Administration Of Axitinib Research Articles

The protective effects of Axitinib on blood-brain barrier dysfunction and ischemia-reperfusion injury in acute ischemic stroke

Background and purposeThe pathophysiological features of acute ischemic stroke (AIS) often involve dysfunction of the blood-brain barrier (BBB), characterized by the degradation of tight junction proteins (Tjs) leading to increased permeability. This dysfunction can exacerbate cerebral injury and contribute to severe complications. The permeability of the BBB fluctuates during different stages of AIS and is influenced by various factors. Developing effective therapies to restore BBB function remains a significant challenge in AIS treatment. High levels of vascular endothelial growth factor (VEGF) in the early stages of AIS have been shown to worsen BBB breakdown and stroke progression. Our study aimed to investigate the protective effects of the VEGF receptor inhibitor Axitinib on BBB dysfunction and cerebral ischemia/reperfusion-induced injury. MethodsBEnd3 cell exposed to oxygen–glucose deprivation (OGD) model was constructed to estimate pharmacological activity of Axitinib (400 ng/ml) on anti-apoptosis and pathological barrier function recovery. In vivo, rats were subjected to a 1 h transient middle cerebral artery occlusion and 23 h reperfusion (tMCAO/R) to investigate the permeability of BBB and cerebral tissue damage. Axitinib was administered through the tail vein at the beginning of reperfusion. BBB integrity was assessed by Evans blue leakage and the expression levels of Tjs claudin-5 and occludin. ResultsOur research revealed that co-incubation with Axitinib enhanced the cell viability of OGD-insulted bEnd3 cells, decreased LDH leakage rate, and suppressed the expression of apoptosis-related proteins cytochrome C and Bax. Axitinib also mitigated the damage to Tjs and facilitated the restoration of transepithelial electrical resistance in OGD-insulted bEnd.3 cells. In vivo, Axitinib administration reduced intracerebral Evans blue leakage and up-regulated the expression of Tjs in the penumbra brain tissue in tMCAO/R rats. Notably, 10 mg/kg Axitinib exerted a significant anti-ischemic effect by decreasing cerebral infarct volume and brain edema volume, improving neurological function, and reducing pro-inflammatory cytokines IL-6 and TNF-α in the brain. ConclusionsOur study highlights Axitinib as a potent protectant of blood-brain barrier function, capable of promoting pathological blood-brain barrier recovery through VEGF inhibition and increased expression of tight junction proteins in AIS. This suggests that VEGF antagonism within the first 24 h post-stroke could be a novel therapeutic approach to enhance blood-brain barrier function and mitigate ischemia-reperfusion injury.

Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.

Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma.

The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC). Clinicopathological data were collected from 36 consecutive patients with metastatic RCC who received axitinib. Thirty-three primary tumours were obtained for immunohistochemistry. Patient-derived xenograft (PDX) models were created by transplanting primary tumours into immunodeficient mice, establishing axitinib-resistant PDX models. RCC cell lines were co-cultured with human renal glomerular endothelial cells (HGECs) treated with siRNA of INSR (HGEC-siINSR). Gene expression alteration was analysed using microarray. The patients with low INSR expression who received axitinib had a poorer outcome. Multivariate analysis showed that INSR expression was the independent predictor of progression-free survival. INSR expression decreased in axitinib-resistant PDX tumours. RCC cell lines showed upregulated interferon responses and highly increased interferon-β levels by co-culturing with HGEC-siINSR. HGECs showed decreased INSR and increased interferon-β after axitinib administration. RCC cell lines co-cultured with HGEC-siINSR showed high programmed death-ligand 1 (PD-L1) expression, which increased after interferon-β administration. Decreased INSR in RCC could be a biomarker to predict axitinib resistance. Regarding the resistant mechanism, vascular endothelial cells with decreased INSR in RCC may secrete interferon-β and induce PD-L1.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.

