Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). Design: This multicenter group-sequential dose escalation phase I study consisted of a placebo-controlled double-masked study of healthy volunteers (cohorts 1 and 2) and an open-label study of patients with nAMD (cohort 3). Participants: Healthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness (CST) ≥300 µm and best-corrected visual acuity score ≥23 letters in the study eye. Methods: In the single-dose cohort of healthy men (cohort 1: steps 1-5), 1 or 2 tivozanib eye drops (30 µL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (cohort 2: steps 1-6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily in 1 eye for 21 days. In the multiple-dose cohort of patients with nAMD (cohort 3, steps 1-3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered 3 times daily in 1 affected eye for 21 days. Main Outcome Measures: The safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated. Results: In total, 40, 48, and 28 participants were enrolled in cohorts 1, 2, and 3, respectively. Serious AEs did not occur in cohorts 1 to 3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to day 22 were -27.6 ± 54.88 (0.5 w/v%; 1 drop, 3 times daily), -35.6 ± 49.64 (1.0 w/v%; 1 drop, 3 times daily), and -43.7 ± 55.19 µm (1.0 w/v%; 2 drops, 3 times daily). Conclusions: Tivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

VEGF-A165a and angiopoietin-2 differently affect the barrier formed by retinal endothelial cells.

Exposure to VEGF-A165a over several days leads to a persistent dysfunction of the very tight barrier formed by immortalized endothelial cells of the bovine retina (iBREC). Elevated permeability of the barrier is indicated by low cell index values determined by electric cell-substrate impedance measurements, by lower amounts of claudin-1, and by disruption of the homogenous and continuous staining of vascular endothelial cadherin at the plasma membrane. Because of findings that suggest modulation of VEGF-A's detrimental effects on the inner blood-retina barrier by the angiogenic growth factor angiopoietin-2, we investigated in more detail in vitro whether this growth factor indeed changes the stability of the barrier formed by retinal endothelial cells or modulates effects of VEGF-A. In view of the clinical relevance of anti-VEGF therapy, we also studied whether blocking VEGF-A-driven signaling is sufficient to prevent barrier dysfunction induced by a combination of both growth factors. Although angiopoietin-2 stimulated proliferation of iBREC, the formed barrier was not weakened at a concentration of 3 nM: Cell index values remained high and expression or subcellular localization of claudin-1 and vascular endothelial cadherin, respectively, were not affected. Angiopoietin-2 enhanced the changes induced by VEGF-A165a and this was more pronounced at lower concentrations of VEGF-A165a. Specific inhibition of the VEGF receptors with tivozanib as well as interfering with binding of VEGF-A to its receptors with bevacizumab prevented the detrimental effects of the growth factors; dual binding of angiopoietin-2 and VEGF-A by faricimab was marginally more efficient. Uptake of extracellular angiopoietin-2 by iBREC can be efficiently prevented by addition of faricimab which is also internalized by the cells. Exposure of the cells to faricimab over several days stabilized their barrier, confirming that inhibition of VEGF-A signaling is not harmful to this cell type. Taken together, our results confirm the dominant role of VEGF-A165a in processes resulting in increased permeability of retinal endothelial cells in which angiopoietin-2 might play a minor modulating role.

A real-world disproportionality analysis of Tivozanib data mining of the public version of FDA adverse event reporting system.

Background: Tivozanib, a vascular endothelial growth factor tyrosine kinase inhibitor, has demonstrated efficacy in a phase III clinical trials for the treatment of renal cell carcinoma. However, comprehensive evaluation of its long-term safety profile in a large sample population remains elusive. The current study assessed Tivozanib-related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System FDA Adverse Event Reporting System. Methods: Disproportionality analyses, utilizing reporting odds ratio proportional reporting ratio Bayesian confidence propagation neural network and multi-item gamma Poisson shrinker (MGPS) algorithms, were conducted to quantify signals of Tivozanib-related AEs. Weibull distribution was used to predict the varying risk incidence of AEs over time. Results: Out of 5,361,420 reports collected from the FAERS database, 1,366 reports of Tivozanib-associated AEs were identified. A total of 94 significant disproportionality preferred terms (PTs) conforming to the four algorithms simultaneously were retained. The most common AEs included fatigue, diarrhea, nausea, blood pressure increased, decreased appetite, and dysphonia, consistent with prior specifications and clinical trials. Unexpected significant AEs such as dyspnea, constipation, pain in extremity, stomatitis, and palmar-plantar erythrodysaesthesia syndrome was observed. The median onset time of Tivozanib-related AEs was 37 days (interquartile range [IQR] 11.75-91 days), with a majority (n = 127, 46.35%) occurring within the initial month following Tivozanib initiation. Conclusion: Our observations align with clinical assertions regarding Tivozanib's safety profile. Additionally, we unveil potential novel and unexpected AE signatures associated with Tivozanib administration, highlighting the imperative for prospective clinical studies to validate these findings and elucidate their causal relationships. These results furnish valuable evidence to steer future clinical inquiries aimed at elucidating the safety profile of Tivozanib.

