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.
650 citations
Northwestern University1, American Society of Clinical Oncology2, New York University3, Memorial Sloan Kettering Cancer Center4, University of North Carolina at Chapel Hill5, University of Pennsylvania6, University of Texas MD Anderson Cancer Center7, Georgetown University8, Christiana Care Health System9, University of Chicago10, University of Utah11, University of Texas Health Science Center at San Antonio12, Washington University in St. Louis13
TL;DR: Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology represents the invaluable contributions of thousands of patients who participate in clinical trials and the scientists who conduct basic and clinical research.
Abstract: A MESSAGE FROM ASCO'S PRESIDENT I remember when ASCO first conceived of publishing an annual report on the most transformative research occurring in cancer care. Thirteen reports later, the progress we have chronicled is remarkable, and this year is no different. The research featured in ASCO's Clinical Cancer Advances 2018 report underscores the impressive gains in our understanding of cancer and in our ability to tailor treatments to tumors' genetic makeup. The ASCO 2018 Advance of the Year, adoptive cell immunotherapy, allows clinicians to genetically reprogram patients' own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy-a type of adoptive cell immunotherapy-has led to remarkable results in young patients with acute lymphoblastic leukemia (ALL) and in adults with lymphoma and multiple myeloma. Researchers are also exploring this approach in other types of cancer. This advance would not be possible without robust federal investment in cancer research. The first clinical trial of CAR T-cell therapy in children with ALL was funded, in part, by grants from the National Cancer Institute (NCI), and researchers at the NCI Center for Cancer Research were the first to report on possible CAR T-cell therapy for multiple myeloma. These discoveries follow decades of prior research on immunology and cancer biology, much of which was supported by federal dollars. In fact, many advances that are highlighted in the 2018 Clinical Cancer Advances report were made possible thanks to our nation's support for biomedical research. Funding from the US National Institutes of Health and the NCI helps researchers pursue critical patient care questions and addresses vital, unmet needs that private industry has little incentive to take on. Federally supported cancer research generates the biomedical innovations that fuel the development and availability of new and improved treatments for patients. We need sustained federal research investment to accelerate the discovery of the next generation of cancer treatments. Another major trend in this year's report is progress in precision medicine approaches to treat cancer. Although precision medicine offers promise to people with cancer and their families, that promise is only as good as our ability to make these treatments available to all patients. My presidential theme, "Delivering Discoveries: Expanding the Reach of Precision Medicine," focuses on tackling this formidable challenge so that new targeted therapies are accessible to anyone who faces a cancer diagnosis. By improving access to high-quality care, harnessing big data on patient outcomes from across the globe, and pursuing innovative clinical trials, I am optimistic that we will speed the delivery of these most promising treatments to more patients. Sincerely, Bruce E. Johnson, FASCO ASCO President, 2017 to 2018.
592 citations
Cites methods from "Cabozantinib in Patients With Advan..."
...A total of 171 men with progressing CRPC were enrolled onto the first study.(40) All men received cabozantinib for the first 12 weeks....
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Cardiff University1, National Cancer Research Institute2, University of Michigan3, Royal Adelaide Hospital4, University of Naples Federico II5, University of Nebraska Medical Center6, Purdue University7, University of Miami8, Nara Medical University9, National Technical University of Athens10, University of Florence11, United Arab Emirates University12, University of Illinois at Urbana–Champaign13, Creighton University14, University of Rome Tor Vergata15, Wayne State University16, University of Glasgow17, New York Medical College18, Mayo Clinic19, Università Campus Bio-Medico20
TL;DR: This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB
387 citations
TL;DR: This analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing.
Abstract: Importance A common justification for high cancer drug prices is the sizable research and development (RD range, $204.1 million to $22 275.0 million). This analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing.
308 citations
TL;DR: It is demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients, and the inhibition of A XL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
Abstract: Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
297 citations
References
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TL;DR: A model by which a combined assessment of all existing lesions, characterized by target lesions and nontarget lesions, is used to extrapolate an overall response to treatment is proposed, which is largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines.
Abstract: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
14,926 citations
TL;DR: Treatment with cabozantinib is suggested to be a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.
Abstract: The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. Mol Cancer Ther; 10(12); 2298–308. ©2011 AACR .
1,041 citations
"Cabozantinib in Patients With Advan..." refers background in this paper
...In vivo, cabozantinib suppresses MET and VEGFR2 signaling, rapidly inducing apoptosis of endothelial cells and tumor cells, resulting in tumor regression in a variety of xenograft models.(16,17) In a xenograft model of CRPC in bone, cabozantinib blocks the progression of osteolytic and osteoblastic lesions....
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TL;DR: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.
Abstract: Purpose This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. Patients and Methods Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with ≥ 25% tumor shrinkage continued open-label sorafenib; patients with ≥ 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. Results Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of ≥ 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo ...
985 citations
TL;DR: Cabozantinib has an acceptable safety profile and is active in MTC, and may provide clinical benefit by simultaneously targeting multiple pathways of importance in M TC, including MET, VEGFR2, and RET.
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 A
501 citations
TL;DR: Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.
Abstract: Purpose A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m 2 intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity. Results In total, 1,050 patients were randomly assigned. The median OS for patients given DP B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P .181). The median PFS time was superior in the DP B arm (9.9 v 7.5 months, stratified log-rank P .001) as was the proportion of patients with OR (49.4% v 35.5%; P .0013). Grade 3 or greater treatment-related toxicity was more common with DP B (75.4% v 56.2%; P .001), as was the number of treatment-related deaths (4.0% v 1.2%; P .005).
431 citations