Review of Suprachoroidal Delivery and its Application in Small Molecule Therapy

Therapies for retinal diseases have witnessed remarkable progress, particularly in the domain of drug delivery routes. Intravitreal injections have especially revolutionized the treatment landscape for various proliferative retinopathies. The emergence of suprachoroidal space as a novel drug delivery site is poised to overcome challenges seen in optimizing drug penetration, targeting, and bioavailability. This approach holds promise for delivering various agents, including steroids, anti-vascular endothelial growth factor molecules, gene vectors, and small molecules, with multiple clinical trials demonstrating this delivery method's potential to reduce treatment burdens and optimize visual outcomes. Particularly, small molecule therapy for retinal diseases finds ease of application through the suprachoroidal route in that small molecule agents have a wide range of targets in disease pathway, greater tissue penetration, and cost-effectiveness in production. The suprachoroidal administration of axitinib, a tyrosine kinase inhibitor, has shown promise in the OASIS trial for treating neovascular age-related macular degeneration. Integrin antagonists and plasma Kallikrein-kinin system inhibitors, also delivered suprachoroidally, exhibit targeted distribution and potential for long-acting therapy.

Effects of axitinib and lenvatinib on cardiovascular function and haemodynamic

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 Research and Innovation programme, under the Marie Skłodowska-Curie European Training Network Background The introduction of novel anticancer treatments, targeting vascular endothelial growth factor receptors (VEGFRs), has changed the therapeutic approach in oncology. However, with their introduction in clinical practice, unanticipated cardiovascular complications emerged, including hypertension, left ventricular dysfunction and thromboembolism [1]. Even though these therapeutics strongly affect haemodynamic balance in patients, the pathophysiological mechanisms by which they impair cardiovascular function are still largely unknown, leading to a reduction of therapeutic dosage or to a temporary or permanent treatment interruption [2]. Purpose The severity of cardiovascular complications following the treatment with VEGFR inhibitors, along with the lack of antihypertensive strategies able to adequately manage these events, require an unequivocal and urgent assessment of their cardiovascular safety. This study aims to determine the extent to which VEGFR inhibitors impact on cardiovascular function, profiling their effect on regional haemodynamic responses. Their cardiovascular assessment represents a valuable opportunity to investigate the mechanisms underlying cardiovascular toxicities induced by these novel antiangiogenic treatments. Methods This study evaluated the haemodynamic effects of selected receptor tyrosine kinase inhibitors (RTKIs), namely axitinib and lenvatinib, in conscious and freely moving rats using the Doppler Flowmetry technique. Male Sprague Dawley Rats (350-450 g) were chronically implanted with pulsed Doppler flow probes (around the renal and mesenteric arteries, and the descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta) [3]. Haemodynamic parameters were measured over 4 days, before and after daily administration of axitinib (3 and 6 mg/kg, 3 and 6 mg/kg/h for 1 h, i.v.), or lenvatinib (3 and 6 mg/kg, 3 and 6 mg/kg/h for 1 h, i.v.). Results Both axitinib and lenvatinib evoked a significant hypertensive response, which progressively increased over the 4 days. This pressor effect was associated with a notable decrease of vascular conductance in the hindquarters. Lenvatinib caused a more marked vasoconstriction in mesenteric and renal vessels when compared to axitinib, which only elicited a renal vasoconstrictive effect at the highest dose used. Conclusions This study showed that the axitinib- and lenvatinib-induced hypertensive response is associated with regionally selective vasoconstrictions, which consistently occur in the hindquarters vascular bed. However, their vasoconstrictive profile differs in the renal and mesenteric vasculature. In addition, the Doppler Flowmetry model showed to be a translational approach to predict the detrimental cardiovascular effects of these anticancer drugs, since the increase in blood pressure observed with this method reflects the hypertensive response reported in clinical practice.

NAXIVA: A phase II neoadjuvant study of axitinib for reducing extent of venous tumor thrombus in clear cell renal cell cancer (RCC) with venous invasion.