Tivozanib-induced activation of the mitochondrial apoptotic pathway and suppression of epithelial-to-mesenchymal transition in oral squamous cell carcinoma.

The potential of tivozanib as a treatment for oral squamous cell carcinoma (OSCC) was explored in this study. We investigated the effects of tivozanib on OSCC using the Ca9-22 and CAL27 cell lines. OSCC is a highly prevalent cancer type with a significant risk of lymphatic metastasis and recurrence, which necessitates the development of innovative treatment approaches. Tivozanib, a vascular endothelial growth factor receptor inhibitor, has shown efficacy in inhibiting neovascularization in various cancer types but has not been thoroughly studied in OSCC. Our comprehensive assessment revealed that tivozanib effectively inhibited OSCC cells. This was accompanied by the suppression of Bcl-2, a reduction in matrix metalloproteinase levels, and the induction of intrinsic pathway-mediated apoptosis. Furthermore, tivozanib contributed to epithelial-to-mesenchymal transition (EMT) inhibition by increasing E-cadherin levels while decreasing N-cadherin levels. These findings highlight the substantial anticancer potential of tivozanib in OSCC and thus its promise as a therapeutic option. Beyond reducing cell viability and inducing apoptosis, the capacity of tivozanib to inhibit EMT and modulate key proteins presents the possibility of a paradigm shift in OSCC treatment.

Combination immune checkpoint and targeted protein kinase inhibitors for the treatment of renal cell carcinomas.

Kidney cancers comprise about 3% of all new malignancies in the United States. Renal cell carcinomas (RCCs) are the most common type of renal malignancy making up about 85% of kidney cancer cases. Signs and symptoms of renal cell carcinomas can result from local tumor growth, paraneoplastic syndromes, or distant metastases. The classic triad of presentation with flank pain, hematuria, and a palpable abdominal mass occurs in fewer than 10% of patients. Most diagnoses result from incidental imaging findings (ultrasonography or abdominal CT imaging) performed for another reason. Localized disease is treated by partial nephrectomy, total nephrectomy, or ablation (tumor destruction with heat or cold). When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting programed cell death protein 1, PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting PD1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for ≥ 6 months], progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 30 analyzed patients, 23% had performance status ≥ 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD for ≥ 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) had ≥ 1 treatment-related adverse event (TRAE). There were 6 grade ≥ 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. CONCLUSIONS: In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.

Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial.

BACKGROUND: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported. METHODS: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed. RESULTS: Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221). CONCLUSIONS: Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population.

Activity of Tivozanib in Non-clear Cell Renal Cell Carcinoma: Subgroup Analysis From a Phase II Randomized Discontinuation Trial.

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogeneous and biologically diverse RCC histologies, including but not limited to papillary, chromophobe, and unclassified subtypes. Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) that demonstrated activity in RCC with clear cell component. The objective of this analysis was to determine the efficacy of tivozanib in histologically unclassified/mixed RCC. METHODS: We identified patients with nccRCC enrolled in Study 201 (NCT00502307) between October 2007 and July 2008. This was a phase II randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGFR-targeted treatment. Clinical outcomes including investigator-assessed objective response rate (ORR), disease control rate (DCR, defined by complete response + partial response + stable disease), and progression-free survival (PFS) were examined. RESULTS: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC: 11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) mixed/unclassified. Of the 46 patients with nccRCC, 38 were continuously treated with tivozanib and the best ORR was 21.1% (confirmed) and 31.6% (confirmed and unconfirmed). The DCR was 73.7% and median PFS was 6.7 months (95% confidence interval, 125-366 days). There were no new safety signals compared to the ITT population. Limitations include the small number of individual nccRCC subtypes and the randomized discontinuation design. CONCLUSION: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. These data add to the body of evidence supporting the use of VEGFR-TKI in advanced nccRCC.

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model.

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib.

HPLC methods for studying pharmacokinetics of tivozanib and in vitro metabolic interaction with dexamethasone in rat.

