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Future Oncology (London, England) Dec 2020Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic... (Review)
Review
Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first of such treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1 inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; B7-H1 Antigen; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor
PubMed: 32856478
DOI: 10.2217/fon-2020-0586 -
Expert Opinion on Drug Safety Apr 2014Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell... (Review)
Review
INTRODUCTION
Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. We review data for axitinib and discuss strategies to manage or prevent adverse events (AEs) and maximize clinical benefit.
AREAS COVERED
A literature search identified key advanced RCC trials of axitinib and other targeted therapies. Each author also contributed a clinical case study to illustrate management approaches in patients who received axitinib following sunitinib in the AXIS Phase III trial. Axitinib has demonstrated a predictable and manageable AE profile in clinical trials; most commonly reported treatment-related events are diarrhea, hypertension, fatigue, nausea, vomiting and dysphonia. Case studies demonstrate that successful management requires patient awareness of potential AEs, regular monitoring and dose modification for specific AEs.
EXPERT OPINION
Improvement in progression-free survival with axitinib versus sorafenib in a Phase III trial supports preferred selection of axitinib in the second-line setting. The safety profile of axitinib versus mammalian target of rapamycin inhibitors and sorafenib also provides the opportunity to personalize treatment in advanced RCC based on the likelihood for specific AEs to occur and on prior toxicities in the first-line setting.
Topics: Axitinib; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 24641566
DOI: 10.1517/14740338.2014.888413 -
Bulletin Du Cancer Oct 2014The objective of this article is to summarize the knowledge as for the side effects related to axitinib in terms of incidence, etiology and symptoms for the effects... (Review)
Review
PURPOSE
The objective of this article is to summarize the knowledge as for the side effects related to axitinib in terms of incidence, etiology and symptoms for the effects requiring a specific management.
METHODS
This article follows upon the recommendations for the clinical practice, published in 2011, which detailed the management of secondary specific toxicities related to targeted therapies prescribed for the treatment of metastatic renal cell carcinoma with a focus on axitinib.
SYNTHESIS
Overall, the toxicity profile of axitinib is better the other tyrosine kinase inhibitors. The ENT side effects and polycythemia, which had not been initially described with other molecules, seem more frequent. Regarding management and follow-up of side effects with axitinib, as for the other targeted therapies used in metastatic renal carcinoma, there are no crucial changes since the recommendations of 2011.
CONCLUSION
The management of side effects remains similar to the recommendations published in 2011. Only preventive measures and management of ENT side effects and polycythemia must be integrated in new thesaurus.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 25373697
DOI: 10.1684/bdc.2014.2042 -
Drug Design, Development and Therapy 2022To evaluate the effect of axitinib on buspirone metabolism in vitro and in vivo.
OBJECTIVE
To evaluate the effect of axitinib on buspirone metabolism in vitro and in vivo.
METHODS
A microsome incubation assay was performed to study the effect and mechanism of axitinib on buspirone metabolizing. In vivo, buspirone was administered with or without axitinib to Sprague-Dawley rats. Plasma samples were collected and subjected to ultra-performance liquid chromatography-tandem mass spectrometry.
RESULTS
In both human liver microsomes (HLMs) and rat liver microsomes (RLMs), axitinib (100 μM) decreased buspirone hydroxylation and N-dealkylation by >85%. Axitinib inhibited buspirone hydroxylation and N-dealkylation, with an IC of 15.76 and 9.74 for RLMs, and 10.63 and 9.902 for HLMs. Axitinib showed noncompetitive inhibition of both 6'-hydroxylation and N-dealkylation. Moreover, coadministration of axitinib and buspirone led to an increase in the maximum plasma concentration (C ) and area under the plasma concentration-time curve (AUC) of buspirone by 4.3- and 5.3-fold, respectively, compared with the control group.
CONCLUSION
Axitinib inhibited buspirone metabolism in vivo and in vitro, which increases the risk of the side effects of buspirone in the clinic. When coadministered with axitinib, a lower dosage of buspirone should be defined to avoid a toxic response. Axitinib is suspected to function as an inhibitor of CYP3A4.
Topics: Animals; Axitinib; Buspirone; Cytochrome P-450 CYP3A; Microsomes, Liver; Rats; Rats, Sprague-Dawley
PubMed: 35795848
DOI: 10.2147/DDDT.S359451 -
Urologia Internationalis 2023Combination therapies of an immune checkpoint inhibitor and a molecular targeted agent are widely accepted as an appropriate initial systemic therapy for metastatic... (Review)
Review
Combination therapies of an immune checkpoint inhibitor and a molecular targeted agent are widely accepted as an appropriate initial systemic therapy for metastatic renal cell carcinoma (RCC), but there is little published evidence regarding the efficacy of this approach in patients with end-stage renal disease (ESRD). Here, we report three patients who were undergoing hemodialysis for ESRD whose metastatic RCC was successfully treated using avelumab plus axitinib. The patients were a 67-year-old man with swollen lymph nodes, a 65-year-old man with pleural dissemination, and a 71-year-old man with lung nodules and an infra-diaphragmatic nodule. They were administered a combination of avelumab plus axitinib as their initial systemic therapy following definitive surgical therapy. The best response of three patients was graded as partial response. No severe adverse events were identified. This is the first report of the use of combination therapy consisting of avelumab plus axitinib in patients with ESRD undergoing hemodialysis. We found that this combination was useful in such patients.
Topics: Male; Humans; Aged; Axitinib; Carcinoma, Renal Cell; Kidney Neoplasms; Retrospective Studies; Renal Dialysis; Kidney Failure, Chronic
PubMed: 36731453
DOI: 10.1159/000528447 -
European Journal of Cancer (Oxford,... Aug 2021
Topics: Aged; Axitinib; Female; Heart Diseases; Humans; Protein Kinase Inhibitors
PubMed: 34126334
DOI: 10.1016/j.ejca.2021.05.011 -
Journal of the European Academy of... Jan 2021
Topics: Antineoplastic Agents; Axitinib; Humans; Kidney Neoplasms; Protein Kinase Inhibitors; Ulcer
PubMed: 32681664
DOI: 10.1111/jdv.16821 -
Health Technology Assessment... Jan 2018Several 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... (Meta-Analysis)
Meta-Analysis Review
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., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy.
DATA SOURCES
A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals.
REVIEW METHODS
A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values.
RESULTS
Four RCTs ( = 2618) and eight non-RCTs ( = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus.
LIMITATIONS
Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS.
CONCLUSIONS
The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016042384.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Cost-Benefit Analysis; Everolimus; Humans; Kidney Neoplasms; Models, Econometric; Nivolumab; Pyridines; Quality-Adjusted Life Years; Sunitinib; Technology Assessment, Biomedical; Vascular Endothelial Growth Factor A
PubMed: 29393024
DOI: 10.3310/hta22060 -
Journal of Controlled Release :... Jul 2022The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless,...
The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.
Topics: Animals; Axitinib; Drug Delivery Systems; Mice; Neovascularization, Pathologic; Ophthalmic Solutions; Peptides; Retina
PubMed: 35537538
DOI: 10.1016/j.jconrel.2022.05.009 -
Nature Reviews. Urology Mar 2023
Topics: Humans; Axitinib; Carcinoma, Renal Cell; Antibodies, Monoclonal, Humanized; Kidney Neoplasms
PubMed: 36797430
DOI: 10.1038/s41585-023-00743-0