Critical appraisal of axitinib in the treatment of advanced renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Ansari J
PROVIDER: S-EPMC3588609 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:The management of renal cell carcinoma (RCC) has undergone significant changes during the past 10 years, with the treatment of metastatic RCC undergoing the most radical changes. These developments reflect an enhanced understanding of this tumor's underlying biology, which was then translated into the development of a new treatment paradigm. Current therapeutic approaches for the management of patients with metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, the natural history of this malignancy, and the treatment efficacy and toxicity of available agents. The treatment options available for patients with metastatic RCC have changed dramatically over the past 6 years. Interferon-? and interleukin-2 were the previous mainstays of therapy, but since December 2005, six new agents have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-?). The current review focuses on the newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is reviewed. The efficacy and safety data from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-naïve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients.
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Project description:BackgroundIn a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.MethodsWe randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.ResultsA total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.ConclusionsProgression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).
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| S-EPMC8798318 | biostudies-literature
Project description:Renal cell carcinoma (RCC) accounts for 3% of all malignancies, and is the most aggressive cancer of the genitourinary system. Metastatic RCC is naturally resistant to chemotherapy and radiotherapy, and immunotherapy is of little benefit. In recent years, the emergence of molecular-targeted therapies has largely changed the therapeutic approach to metastatic RCC. These novel multikinase inhibitors have now become first-choice therapy because of their activity in inhibiting both cell proliferation and tumor angiogenesis. Sorafenib is the first tyrosine kinase inhibitor found to be effective in treating patients with metastatic RCC. Due to its good efficacy and safety, this agent is recommended as both first-line and second-line therapy for metastatic RCC in the People's Republic of China. Sorafenib seems to be more effective in patients of Chinese ethnicity than in western patients, and is well tolerated with a manageable toxicity profile, even at higher dosages and when used in combination with other anticancer agents. Novel biomarkers for predicting the efficacy of sorafenib have potential clinical value for guiding individualized targeted therapy.
| S-EPMC4057324 | biostudies-literature
Project description:Targeted agents have revolutionized the management of metastatic renal cell carcinoma (RCC). Axitinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), has been an important addition to currently available therapies for advanced RCC. Its ability to inhibit VEGFRs at nanomolar concentrations distinguishes it as a potent tyrosine kinase inhibitor, with increased selectivity for VEGFR-1, 2, and 3 at clinically applicable concentrations. The phase 3 AXIS trial has established its superiority in prolonging progression-free survival (PFS) in previously treated RCC patients (median PFS 6.7 months for axitinib vs. 4.7 months for sorafenib). Common toxicities of axitinib include hypertension, diarrhea, nausea, hand-foot syndrome, fatigue, and hypothyroidism. Axitinib-induced diastolic blood pressure elevation may be associated with improved clinical outcome, likely reflecting the "on-target" effect of axitinib. Dose escalation to achieve therapeutic plasma drug levels is of considerable clinical interest. Although axitinib has established efficacy in patients treated with one previous agent, its use in the frontline setting is currently the subject of ongoing research.
| S-EPMC3873008 | biostudies-other
Project description:Aim: Immunomodulatory mechanisms contributing to angiogenic inhibition in renal tumors are not well characterized. We report associations between efficacy and tumor-associated immune cells and mRNA/miRNA expression in patients from AXIS. Materials & methods: Immunohistochemistry (n = 52) and mRNA/miRNA expression analyses (n = 72) were performed on tumor samples. Results: In axitinib-treated patients, higher CXCR4 and TLR3 expression, respectively, was associated with longer progression-free survival (hazard ratio; 95% CI: 0.3; 0.1-0.8 and 0.4; 0.2-0.9) and showed interaction with treatment (p = 0.029 and p < 0.001); lower CCR7 expression was associated with objective response (odds ratio: 0.1; 95% CI: 0.01-1.0) and longer overall survival (hazard ratio: 3.9; 95% CI: 1.4-10.3). Conclusion: CCR7, CXCR4 and TLR3 expression levels may be prognostic/predictive of clinical benefit with axitinib. Clinical trial identifier: ClinicalTrials.gov NCT00678392.