275 Background: Venous tumor thrombus (VTT) extension occurs in 4-15% cases of renal cell cancer (RCC). The Mayo classification distinguishes 4 levels of VTT extension between the renal vein and supradiaphragmatic inferior vena cava (IVC). Although surgery is performed with curative intent, mortality is high (5-15%) with complications increasing with the level of the VTT. 5-year survival rates are poor; ~40-65% in non-metastatic RCC. It is hypothesised that neoadjuvant targeted therapy could downstage the VTT reducing the extent of surgery, leading to reduced surgical morbidity and mortality, and increased survival. However, level I or II evidence is lacking. NAXIVA provides the first level II evidence in this patient group, assessing the response of VTT to axitinib. Extensive translational sampling will provide in depth interrogation of VTT (using genomics, proteomics, immunophenotyping and metabolomics) to examine the role of the tumor microenvironment of VTT and response to axitinib. Methods: NAXIVA was a single arm, single agent, multi-center phase 2 feasibility study of axitinib in patients with both metastatic and non-metastatic clear cell RCC prior to nephrectomy and thrombectomy. A Simon two stage minimax design was adopted and the trial designed for adequate power to distinguish a <5% from a >25% improvement in the Mayo VTT level. 21 patients were recruited over a 24 month period between 15/Dec/2017 and 06/Jan/2020 at 5 sites across the UK. Patients were treated with 8 weeks of axitinib (starting dose 5mg bd, increasing to 10mg bd as tolerated) prior to planned surgery. The primary endpoint was the percentage of evaluable patients with an improvement in VTT according to the Mayo classification (assessed using MRI abdomen scans at screening and week 9, prior to surgery. Secondary endpoints were percentage change in surgical approach, percentage change in VTT height, response rate (by RECIST) and evaluation of surgical morbidity assessed by Clavien-Dindo classification. Results: The percentage of evaluable patients with an improvement in VTT according to the Mayo classification was 26.58% [80% CI: 15.76%, 39.74%] (6 of 21 evaluable patients). 35.29% (6 of 17 patients who progressed to surgery) had a change in surgical approach to a less invasive option. There was a median percentage reduction in VTT height of 21.49% (SD=27.60%). The response rate (by RECIST) in the evaluable population was 61.90% SD, 14.29% PR, 9.52% PD. In terms of surgical morbidity 11.76% (2 of 17 patients who progressed to surgery) experienced a Clavien-Dindo 3 or greater complication (0 CD3, 1 CD4, 1 CD5). Conclusions: NAXIVA provides unique prospective data on the feasibility of neoadjuvant axitinib administration to down stage IVC VTT and reduce the extent of surgery. Work is ongoing to establish predictors of response. Clinical trial information: NCT03494816 .