Tivozanib is a recently approved tyrosine kinase inhibitor for the treatment of renal cell carcinoma. In this work, two new HPLC methods coupled with fluorescence (FLD), or photodiode array detectors (PDA) were developed and used for the first time for tivozanib quantification in rat plasma and liver microsomes. The described methods were efficient with a 4-min runtime employing a Gemini-NX C18 column (50 × 2.1 mm, 3 µm) and a mobile phase of acetonitrile and ammonium acetate buffer (pH 4.7, 10 mM) (40:60, v/v) delivered at a flow rate of 0.4 mL/min. The use of HPLC-FLD allowed the quantification of 50 ng/ mL tivozanib using only 100 µL rat plasma. The HPLC-FLD method was validated according to the US food and drug administration (FDA) bioanalytical guidelines and was applied successfully in a rat pharmacokinetic study (n = 7) following oral administration of 1 mg/ kg tivozanib. Furthermore, HPLC-PDA was used for monitoring the depletion of 1 µM (454.9 ng/mL) tivozanib in rat liver microsomes and was applied to study the effect of dexamethasone induction on tivozanib metabolism in vitro. Results showed that dexamethasone enhanced the intrinsic clearance of tivozanib by 60 % suggesting a potential drug-drug interaction at the metabolism level. Dexamethasone is commonly used in the management of cancer disease and thus coadministration with tivozanib therapy may cause treatment failure in patients. The simplicity, speed and cost-effectiveness of the reported methods are ideal for supporting in vivo and in vitro tivozanib studies, including drug-drug interaction studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.

Rule of five violations among the FDA-approved small molecule protein kinase inhibitors.

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs in the pharmaceutical industry. Overall, the US FDA has approved 74 small molecule protein kinase inhibitors, nearly all of which are orally effective. Of the 74 approved drugs, thirty-nine block receptor protein-tyrosine kinases, nineteen target nonreceptor protein-tyrosine kinases, twelve are directed against protein-serine/threonine protein kinases, and four target dual specificity protein kinases. The data indicate that 65 of these medicinals are approved for the management of neoplasms (51 against solid tumors such as breast, colon, and lung cancers, eight against nonsolid tumors such as leukemia, and six against both types of tumors). Nine of the FDA-approved kinase inhibitors form covalent bonds with their target enzymes and they are accordingly classified as TCIs (targeted covalent inhibitors). Medicinal chemists have examined the physicochemical properties of drugs that are orally effective. Lipinski's rule of five (Ro5) is a computational procedure that is used to estimate solubility, membrane permeability, and pharmacological effectiveness in the drug-discovery setting. It relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient. Other important descriptors include the lipophilic efficiency, the polar surface area, and the number of rotatable bonds and aromatic rings. We tabulated these and other properties of the FDA-approved kinase inhibitors. Of the 74 approved drugs, 30 fail to comply with the rule of five.

Current Status of Tivozanib in the Treatment of Patients With Advanced Renal Cell Carcinoma.

The introduction of tyrosine kinase inhibitors (TKIs) against vascular endothelial growth factor receptors (VEGFRs) has transformed the therapeutic landscape for patients with advanced renal cell carcinoma (RCC). However, dose reductions and interruptions are frequently needed due to limited toxicity, mostly from off-target effects. Tivozanib is a potent, selective VEGFR TKI with weak off-target effects. TIVO-1 and TIVO-3 were randomized controlled phase 3 trials that investigated the efficacy and safety of tivozanib versus sorafenib as initial targeted therapy and after failing two previous lines (including targeted therapy), respectively. Tivozanib did not confer any survival advantage, but it significantly increased progression-free survival, response rates, and the duration of responses with a superior safety profile. Although results from subgroup analysis need to be interpreted cautiously, tivozanib demonstrated superiority after two previous lines of VEGFR TKIs or after axitinib, another selective VEGFR inhibitor. Tivozanib also demonstrated durable activity after therapy with an immune-checkpoint inhibitor, while an ongoing study investigating the combination of tivozanib/nivolumab has shown promising preliminary results regarding efficacy and safety. In conclusion, tivozanib was recently added to our therapeutic armamentarium against advanced RCC. Ongoing rational therapeutic combinations of tivozanib will determine the optimal setting in which the maximum benefit can be derived.

