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British Journal of Cancer Oct 2023Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.
BACKGROUND
Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.
METHODS
Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata.
RESULTS
Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events.
CONCLUSIONS
Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials.
CLINICAL TRIAL REGISTRATION
ISRCTN 60791336.
Topics: Humans; Axitinib; Leiomyosarcoma; Sarcoma, Synovial; Hemangiosarcoma; Vascular Endothelial Growth Factor A; Sarcoma; Soft Tissue Neoplasms; Angiogenesis Inhibitors; Treatment Outcome
PubMed: 37684354
DOI: 10.1038/s41416-023-02416-6 -
International Journal of Pharmaceutics Apr 2019The development of new blood vessels is directly related to the occurrence of eye diseases. Anti-angiogenic drugs can theoretically be extended to the treatment of... (Comparative Study)
Comparative Study
The development of new blood vessels is directly related to the occurrence of eye diseases. Anti-angiogenic drugs can theoretically be extended to the treatment of ophthalmic diseases. In this study, axitinib, a class of tyrosine kinase inhibitors, was loaded via the amphiphilic copolymer MPEG-PCL, improving its dispersibility in water. Axitinib-loaded micelles showed low toxicity in concentration gradient assays. Additionally, multiple doses by scratch assay confirmed that axitinib had no significant effect on normal cell migration, and biosafety test results showed good cell compatibility. After we established the corneal neovascularization model after an alkali burn in rats, the anti-angiogenic efficacy was tested, with dexamethasone as a positive control. The results showed that axitinib-loaded micelles had anti-angiogenic effects without obvious tissue toxicity. As a class of targeted tyrosine kinase inhibitors, axitinib can be used in the treatment of ocular neovascular diseases through nanocrystallization.
Topics: Administration, Ophthalmic; Angiogenesis Inhibitors; Animals; Axitinib; Cell Movement; Dexamethasone; Disease Models, Animal; Drug Carriers; Male; Micelles; Neovascularization, Pathologic; Polyesters; Polyethylene Glycols; Protein Kinase Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley
PubMed: 30710659
DOI: 10.1016/j.ijpharm.2019.01.051 -
Oncotarget 2022GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to...
GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to determine whether it interacted with axitinib to enhance tumor cell killing. GZ17-6.02 interacted in an arithmetically greater than additive fashion with axitinib to kill kidney cancer cells. GZ17-6.02 and axitinib cooperated to inactivate ERBB2, c-MET, c-KIT, c-SRC, the AMPK, STAT3, STAT5 and eIF2α and to activate PERK, ULK1 and ATG13. The drugs interacted to increase the expression of FAS-L and to decrease the levels of MCL1, BCL-XL, and HDACs 1-3. The drugs as single agents inactivated the Hippo pathway. GZ17-6.02 and axitinib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, eIF2α, toxic BH3 domain proteins or CD95/FADD significantly reduced drug combination lethality. GZ17-6.02 and axitinib increased the expression of BAK, BIM, Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs increased phosphorylation of ULK1 S757 and ATG13 S318 and decreased the phosphorylation of mTORC1 and mTORC2, effects blocked by knock down of AMPKα. Knock down of Beclin1 or ATG5 prevented the drug combination reducing expression of HDACs 1-3 and from enhancing the expression of MHCA. Knock down of HDACs 1-3 enhanced MHCA expression. We conclude that GZ17-6.02 and axitinib interact to kill requiring ER stress signaling, autophagy and death receptor signaling. Autophagic degradation of HDACs played a key role in enhancing MHCA expression and of a potential improved response to checkpoint inhibitory immunotherapy.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Autophagy; Axitinib; Beclin-1; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Eukaryotic Initiation Factor-2; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Myeloid Cell Leukemia Sequence 1 Protein; Receptors, Death Domain; STAT5 Transcription Factor
PubMed: 35136485
DOI: 10.18632/oncotarget.28189 -
Archivos Espanoles de Urologia May 2019Following first-line treatment progression in metastatic renal carcinoma, different options for second-line treatment are available, with axitinib being one of them. The...