MP72-06 CORRELATION OF THE INSULIN RECEPTOR EXPRESSION AND THE RESISTANCE TO VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN ADVANCED CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II1 Apr 2018MP72-06 CORRELATION OF THE INSULIN RECEPTOR EXPRESSION AND THE RESISTANCE TO VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN ADVANCED CLEAR CELL RENAL CELL CARCINOMA Masayuki Takahashi, Kei Daizumoto, Yayoi Fukuhara, Keisuke Ozaki, Megumi Tsuda, Yoshito Kusuhara, Hidehisa Mori, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Tomoharu Fukumori, and Hiroomi Kanayama Masayuki TakahashiMasayuki Takahashi More articles by this author , Kei DaizumotoKei Daizumoto More articles by this author , Yayoi FukuharaYayoi Fukuhara More articles by this author , Keisuke OzakiKeisuke Ozaki More articles by this author , Megumi TsudaMegumi Tsuda More articles by this author , Yoshito KusuharaYoshito Kusuhara More articles by this author , Hidehisa MoriHidehisa Mori More articles by this author , Tomoya FukawaTomoya Fukawa More articles by this author , Yasuyo YamamotoYasuyo Yamamoto More articles by this author , Kunihisa YamaguchiKunihisa Yamaguchi More articles by this author , Tomoharu FukumoriTomoharu Fukumori More articles by this author , and Hiroomi KanayamaHiroomi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2290AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) demonstrate the significant efficacy for advanced clear cell renal cell carcinoma (ccRCC), however, it eventually becomes resistant to VEGFR-TKIs during the treatment. So far, the mechanisms for the resistance to VEGFR-TKIs remain to be fully elucidated. Previously we have identified the gene set which could predict poor prognosis of ccRCC patients (Takahashi M et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001). We examined whether the insulin receptor (INSR) expression in the gene set may correlate with the resistance to VEGFR-TKIs. METHODS The INSR expression was examined immunohistochemically in the nephrectomy specimens of the RCC patients (n=33) who then received axitinib as the VEGFR-TKI and correlated with their survival outcome. We compared the INSR expression of the nephrectomy or metastasectomy specimens before and after the administration of VEGFR-TKIs in 5 cases. The INSR expression of the human renal glomerular endothelial cells (HGEC) was compared before and after the administration of axitinib by Western blotting. In addition, we established patient derived Xenograft model (PDX) of ccRCC. Tumors of PDX were resected when it regrew and showed the resistance for axitinib and the INSR expression was compared before and after the treatment by Western blotting. RESULTS The INSR was expressed at the vessels surrounding tumor cells. Progression-free survival (PFS) was significantly shorter in the INSR-negative group than in the INSR-positive group. Multivariate analysis revealed that the INSR expression was the significantly independent predictor of PFS. In the specimens resected after VEGFR-TKI, the INSR expression was more frequently decreased. As the concentration of axitinib increased, the INSR expression in the HGEC was decreased. The tumors of PDX that were resected after demonstrating the resistance to axitinib had the decreased INSR expression. CONCLUSIONS The decreased INSR expression could be correlated with the resistance to VEGFR-TKI and its expression may be useful in selecting appropriate drugs for advanced ccRCC patients. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e954 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Masayuki Takahashi More articles by this author Kei Daizumoto More articles by this author Yayoi Fukuhara More articles by this author Keisuke Ozaki More articles by this author Megumi Tsuda More articles by this author Yoshito Kusuhara More articles by this author Hidehisa Mori More articles by this author Tomoya Fukawa More articles by this author Yasuyo Yamamoto More articles by this author Kunihisa Yamaguchi More articles by this author Tomoharu Fukumori More articles by this author Hiroomi Kanayama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A FavorAx study of axitinib in favorable risk patients with metastatic renal cell carcinoma.

666 Background: Targeted therapy with axitinib resulted in a greater objective response rate and prolonged progression-free survival (PFS) compared to sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC) in AXIS study. 75% of patients had intermediate and poor IMDC prognosis. In this phase 2 study, we assessed the activity of axitinib in mRCC patients with favourable risk and a history of prior VEGFR-directed therapy. Methods: Patients were required to have clear cell mRCC, favourable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. The primary endpoint of the study was PFS. Additional endpoints included response rate, safety, and overall survival (OS). Results: A total of 21 patients were enrolled, 62% of whom were male. Median age was 59 years. 11 (52%) patients had 2 and more metastatic sites. 67% and 33% of patients received first-line sunitinib or pazopanib with a median PFS of 17 months (95% CI 14-20). After a median follow-up of 16 months, the median PFS and OS was not yet reached. The current study did achieve its primary endpoint based on the 10-month PFS of 71.4%. 3 (14.3%) patients had confirmed partial responses and 14 (66.7%) had stable disease. No grade 3/4 treatment-related adverse events were observed; the most frequent grade 1/2 treatment-related adverse events were hypertension (57.1%), fatigue (57.1%), GI (33%) and skin (19%) toxicity. 7 patients had dose-escalation of axitinib and 1 patient had dose reduction. Conclusions: The encouraging PFS and favorable safety profile observed in FavorAx study support the administration of axitinib in mRCC patients with favourable IMDC risk and a history of prior sunitinib or pazopanib. Clinical trial information: NCT02700568.

Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice

AimAn increased density of intraplaque (IP) microvessels in ruptured versus nonruptured human plaques suggests that IP neovascularization has a major causative effect on plaque development and instability. Possibly, vascular endothelial growth factor (VEGF) or other angiogenic factors mediate IP microvessel growth and plaque destabilization. Because apolipoprotein deficient mice with a heterozygous mutation (C1039G+/−) in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−) manifest substantial IP neovascularization, they represent a unique tool to further investigate angiogenesis and its role in atherosclerosis. Here, we examined whether administration of axitinib (inhibitor of VEGF receptor-1,-2 and -3) inhibits IP neovascularization and stabilizes atherosclerotic plaques. MethodsApoE−/−Fbn1C1039G+/− mice were fed a western diet (WD) for 20weeks. After 14weeks WD, mice received axitinib (35μg/g) or solvent i.p. 4×/week for 6weeks. Cardiac function was monitored to evaluate the effect of axitinib on atherosclerosis-driven complications such as myocardial infarction. ResultsAxitinib significantly reduced IP neovascularization, with subsequent less prevalence of IP haemorrhages. The smooth muscle cell content doubled, whereas the amount of macrophages decreased. Overall cardiac function was improved in axitinib-treated animals. Moreover, the number of animals with myocardial infarction was decreased by 40%. Coronary plaque formation was observed in almost all control animals whereas treated animals showed a 30% reduction in the occurrence of coronary plaques. ConclusionsInhibition of VEGF receptor signalling by axitinib attenuates intraplaque angiogenesis and plaque destabilization in mice.

Inhibition of VEGF receptor signaling attenuates intraplaque angiogenesis and plaque destabilization in a mouse model of advanced atherosclerosis

Aim: Intraplaque (IP) microvessels have a major causative effect on atherosclerotic plaque development. An increase in microvessel density in ruptured versus nonruptured human plaques suggests that VEGF and other angiogenic factors promote atherosclerosis and potentially destabilize plaques. Because apolipoprotein deficient mice with a heterozygous mutation (C1039G+/-) in the fibrillin-1 gene (ApoE-/-Fbn1C1039G+/-) manifest substantial IP neovascularization, they represent a unique tool to investigate angiogenesis and its role in atherosclerosis. Here, we examined whether administration of axitinib (inhibitor of VEGF receptor-1,-2 and -3) inhibits IP neovascularization and stabilizes atherosclerotic plaques.

Association of axitinib plasma exposure and genetic polymorphisms of ABC transporters with axitinib-induced toxicities in patients with renal cell carcinoma.

Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors, approved for advanced renal cell carcinoma (RCC). Associations between axitinib plasma exposure, genetic polymorphisms of ABC transporters and axitinib-induced toxicities have not been adequately explored. Twenty RCC patients treated with axitinib were enrolled in this study. Blood samples were collected 0, 0.5, 1, 2, 4, and 6h after administration of axitinib on day 1 and at steady state. Plasma concentrations of axitinib were analyzed by UPLC-MS/MS. The ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) genetic polymorphisms were determined by real-time PCR. ABCB1 haplotype was associated with increased dose-adjusted area under the plasma concentration-time curve (AUC) of axitinib at steady state. The incidence of fatigue during therapy was associated with high AUC0-6 of axitinib (P=0.013). The treatment period without discontinuation or dose reduction due to adverse events in patients with high AUC0-6 of axitinib was significantly shorter than for those with low AUC0-6 (P=0.024). No significant differences were found in the frequency of adverse events among the ABCG2 genotype and ABCB1 haplotype groups. Our results have demonstrated that adverse events leading to discontinuation or dose reduction in axitinib were associated with increased axitinib plasma exposure, but not directly with genetic polymorphisms of ABC transporters. Therefore, measurement of steady state axitinib plasma concentrations may be useful in avoiding adverse events in axitinib therapy.

