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Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Tivozanib is a novel and highly selective VEGF1-3 receptor oral TKI. In a phase III study of 517 patients with advanced clear-cell RCC, tivozanib was compared to sorafenib. Seventy percent of patients were treatment-naïve with 30% of patients having received prior cytokine therapy. Despite better than expected results for sorafenib, median PFS and response rates were superior for tivozanib (11.9 months versus 9.1 months; HR 0.797; p = 0.042 with response rates of 33% versus 23%; p = 0.014). Long-term follow-up data failed to demonstrate any survival benefit for tivozanib over sorafenib median OS 28.8 months (95% CI 22.5–NA) versus 29.3 months (95% CI 29.3–NA; p = 0.105) with results confounded by unbalanced cross-over following failure of first-line treatment. Only 10% of patients in the tivozanib arm received subsequent anti-VEGF treatments (with only 36% receiving any further treatment lines at all), compared to 70% in the sorafenib arm.66 The high selectivity of tivozanib for the VEGFR was characterized by lower rates of certain off-target AEs and fewer dose adjustments, so it remains a valid option for selected patients.
Renal Pathophysiology
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Herman S. Fernando, Mohamed Yehia Abdallah, Iqbal S. Shergill
Sorafenib is an oral multikinase inhibitor with activity against Raf-1 serine/threonine kinase, B-Raf, vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT-3) and c-KIT. Sunitinib is an oxindol tyrosine kinase (TK) inhibitor. It selectively inhibits PDGFR, VEGFR, c-KIT and FLT-3 and has antitumour and anti-angiogenic activity. Pazopanib is an oral angiogenesis inhibitor that targets VEGFR, PDGFR, and c-KIT. Tivozanib is a new oral selective tyrosine kinase inhibitor targeting all three VEGF receptors. Bevacizumab is a humanised monoclonal antibody that binds isoforms of VEGF-A. Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR).
Renal cell cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Tivozanib, is a novel and highly selective VEGF1-3 oral rTKI. In a phase III study of 517 patients with advanced clear cell RCC, Tivozanib was compared to Sorafenib. Seventy per cent of patients were treatment-naive with 30% of patients having received prior cytokine therapy. Despite better than expected results for Sorafenib, median PFS and response rates were superior for Tivozanib (11.9 months versus 9.1 months; HR 0.797; p = 0.042 with response rates of 33% versus 23%; p = 0.014). Longterm follow-up data failed to demonstrate any survival benefit for tivozanib over sorafenib (median OS 28.8 months (95 % CI 22.5-NA) versus 29.3 months (95% CI 29.3-NA; p = 0.105) with results confounded by unbalanced cross-over following failure of first-line treatment. Only 10% of patients in the Tivozanib arm received subsequent anti-VEGF treatments (with only 36% receiving any further treatment lines at all), compared to 70% in the Sorafenib arm.118 The highly selective VEGFR targeting of Tivozanib treatment was characterized by lower rates of certain off-target AEs and fewer dose adjustments. US or European approval has not been forthcoming and Tivozanib currently remains unlicensed.
Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients
Published in OncoImmunology, 2020
Suresh Gopi Kalathil, Katy Wang, Alan Hutson, Renuka Iyer, Yasmin Thanavala
Tivozanib is a potent and highly specific kinase inhibitor that targets vascular endothelial growth factor receptor-1 VEGFR1, VEGFR2, and VEGFR3 at very low concentrations and with a long half-life.5 Tivozanib also inhibits other kinases such as c-Kit and PDGFR-β involved in the signaling cascade.6,7 The potential of VEGF/VEGFR pathway as a therapeutic target has been validated in solid tumors including drug resistant epithelial ovarian cancer where blockade of VEGF receptors by tivozanib reduced proliferative and invasive characteristics of epithelial ovarian cancer cells in vitro.8Tivozanib treated patients demonstrated better response rate and PFS with favorable safety profile in advanced renal cell carcinoma.6,7 In metastatic colorectal cancer, treatment with tivozanib/FOLFOX6 resulted in PFS and overall response rate comparable to bevacizumab.9 Tivozanib specific progression-free survival in metastatic colorectal patients was associated with low-serum neuropilin-1 (NRP-1) levels and NRP-1 seemed to be a biomarker of tivozanib response in clinical trials.9,10 Additionally, antitumor efficacy of tivozanib has been evaluated in solid tumors such as gastrointestinal cancers and breast cancer.8,10 Safety and tolerability profiles of tivozanib have been shown to be acceptable when used in combination therapy.11
The role of tivozanib in advanced renal cell carcinoma therapy
Published in Expert Review of Anticancer Therapy, 2018
Bernard Escudier, Camillo Porta, Tim Eisen, Jonathan Belsey, Damilola Gibson, Jonathan Morgan, Robert Motzer
Forty-one patients with solid tumors (9 with RCC) for which no established therapy existed received daily oral tivozanib for 4 weeks followed by 2 weeks off. An initial cohort of patients (n = 7) received a starting dose of 2.0 mg of tivozanib, which was based on the level at which no adverse effects were observed in preclinical evaluation. However, at this dose, DLTs of Grade 3 asymptomatic proteinuria coinciding with hypertension and Grade 3 ataxia were observed during Cycle 1. Subsequent cohorts received doses of 1.0 mg (n = 18) and 1.5 mg (n = 16). The 1.5 mg dose was determined to be the MTD (the highest dose at which no more than one in six patients experienced a DLT during Cycle 1). In this cohort, the DLTs were asymptomatic reversible transaminase elevation, uncontrolled hypertension, and fatigue and dyspnea. The tolerability and clinical activity observed in this study suggested a recommended tivozanib dose of 1.5 mg for further evaluation in clinical studies.
Tivozanib for the treatment of renal cell carcinoma
Published in Expert Opinion on Pharmacotherapy, 2018
Matteo Santoni, Francesco Massari, Francesco Piva, Francesco Carrozza, Vincenzo Di Nunno, Alessia Cimadamore, Angelo Martignetti, Rodolfo Montironi, Nicola Battelli
About 25% of RCC patients are metastatic at first diagnosis, whereas approximately 20–25% of those who underwent radical nephrectomy will present recurrent or metastatic disease [6,7]. The treatment of these patients has been completely changed by the development of novel target agents, including VEGFR-tyrosine kinase inhibitors (TKIs) sorafenib [8], sunitinib [9], pazopanib [10], axitinib [11], lenvatinib [12], and cabozantinib [13], mammalian target of rapamycin (mTOR) inhibitors temsirolimus [14] and everolimus [15]. These agents are characterized by considerably distinct mechanisms of action [16–21] that reflect the differences in terms of objective response rate (ORR), progression-free survival (PFS) and tolerability [8−15]. On this scenario, the efficacy and safety of tivozanib have been assessed.