Tivozanib: A New Hope for Treating Renal Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a diverse collection of malignancies with varying histological characteristics, molecular changes, prognosis, and therapeutic response. Tivozanib was first approved in March 2021 by USFDA with the brand name Fotivda. Tivozanib hydrochloride monohydrate is an oral medication that is used to treat relapsed or refractory renal cell carcinoma. OBJECTIVE: In this review, we explain renal cell carcinoma and its different types of treatment by the anti-renal carcinoma drugs. METHODS: A comprehensive literature search was conducted in the relevant databases, like ScienceDirect, PubMed, ResearchGate, and Google Scholar, to identify the studies. CONCLUSION: Tivozanib is an oral VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibitor that is extremely selective and powerful. It has much less affinity for other receptor tyrosine kinases than multi-targeted TKIs now in clinical use. Because of its long half-life in circulation, it may be able to block VEGFRs more consistently. Doserelated controllable hypertension is its most commonly seen drug-related side event. Fatigue, hoarseness, and diarrhea, which are all common side effects, are not dose-related. Because of its target specificity, tivozanib can work well with other medications that have low side effects. Blocking both the VEGF and mTOR signaling pathways at the same time provides the benefit of synergistic antitumor efficacy while also preventing treatment resistance. Thus, overall we can say that the drug tivozanib is suitable for treatment in patients with renal cell carcinoma and can be investigated in multi-center clinical trials.

Tivozanib in Patients with Advanced Renal Cell Carcinoma Previously Treated With Axitinib: Subgroup Analysis from TIVO-3.

BACKGROUND: In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib. METHODS: We identified patients from the intention to treat (ITT) population, in the TIVO-3 trial, who received treatment with axitinib before enrolment in the study and evaluated PFS, response rate (RR), and safety. RESULTS: Out of 350 patients, 172 (83:89, tivozanib:sorafenib) had received prior treatment with axitinib in TIVO-3. In this subgroup, PFS was 5.5 months with tivozanib and 3.7 months with sorafenib (HR 0.68). RR was 13% and 8% favoring tivozanib. CONCLUSIONS: Tivozanib is active in the treatment of patients with mRCC who have progressed on prior therapies, including axitinib.

Atezolizumab plus tivozanib for immunologically cold tumor types: the IMMCO-1 trial.

Immune checkpoint inhibitor therapy represents a significant advance in cancer care. The interaction between PD-1 and PD-L1 induces immune tolerance and the inhibition of this interaction is an effective treatment strategy for numerous malignancies. Despite its demonstrated potential, immunotherapy is not clinically effective in immunogenically 'cold' tumors such as pancreatic cancer, prostate cancer and neuroendocrine tumors. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade in tumors that have traditionally shown a lack of clinical response to immunotherapy. This signal-seeking, single-arm, prospective clinical trial aims to determine the objective response of tivozanib and atezolizumab in advanced immunogenically cold solid tumors. Clinical Trial Registration: NCT05000294 (ClinicalTrials.gov).

Initial research on the effect and mechanism of Tivozanib on pulsed dye laser induced angiogenesis.

INTRODUCTION: Pulsed dye laser (PDL) is the main treatment for port wine stain (PWS), but a considerable number of patients show low clearances. The reason for the poor efficacy is related to PDL-induced angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in PDL-induced angiogenesis and can activate the tyrosine kinase activity of VEGF receptor (VEGFR) in endothelial cells. It triggers a full range of responses, and then participates in the regulation of angiogenesis. Tivozanib is an inhibitor of VEGFR tyrosine kinase activity, which can block the pro-angiogenic effect of VEGF and reduce vascular permeability. METHOD: Different energy densities of PDL were used to irradiate the abdominal skin of rats. According to the general and pathological changes of the irradiated area, the energy density of 8 J/cm2 with smaller scab and stronger vascular effect was selected for follow-up experiments. Divided the rat abdomen skin into four areas, irradiated three of them uniformly with an energy density of 8 J/cm2 , and applied different concentrations of Tivozanib coating agent to the laser irradiation area, and grouped them as follows: (1) vacant group, (2) control group, (3) 0.5% Tivozanib group, (4) 1% Tivozanib group. Camera and dermoscopy were used to observe skin changes. Hematoxylin-eosin staining, immunohistochemical staining, and blood vessels were counted to detect dermal vascular regeneration. Transcriptome sequencing and real-time polymerase chain reaction (PCR) were conducted to elucidate the mechanism and validate the reliability. RESULTS: The number of blood vessels in the 0.5% Tivozanib group and 1% Tivozanib group was significantly reduced on the 7, 10, and 14 days compared with the control group. The number of blood vessels in the 1% Tivozanib group was significantly reduced compared with the 0.5% Tivozanib group, indicating that Tivozanib successfully inhibited PDL-induced angiogenesis, and the inhibitory effect of 1% Tivozanib was more significant than that of 0.5% Tivozanib. Transcriptome sequencing results showed a total of 588 significantly differentially expressed genes, including 90 upregulated genes and 498 downregulated genes. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the significantly differentially expressed genes were mainly enriched in the metabolic pathways which were closely related to angiogenesis. Finally, real-time PCR was used to verify the genes with higher expression differences, the top ranking and closely related to angiogenesis, namely, Cxcl1, Cxcl2, Cxcl3, Cxcl6, Ccl3, Csf3, IL1ß, iNOS, Mmp9, Mmp13, Plau, Ets1, Spp1, Nr4a1. The results were consistent with the trend of transcriptome sequencing results, which proved the reliability of this study. CONCLUSION: This study explored the inhibitory effect of Tivozanib on PDL-induced angiogenesis, and provided a new idea for the treatment of clinical PWS. Transcriptome sequencing explored the mechanism and provided reliable clues for later in-depth research.