Assessment of Efficacy, Safety, and Quality of Life of 124 Patients Treated With Axitinib as Second-Line Therapy for Metastatic Renal-Cell Carcinoma: Experience in Real-World Clinical Practice in Japan

PurposeTo comprehensively analyze the efficacy of axitinib for metastatic renal-cell carcinoma (mRCC) patients. Patients and MethodsThis study included 124 consecutive Japanese patients treated with axitinib as second-line systemic therapy for mRCC in a routine clinical setting. ResultsIn addition to 4 indeterminate patients (3.2%), 0 (0%), 21 (16.9%), 87 (70.2%), and 12 (9.7%) were judged to show complete response, partial response, stable disease, and progressive disease, respectively, as the best responses to axitinib. The median progression-free survival (PFS) and overall survival (OS) after initiating treatment with axitinib were 9.3 and 27.0 months, respectively. Multivariate analyses of several parameters identified the following independent predictors of PFS and OS: Memorial Sloan Kettering Cancer Center (MSKCC) classification and C-reactive protein level for PFS; and MSKCC classification, C-reactive protein level, bone metastasis, and liver metastasis for OS. Common grade 3 or higher adverse events associated with axitinib were hypertension in 41 (33.1%), proteinuria in 14 (11.3%), and hand–foot syndrome in 14 (11.3%). Quality-of-life analysis using the Medical Outcomes Study 36-Item Short Form showed that 2 scores were significantly improved 12 weeks after the administration of axitinib, while there were no significant differences in the remaining 6 scores between surveys administered before and 12 weeks after the treatment with axitinib. ConclusionFavorable disease control could be achieved with acceptable tolerability by introducing axitinib as second-line systemic therapy, resulting in improvement of the prognosis and quality of life of Japanese patients with mRCC.

Feasibly of axitinib as first-line therapy for advanced or metastatic renal cell carcinoma: a single-institution experience in Japan.

BackgroundClinical benefit of axitinib as a first line agent to treat patients with metastatic renal cell carcinoma (mRCC), or locally advanced renal cell carcinoma (RCC) have not been clearly demonstrated. The aim of this study was to evaluate the efficacy and safety of axitinib as first-line therapy in Japanese patients with locally advanced RCC or mRCC.MethodsIn this retrospective study, we focused on eighteen patients who underwent first-line therapy with axitinib between May 2012 and May 2014 at Hirosaki University. Axitinib was orally administered at a dose of 10 mg daily. Progression-free survival (PFS) was the primary endpoint, while secondary endpoints included overall response rate (ORR) and adverse events (AEs).ResultsAll patients had histologically proven clear cell RCC. The median duration of the administration of axitinib was 10.8 months. According to the response evaluation criteria for solid tumors, five patients (27.8%) achieved a partial response and nine (50%) had stable disease. The 1-year PFS rate was 84.4%, and the median PFS was 20.4 months (95% confidence interval, 17.5 – 21.7). No serious AEs were reported during the study, and there were no toxicity-related deaths.ConclusionsIn the current study, axitinib showed acceptable oncological outcomes and favorable safety profile as first-line therapy for locally advanced RCC or mRCC in treatment-naïve Japanese patients. Thus, first-line therapy with axitinib may provide a feasible option for treatment of advanced RCC or mRCC patients.

Topical axitinib suppresses angiogenesis pathways induced by pulsed dye laser.