| S-EPMC8459336 | biostudies-literature
Project description:Over the last seven years, seven targeted agents have been approved in the treatment of advanced or metastatic renal cell cancer, changing the therapeutic approach and prognosis of the disease dramatically. The latest agent with demonstrated efficacy is axitinib (Inlyta(®)). This new generation of tyrosine kinase agent differs from previously existing agents by its greater activity potency of inhibition of vascular endothelial growth factor-receptor (VEGFR1-3). This efficacy has been tested in phase II and III clinical trials. Axitinib is the only targeted agent that benefits from recommended titration, with intra-patient dose escalation. The toxicity profile of the drug is tolerable. This paper reviews the mechanism of action of axitinib, its metabolism, and its pharmacokinetic profile. Clinical data of efficacy and safety is also detailed. The agent has been integrated in the international therapeutic guidelines, as a standard in treatment of renal cell cancer patients, previously treated through antiangiogenic therapy.
| S-EPMC3825605 | biostudies-other
Project description:BackgroundAxitinib is a next-generation, selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors. It is approved for the treatment of metastatic renal cell carcinoma (mRCC) based on a demonstrated progression-free survival advantage over sorafenib in the second-line treatment setting. However, given the variety of available targeted therapies for mRCC, appropriate patient selection for the available therapies remains a significant clinical challenge.PurposeThis review summarizes the available evidence on the clinical, toxicity, and pharmacologic considerations for determining appropriate patient selection for axitinib therapy. In addition, it describes recent data on the use of predictive biomarkers to guide clinical management. This paper consists of material obtained via PubMed and Medline literature searches through October 2015.ConclusionAxitinib has a well-established role in the management of mRCC. Consistent clinical efficacy has been demonstrated across prognostic risk groups and prior therapeutic exposures. Although axitinib is generally well tolerated, appropriate toxicity management is critical to maximizing drug delivery and optimizing treatment outcomes. Although incident hypertension has been associated with improved clinical outcomes on axitinib, there are currently no validated clinical or genetic predictive biomarkers to guide patient selection.
| S-EPMC4822864 | biostudies-literature
Project description:The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.
| S-EPMC7060483 | biostudies-literature
Project description:BackgroundThere now exist several viable first-line treatment options for metastatic renal cell carcinoma, making the choice of initial therapy difficult. Considering metrics other than patient factors may be necessary to select the most appropriate therapy. We aimed to assess the cost-effectiveness of the three combination therapies currently approved in treatment-naïve advanced or metastatic renal cell carcinoma-nivolumab + ipilimumab (NI), pembrolizumab + axitinib (PA), and avelumab + axitinib (AA)-from a US payer perspective.Patients and methodsOur analysis was performed based on previously obtained data derived from progression-free survival and overall survival curves from CheckMate 214, KEYNOTE 426, and JAVELIN Renal 101.ResultsThe total costs of each treatment were found to be $437,556.12 for NI, $450,597.15 for PA, and $542,882.34 for AA, with quality-adjusted life-year (QALY) values of 4.04, 3.77, and 2.95 for each combination, respectively. The incremental cost-effectiveness ratio (ICER) of NI versus PA was ($47,504.73/QALY); for NI versus AA, it was ($96,533.11/QALY); for PA versus AA, it was ($113,015.87/QALY). Net health benefit scaled against a willingness-to-pay threshold of $150,000 per QALY was positive for NI versus PA at 0.36 and versus AA at 1.79, and this index was also positive for PA versus AA at 1.43, indicating that the additional value of these therapies versus their alternatives is greater than the extra cost.ConclusionNI was found to be the most cost-effective treatment option compared with the other considered therapies. PA was found to be cost effective compared to AA. When patient factors such as social issues and pre-existing conditions do not dictate their first-line therapy, clinicians may use this additional information to make financially conscious choices.
| S-EPMC9643032 | biostudies-literature