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Cancer Chemotherapy and Pharmacology Mar 2015Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.
METHODS
The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).
RESULTS
Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods.
CONCLUSIONS
Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.
Topics: Adult; Axitinib; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors; Electrocardiography; Female; Heart Rate; Humans; Imidazoles; Indazoles; Ketoconazole; Male; Models, Biological; Protein Kinase Inhibitors; Single-Blind Method
PubMed: 25589220
DOI: 10.1007/s00280-015-2677-z -
Journal For Immunotherapy of Cancer Feb 2022Mucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a...
BACKGROUND
Mucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising response rate in patients with metastatic mucosal melanoma (MM) in a phase Ib study. Here, we report the updated overall survival (OS), duration of response (DoR), and biomarker analysis results.
METHODS
Patients with advanced MM received toripalimab 1 or 3 mg/kg intravenously every 2 weeks combined with axitinib 5 mg orally two times per day until disease progression or unacceptable toxicity. Tumor programmed cell death ligand-1 (PD-L1) expression, tumor mutational burden (TMB), and gene expression profile (GEP) by messenger RNA sequencing were evaluated for correlation with survival.
RESULTS
As of April 2, 2021, the median follow-up was 42.5 months. Among 29 chemotherapy-naïve patients with metastatic MM, the median OS was 20.7 months (95% CI 9.7 to 32.7 months); the median progression-free survival (PFS) was 7.5 months (95% CI 3.8 to 14.8 months); and the median DoR was 13.4 months (95% CI 5.5 to 20.6 months). The OS rates of 1, 2, and 3 years were 62.1%, 44.8%, and 31.0%, respectively. Biomarker analysis found that PD-L1 expression and TMB level were not associated with survival benefits. In contrast, a 12-GEP signature correlated with improved PFS (17.7 vs 5.7 months, p=0.0083) and OS (35.6 vs 17.6 months, p=0.039).
CONCLUSIONS
The 3-year survival update confirmed the antitumor activity and long-term survival benefit of the toripalimab plus axitinib combination in patients with advanced MM. The 12-gene GEP is of value in predicting the outcomes of vascular endothelial growth factor receptor-tyrosine kinase inhibitor and PD-1 blockade combination therapy, but requires further validation.
TRIAL REGISTRATION NUMBERS
NCT03086174.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Biomarkers, Tumor; Female; Humans; Male; Melanoma; Prospective Studies; Survival Analysis; Time Factors
PubMed: 35193932
DOI: 10.1136/jitc-2021-004036 -
Journal For Immunotherapy of Cancer Oct 2020No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death...
BACKGROUND
No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB.
METHODS
Adult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint.
RESULTS
Between June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0-1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events.
CONCLUSION
The combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Female; Glioblastoma; Humans; Middle Aged
PubMed: 33067319
DOI: 10.1136/jitc-2020-001146 -
Clinical Genitourinary Cancer Jun 2019Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.
PATIENTS AND METHODS
AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.
RESULTS
Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.
CONCLUSION
In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.
Topics: Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Kidney Neoplasms; Male; Prognosis; Sorafenib; Treatment Outcome
PubMed: 31072748
DOI: 10.1016/j.clgc.2019.03.017 -
Assay and Drug Development Technologies 2019in vitro in vitro ± ± ± in vitro
in vitro in vitro ± ± ± in vitro
Topics: Axitinib; Calorimetry, Differential Scanning; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Compounding; Humans; Macular Degeneration; Molecular Structure; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Structure-Activity Relationship; Surface Properties; Wound Healing
PubMed: 31184962
DOI: 10.1089/adt.2019.920 -
Cancer Discovery Apr 2018Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.
Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.
Topics: Antibodies, Monoclonal, Humanized; Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms
PubMed: 29475884
DOI: 10.1158/2159-8290.CD-RW2018-032 -
European Urology Focus Jan 2023No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab...
Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System.
No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients' conditions associated with the above AEs when selecting between these two therapies. PATIENT SUMMARY: Herein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.
Topics: United States; Humans; Pharmacovigilance; Carcinoma, Renal Cell; Axitinib; United States Food and Drug Administration; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Kidney Neoplasms
PubMed: 35915038
DOI: 10.1016/j.euf.2022.07.003 -
The Lancet. Oncology Jul 2014
Topics: Axitinib; Humans; Imidazoles; Indazoles; Protein Kinase Inhibitors; Thyroid Neoplasms; Vascular Endothelial Growth Factor A
PubMed: 25121176
DOI: 10.1016/s1470-2045(14)70249-9 -
Association between takotsubo cardiomyopathy and axitinib: case report and review of the literature.Journal of Clinical Oncology : Official... Jan 2015
Review
Topics: Aged; Axitinib; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Humans; Imidazoles; Indazoles; Liver Neoplasms; Protein Kinase Inhibitors; Takotsubo Cardiomyopathy; Treatment Outcome
PubMed: 24567431
DOI: 10.1200/JCO.2013.48.7280 -
European Journal of Cancer (Oxford,... Apr 2020Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as...
INTRODUCTION
Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC.
METHODS
This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review.
RESULTS
Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%).
CONCLUSIONS
Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02489695.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Axitinib; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Remission Induction
PubMed: 32146304
DOI: 10.1016/j.ejca.2020.02.001