The recurrence of port-wine stain (PWS) blood vessels by pulsed dye laser (PDL)-induced angiogenesis is a critical barrier that must be overcome to achieve a better therapeutic outcome. To determine whether PDL-induced angiogenesis can be suppressed by topical axitinib. The mRNA expression profiles of 86 angiogenic genes and phosphorylation levels of extracellular signal regulated kinases (ERKs), phosphorylated protein kinase B (AKT) and ribosomal protein S6 kinase (p70S6K) in rodent skin were examined with or without topical axitinib administration after PDL exposure. The PDL-induced increased transcriptional levels of angiogenic genes peaked at days 3-7 post-PDL exposure. Topical application of 0·5% axitinib effectively suppressed the PDL-induced increase in mRNA levels of the examined angiogenic genes and activation of AKT, P70S6K and ERK from days 1 to 7 post-PDL exposure. After topical administration, axitinib penetrated into rodent skin to an approximate depth of 929·5μm. Topical application of 0·5% axitinib can systematically suppress the PDL-induced early stages of angiogenesis via inhibition of the AKT/mammalian target of rapamycin/p70S6K and Src homology 2 domain containing transforming protein-1/mitogen-activated protein kinase kinase/ERK pathway cascades.

P1-5-4 - Association of Abcg2 Polymorphism with Plasma Concentrations of Axitinib in Patients with Renal Cell Carcinoma

Background: Axitinib is a selective inhibitor for VEGF receptors 1, 2, and 3 on renal cell carcinoma (RCC). The plasma concentrations and area under the blood concentration-time curve (AUC) of axitinib are known to correlate with response rate and survival rate in RCC patients. Breast cancer resistance protein (BCRP, ABCG2 gene) is an efflux ABC transporter, which is expressed at the apical membrane in intestine, and is involved in the absorption and excretion of various drugs. Several studies have demonstrated that ABCG2 polymorphism affects blood concentrations of oral anticancer drugs, especially molecular targeted drugs. To explore the relationship between pharmacokinetics and pharmacogenetics, we analyzed plasma concentrations of axitinib and ABCG2 polymorphism in RCC patients.Method: Eight RCC patients treated with axitinib at Nagoya University Hospital were enrolled in this study. All patients were orally administered 5mg axitinib twice a day. The blood samples were collected before (0 hr) and 0.5, 1, 2, 4 and 6 hr after administration of axitinib (6 points) on day 1 and day 8, respectively. The plasma concentrations of axitinb were analyzed by UPLC-MS/MS. The genetic polymorphism of ABCG2 was determined by real-time PCR. This study was approved by the ethical committee of Nagoya University Hospital, and all patients gave written informed consent.Result: The standard concentration-curve of axitinib in human plasma was linear in the range of 1-100 ng/mL. Intra- and inter-day precision ranged from 1.5 to 7.9% and accuracy were all less than 15%. The maximum concentration and AUC of axitinb in one patient carrying ABCG2 421A/A genotype were markedly higher than those carrying ABCG2 421C/A or C/C genotype on day 8.Conclusion: The plasma concentration of axitinb was analyzed accurately and reproducibly by UPLC-MS/MS. Our findings suggest that ABCG2 polymorphism, especially 421A/A genotype, may influence the plasma concentration of axitinib.

Common questions regarding clinical use of axitinib in advanced renal cell carcinoma.

An overview of the responses to some of the most frequently asked questions regarding axitinib administration and dosage modifications used in clinical practice are presented. Axitinib was approved for second-line treatment of advanced renal cell carcinoma by the Food and Drug Administration on January 27, 2012. Inquiries received over the first six months after the approval date were reviewed. A large number of questions were related to administration of axitinib in different patient populations or in patients with various comorbidities, such as its (1) use in patients unable to swallow oral medication or administration of axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants, and (5) dosage modifications. Responses to these inquiries were provided based on the published literature or from data on file from the manufacturer. The dosage of axitinib can be adjusted for use in patients with hepatic impairment or in patients who cannot otherwise tolerate the usual regimen. Patients taking concomitant warfarin can also take axitinib, and patients who cannot swallow oral medications can receive a liquid formulation of the drug, though its efficacy and comparability to the tablet formulation has not been tested. Based on the published literature and company data on file, the axitinib dosage may be modified to accommodate patients with renal or hepatic impairment, who cannot swallow oral medication, are receiving concomitant warfarin, or who cannot otherwise tolerate the standard dosage regimen. For patients who cannot swallow, an oral suspension can be prepared because crushing axitinib is not recommended.

Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma.

Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(®)), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.

Phase II trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.

441^ Background: Previous studies have shown minimal impact of tyrosine kinase inhibitors on primary renal tumors. In this phase II trial, we investigate the safety and role of the axitinib in downsizing tumors in patients with non-metastatic clear cell renal cell carcinoma (RCC) prior to surgical resection. Methods: Patients with clinical stage T2-T3b N0 M0 biopsy-proven RCC were eligible for this study. Patients received axitinib daily for 12 weeks prior to surgery. The primary outcome was objective response rate. Secondary outcomes included safety, tolerability, feasibility of administration of axitinib and quality of life (using FKSI-15). A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: Twenty-four patients were treated between 2011 and 2013. All patients had biopsy-proven clear cell RCC. Twenty-three patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. One patient stopped treatment before 12 weeks due to adverse events (AEs) and was taken to surgery early. Median reduction of primary renal tumor size was 28.3% (range 5.3-42.9%). Eleven patients (45.8%) experienced a partial response by RECIST, and 13 patients had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. No grade 4 AEs were observed. Intraoperatively, no complications or unusual bleeding were encountered. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted, while no grade 4 or 5 complications occurred. FKSI-15 did change over time (p &lt; 0.0001), with quality of life worsening in comparison to the screening assessment by week 7 (p = 0.0004). However, by week 19, quality of life was not found to be statistically different from screening (p = 0.3344). Conclusions: Axitinib was clinically active and well tolerated in the neoadjuvant setting in patients with locally advanced non-metastatic ccRCC. Clinical trial information: NCT01263769.

Stratification of 18F-Labeled PET Imaging Agents for the Assessment of Antiangiogenic Therapy Responses in Tumors

Successful antiangiogenic therapies have been developed for the treatment of various cancers, but not all patients respond. Therefore, the early determination of therapy efficacy is essential for patient management. This study was done to evaluate the utility of various PET imaging biomarkers for early determination of the response to therapy with the antiangiogenic agent axitinib, a multiple receptor tyrosine kinase inhibitor, in tumors with diverse biologic characteristics. Mice bearing U87-MG and MDA-MB-231 subcutaneous tumors were treated with axitinib (25 mg/kg intraperitoneally daily for 10 d), and tumor volumes were assessed with caliper measurements. The animals were concurrently imaged longitudinally with (18)F-FDG, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), and 2-(18)F-fluoroethyl-triazolyl conjugated c(RGDyK) peptide ((18)F-FtRGD) to determine the optimal radiopharmaceutical for measuring the early treatment response in the 2 tumor types. Daily administration of axitinib successfully retarded the growth of both U87-MG and MDA-MB-231 subcutaneous tumors, with significant differences in tumor volumes being observed from day 7 after therapy on. (18)F-FDG revealed a treatment efficacy response only at day 10 after treatment in both U87-MG tumor-bearing and MDA-MB-231 tumor-bearing animals. (18)F-FLT afforded earlier detection of the therapy response, revealing a significant difference between drug- and vehicle-treated animals at day 3 for animals bearing U87-MG tumors and at day 7 for animals bearing the more slowly growing MDA-MB-231 tumors. (18)F-FtRGD showed a rapid change in tumor retention that reached significance by day 7 in U87-MG tumor-bearing animals; in contrast, no significant difference in tumor retention was observed in MDA-MB-231 tumor-bearing animals. Longitudinal imaging with different radiopharmaceuticals displays various characteristics in different tumor types, depending on their biologic characteristics. Such studies may provide clinically important information to guide patient management and monitor the response to antiangiogenic therapy with the optimum noninvasive imaging agent in the relevant cancer type.