Following first-line treatment progression in metastatic renal carcinoma, different options for second-line treatment are available, with axitinib being one of them. The objective of this article is to evaluate the results of Axitinib in a real practice setting. METHODS: From December 2011 to October 2016, we treated 19 patients with CCRM with Axitinib, 3 patients in third line and 16 patients in second line after progression on Sunitinib or Pazopanib. We performed a retrospective study of the last 16 patients, analyzing the effectiveness and safety of the drug. RESULTS: The median progression-free survival (PFS) was 9 months and the median overall survival with 8 dead patients was 59 months. Overall, toxicity by Axitinib was very common, diarrhea 87.5%, asthenia 75%, dysphonia 56.25%, hypertension 37.5% and anorexia 37.5%, although most are grade 1-2 toxicities controlled with hygiene-diet measures and treatment recommendations. CONCLUSIONS: Axitinib is a drug that has been shown to increase PFS after 1st line progression, with a tolerable toxic profile. With the approval of nivolumab and cabozantinib, the place of Axitinib in sequential therapy is yet to be defined.
Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 31070131
DOI: No ID Found -
The Oncologist Apr 2023Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC) in a randomized phase III trial. We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial (NCT02493751).
MATERIALS AND METHODS
In this open-label, multicenter, phase Ib study, patients with untreated aRCC received avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily or with axitinib for 7 days followed by avelumab plus axitinib. Safety and efficacy were assessed in all patients receiving at least one dose of avelumab or axitinib.
RESULTS
Overall, 55 patients were enrolled and treated. Median follow-up was 55.7 months (95% CI, 54.5-58.7). Treatment-related adverse events of any grade or grade ≥3 occurred in 54 (98.2%) and 34 (61.8%) patients, respectively. The confirmed objective response rate was 60.0% (95% CI, 45.9-73.0), including complete response in 10.9% of patients. Median duration of response was 35.9 months (95% CI, 12.7-52.9); the probability of response was 65.8% (95% CI, 46.7-79.4) at 2 years. Median progression-free survival was 8.3 months (95% CI, 5.3-32.0). Median overall survival was not reached (95% CI, 40.8-not estimable); the 5-year overall survival rate was 57.3% (95% CI, 41.2-70.5).
CONCLUSION
Five-year follow-up for combination treatment with avelumab plus axitinib in previously untreated patients with aRCC showed long-term clinical activity with no new safety signals, supporting use of this regimen within its approved indication in clinical practice (Clinicaltrials.gov NCT02493751).
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Kidney Neoplasms; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36576173
DOI: 10.1093/oncolo/oyac243 -
ChemMedChem Nov 2018The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this...
The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned "on" and "off", as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.
Topics: Animals; Axitinib; Binding Sites; Dose-Response Relationship, Drug; Enzyme Assays; Human Umbilical Vein Endothelial Cells; Humans; Isomerism; Mice; Molecular Docking Simulation; NIH 3T3 Cells; Protein Kinase Inhibitors; Ultraviolet Rays; Vascular Endothelial Growth Factor Receptor-2
PubMed: 30199151
DOI: 10.1002/cmdc.201800531 -
Nature Reviews. Clinical Oncology Apr 2019
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Congresses as Topic; Humans; Kidney Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 30833679
DOI: 10.1038/s41571-019-0193-5 -
American Journal of Health-system... Jul 2014An overview of the responses to some of the most frequently asked questions regarding axitinib administration and dosage modifications used in clinical practice are... (Review)
Review
PURPOSE
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.
SUMMARY
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.
CONCLUSION
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.
Topics: Animals; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Pharmaceutical Solutions; Protein Kinase Inhibitors
PubMed: 24939498
DOI: 10.2146/ajhp130581 -
International Journal of Molecular... Sep 2019This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib.... (Review)
Review
This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Hypertension; Kidney Neoplasms; Phenylurea Compounds; Quinolines; Sorafenib; Sunitinib
PubMed: 31547602
DOI: 10.3390/ijms20194712 -
British Journal of Cancer Aug 2023The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC).
BACKGROUND
The study aimed to examine the significance of insulin receptor (INSR) expression in predicting resistance to axitinib in clear cell renal cell carcinoma (ccRCC).
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Topics: Humans; Animals; Mice; Carcinoma, Renal Cell; Axitinib; B7-H1 Antigen; Kidney Neoplasms; Insulin; Receptor, Insulin; Endothelial Cells; Interferon-beta; Gene Expression
PubMed: 37355721
DOI: 10.1038/s41416-023-02325-8