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Toni K Choueiri, Colin Hessel, Susan Halabi, Ben Sanford, M Dror Michaelson, Olwen Hahn, Meghara Walsh, Thomas Olencki, Joel Picus, Eric J Small, Shaker Dakhil, Darren R Feldman, Milan Mangeshkar, Christian Scheffold, Daniel George, Michael J Morris
BACKGROUND: The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). PATIENTS AND METHODS: Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off)...
March 15, 2018: European Journal of Cancer
M Fioramonti, V Fausti, F Pantano, M Iuliani, G Ribelli, F Lotti, Y Pignochino, G Grignani, D Santini, G Tonini, B Vincenzi
Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions...
March 8, 2018: Scientific Reports
Judit Kocsis, Éva Szekanecz, Ali Bassam, Andrea Uhlyarik, Zsuzsanna Pápai, Gábor Rubovszky, Emese Mezősi, Károly Rucz, Ildikó Garai, Endre Nagy, Iván Uray, Zsolt Horváth
BACKGROUND: Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers...
March 5, 2018: Experimental and Clinical Endocrinology & Diabetes
Jean-Charles Nault, Peter R Galle, Jens U Marquardt
Hepatocellular carcinomas (HCC) are characterized by considerable phenotypic and molecular heterogeneity. Treatment and design of clinical trials are particularly challenging due a co-existing liver disease present in the majority of patients which limits aggressive therapeutic options. Despite positive results in recent phase III clinical trials, that confirmed the high value of antiangiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities, failure of several large randomized controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of findings from translational studies to overcome this unmet clinical need...
March 2, 2018: Journal of Hepatology
Lian-Jie Ren, Hua-Jing Wu, Li-Han Sun, Xue Xu, Li-Ying Mo, Lei Zhang, Jun-Ying Zhang, Chun-Yong Wu
Cabozantinib (CBZ) could be used for the treatment of progressive, metastatic medullary thyroid cancer. Its major oxidative metabolite is cabozantinib N-oxide (CBN) which contains a structural alert associated with mutagenicity, yet the pharmacokinetics study lacks the simultaneous investigation of CBN and dose proportionality. In current study a simple LC-MS/MS method was developed and validated for the simultaneous estimation and pharmacokinetic investigation of CBZ and CBN in rat plasma. The analytes were separated on a Waters Atlantics C18 column (2...
March 3, 2018: Biomedical Chromatography: BMC
Elvira Schmidt, Johanna Lister, Monika Neumann, Witold Wiecek, Shuai Fu, Anne-Lise Vataire, Jelena Sostar, Shengnan Huang, Florence Marteau
BACKGROUND: Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC). OBJECTIVE: To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC. METHODS: We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS)...
February 28, 2018: Targeted Oncology
Sadakatsu Ikeda, Igor F Tsigelny, Åge A Skjevik, Yuko Kono, Michel Mendler, Alexander Kuo, Jason K Sicklick, Gregory Heestand, Kimberly C Banks, AmirAli Talasaz, Richard B Lanman, Scott Lippman, Razelle Kurzrock
BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated...
February 27, 2018: Oncologist
Nizar M Tannir, Sumanta K Pal, Michael B Atkins
The management of advanced clear-cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second-line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small-molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small-molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin...
February 27, 2018: Oncologist
George E Naoum, Michael Morkos, Brian Kim, Waleed Arafat
Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15-20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC...
February 19, 2018: Molecular Cancer
Guilherme Rabinowits, Cecilia Lezcano, Paul J Catalano, Patricia McHugh, Hailey Becker, Megan M Reilly, Julian Huang, Ayushi Tyagi, Manisha Thakuria, Scott C Bresler, Lynette M Sholl, Geoffrey I Shapiro, Robert Haddad, James A DeCaprio
BACKGROUND: This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC). EXPERIMENTAL DESIGN: This prospective, phase II, single-institution trial enrolled patients with platinum-failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity...