Tivozanib for the treatment of advanced renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for 2.4% of cancers, with clear cell kidney cancer being the most common histologic subtype. Despite recent therapeutic advances, the prognosis for patients with advanced disease remains poor, with a 5-year survival rate of only 13.9% reported in the United States. Tivozanib is a novel inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 and has recently been approved by the US FDA for use in patients with relapsed or recurrent advanced RCC following two or more prior systemic therapies. AREAS COVERED: Here, the authors provide a review focusing on the development of tivozanib, compare tivozanib to other agents in the VEGFR inhibitor class, detail how tivozanib fits into current treatment landscape, and describe ongoing studies involving this agent. EXPERT OPINION: Given tivozanib's excellent safety profile and demonstrated clinical benefit in patients with pretreated disease, tivozanib is likely to be heavily utilized in the later-line setting. The ongoing TINIVO-2 study may further impact the treatment landscape by evaluating the use of tivozanib plus nivolumab in patients who have progressed on an immune checkpoint inhibitor.

Tivozanib in relapsed or refractory advanced renal cell carcinoma: a focus on US approval.

INTRODUCTION: Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR)-inhibitor designed to, more specifically, bind to the VEGF receptor with fewer off-target interactions with other tyrosine kinase receptors in the treatment of advanced renal cell carcinoma (RCC). AREAS COVERED: Both preclinical and early clinical studies have suggested tivozanib could be a more potent VEGFR inhibitor with less off-target toxicities for patients. After a complicated clinical development process, the drug was approved by the FDA for third- and fourth-line use in relapsed, refractory renal cell carcinoma (RCC) in March of 2021 based on the results of the TIVO-3 trial. However, questions remain regarding the proper incorporation of tivozanib in the current treatment landscape of RCC. EXPERT OPINION: Here, we review the existing literature surrounding tivozanib and comment on its optimal use in current and future clinical practice. We suggest that tivozanib may be considered in relapsed, refractory RCC in the later-line treatment setting following progression on both immune checkpoint inhibitors (ICIs) and nonselective VEGFR-TKIs. We anticipate the application of tivozanib in RCC will continue to evolve as trials exploring tivozanib in combination with ICIs may move this drug earlier in the future treatment landscape of RCC.

Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A165 No Longer Depends on the Growth Factor's Presence.

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A165 depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes-determined as a measure of permeability-was persistently reduced by exposure to the growth factor. Late after addition of VEGF-A165 protein levels of claudin-1 and CD49e were significantly lower, those of CD29 significantly higher, and the plasmalemma vesicle associated protein was no longer detected. Nuclear levels of ß-catenin were only elevated on day two. Extracellular levels of VEGF-A-measured by ELISA-were very low. Similar to the binding of the growth factor by brolucizumab, inhibition of VEGFR2 by tyrosine kinase inhibitors tivozanib or nintedanib led to complete, although transient, recovery of the low cell index when added early, though was inefficient when added three or six days later. Additional inhibition of other receptor tyrosine kinases by nintedanib was similarly unsuccessful, but additional blocking of c-kit by tivozanib led to sustained recovery of the low cell index, an effect observed only when the inhibitor was added early. From these data, we conclude that several days after the addition of VEGF-A165 to iBREC, barrier dysfunction is mainly sustained by increased paracellular flow and impaired adhesion. Even more important, these changes are most likely no longer VEGF-A-controlled.

Tivozanib in renal cell carcinoma: a systematic review of the evidence and its dissemination in the scientific literature.

BACKGROUND: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis. METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods. RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results. CONCLUSION: EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.