February 14, 2018: Oncologist
Apurva K Srivastava, Melinda G Hollingshead, Jeevan P Govindharajulu, Joseph M Covey, Dane Liston, Melanie A Simpson, James O Peggins, Donald P Bottaro, John J Wright, Robert J Kinders, James H Doroshow, Ralph E Parchment
The development of molecularly targeted agents has benefited from use of pharmacodynamic (PD) markers to identify "biologically effective doses" (BEDs) below maximum tolerable doses, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such PD-based BED regimens and effectiveness comparisons using MET kinase small molecule inhibitors. Utilizing PD biomarker measurements of MET signaling (tumor pY1234/1235 MET/total MET ratio) in a Phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5)...
February 14, 2018: Molecular Cancer Therapeutics
Ekaterini Christina Tampaki, Athanasios Tampakis, Raoul Droeser, Efstratios Patsouris, Gregory Kouraklis
No abstract text is available yet for this article.
February 14, 2018: Cancer Biology & Therapy
Mengqi Jia, Yanxia Guo, Deyu Zhu, Nianzhao Zhang, Lin Li, Jin Jiang, Yiwen Dong, Qingqing Xu, Xiulei Zhang, Meijuan Wang, Haina Yu, Fang Wang, Keli Tian, Jinsan Zhang, Charles Y F Young, Hongxiang Lou, Huiqing Yuan
Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues...
February 1, 2018: Biochimica et Biophysica Acta
Kan Chen, Yun Gao, Fei Shi, Guangqiang Cao, Jiandong Bao
Medullary thyroid carcinoma (MTC) is a rare malignancy originating from calcitonin-producing parafollicular C cells of the thyroid. Neither radiotherapy nor chemotherapy has demonstrated durable objective responses in patients with advanced MTC. Vandetanib and cabozantinib are the 2 tyrosine kinase inhibitors recently approved by the US Food and Drug Administration, which are not affordable for most Chinese patients. Herein, we report a case of an MTC patient who responded to apatinib, a Chinese homemade tyrosine kinase inhibitor-targeted vascular endothelial growth factor receptor...
2018: OncoTargets and Therapy
Steve J Edwards, Victoria Wakefield, Peter Cain, Charlotta Karner, Kayleigh Kew, Mariana Bacelar, Natalie Masento, Fatima Salih
BACKGROUND: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta®, Pfizer Inc., NY, USA), cabozantinib (Cabometyx®, Ipsen, Slough, UK), everolimus (Afinitor®, Novartis, Basel, Switzerland), nivolumab (Opdivo®, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent®, Pfizer, Inc...
January 2018: Health Technology Assessment: HTA
David Cella, Bernard Escudier, Nizar M Tannir, Thomas Powles, Frede Donskov, Katriina Peltola, Manuela Schmidinger, Daniel Y C Heng, Paul N Mainwaring, Hans J Hammers, Jae Lyun Lee, Bruce J Roth, Florence Marteau, Paul Williams, John Baer, Milan Mangeshkar, Christian Scheffold, Thomas E Hutson, Sumanta Pal, Robert J Motzer, Toni K Choueiri
Purpose In the phase III METEOR trial ( identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study...
January 29, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
David M Gill, Andrew W Hahn, Peter Hale, Benjamin L Maughan
Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment...
January 24, 2018: Current Treatment Options in Oncology
Robert Roskoski, Abdollah Sadeghi-Nejad
RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases owing to the requirement for additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma...
December 25, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Jordan N Markowitz, Karen M Fancher
Cabozantinib is an oral, small-molecule, multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It has been approved by the United States Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article...
December 28, 2017: Pharmacotherapy
Faiza Abdul Rashid, Qaisar Mansoor, Sobia Tabassum, Hafsa Aziz, Waleed O Arfat, George E Naoum, Muhammad Ismail, Ammad Ahmad Farooqi
Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer...
December 15, 2017: Journal of Cellular Biochemistry
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