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Clinical Genitourinary Cancer Oct 2021This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma.
BACKGROUND
This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma.
PATIENTS AND METHODS
This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted.
RESULTS
Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group.
CONCLUSIONS
Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 34006498
DOI: 10.1016/j.clgc.2021.04.007 -
Pazopanib: Evidence review and clinical practice in the management of advanced renal cell carcinoma.BMC Pharmacology & Toxicology Nov 2018Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics...
BACKGROUND
Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice.
METHODS
A non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer.
RESULTS
The efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all.
CONCLUSIONS
This paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles.
Topics: Angiogenesis Inhibitors; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Quality of Life; Sulfonamides; Treatment Outcome
PubMed: 30477570
DOI: 10.1186/s40360-018-0264-8 -
Cancer May 2009Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this... (Review)
Review
Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this pathway, namely, the potent proangiogenic factor, vascular endothelial growth factor (VEGF). Thus, VEGF-targeted therapeutics have undergone extensive clinical testing in RCC. Approaches to bind circulating VEGF protein (eg, bevacizumab) and small molecule inhibitors of the receptor on which the VEGF ligand binds (eg, sunitinib, sorafenib, axitinib, and pazopanib) have been tested. Robust clinical effects have been observed, including high objective response rates, prolonged progression-free survival, and evidence of long overall survival for patients with metastatic RCC patients who are treated with these agents. Future directions include investigation of combination and sequenced therapy, elucidation of mechanisms of response and resistance, and exploration of the effect of these agents in other disease settings.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A
PubMed: 19402073
DOI: 10.1002/cncr.24227 -
PharmacoEconomics Mar 2019The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011. (Review)
Review
BACKGROUND
The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011.
OBJECTIVE
The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review.
METHODS
We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost-effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables.
RESULTS
We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time.
CONCLUSION
RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research.
Topics: Carcinoma, Renal Cell; Cost of Illness; Cost-Benefit Analysis; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Time Factors
PubMed: 30467701
DOI: 10.1007/s40273-018-0746-y -
Pharmacology Research & Perspectives Jun 2019Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)...
Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.
Topics: Animals; Arterial Pressure; Disease Models, Animal; Drug Administration Schedule; Humans; Hypertension; Indazoles; Male; Piperidines; Pyrimidines; Quinazolines; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfonamides
PubMed: 31164986
DOI: 10.1002/prp2.477 -
British Journal of Cancer Sep 2018Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated...
BACKGROUND
Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
METHODS
mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
RESULTS
Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
CONCLUSIONS
Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
Topics: Carcinoma, Transitional Cell; DNA Copy Number Variations; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Indazoles; Kidney Neoplasms; Male; Microtubule-Associated Proteins; Mutation; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 3; Sequence Analysis, DNA; Sulfonamides; Survival Analysis; Treatment Outcome; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 30220708
DOI: 10.1038/s41416-018-0261-0 -
British Journal of Cancer Aug 2012Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in...
BACKGROUND
Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.
METHODS
Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.
RESULTS
At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05).
CONCLUSION
Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.
Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Cytokines; Disease-Free Survival; Female; Humans; Indazoles; Interleukin-12 Subunit p40; Male; Membrane Proteins; Middle Aged; Placenta Growth Factor; Polycomb-Group Proteins; Pregnancy Proteins; Pyrimidines; Repressor Proteins; Sarcoma; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Young Adult
PubMed: 22805326
DOI: 10.1038/bjc.2012.328 -
Patient Preference and Adherence 2014The last decade has seen a surge in the treatment options for metastatic renal cell carcinoma and life expectancies are now approaching 3 years from diagnosis. There is... (Review)
Review
The last decade has seen a surge in the treatment options for metastatic renal cell carcinoma and life expectancies are now approaching 3 years from diagnosis. There is some suggestion that, for now at least, we may have reached a plateau in efficacy. Patients are often stable and on treatment for years rather than months. Attention has therefore shifted to a focus on patient preference rather than reported frequency of toxicities. The standard first-line treatment for metastatic clear-cell renal cancer is either sunitinib or pazopanib. The COMPARZ trial has shown that sunitinib and pazopanib have similar efficacy. The PISCES trial, with its unique design, has evaluated patient preference between pazopanib and sunitinib. This review explores the factors involved in treatment preference in patients with renal cancer and in particular the choice between pazopanib and sunitinib.
PubMed: 24790418
DOI: 10.2147/PPA.S38989 -
International Journal of Molecular... Apr 2023Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main...
Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells. Wound healing, spheroid expansion, proliferation and migration were evaluated in HepG2 cells following IH or SH exposure. The HIF-1α, endothelin-1 and VEGF protein levels and/or mRNA expression were assessed, as were the effects of HIF-1 (acriflavine), endothelin-1 (macitentan) and VEGF (pazopanib) inhibition. Both SH and IH stimulated wound healing, spheroid expansion and proliferation of HepG2 cells. HIF-1 and VEGF, but not endothelin-1, expression increased with IH exposure but not with SH exposure. Acriflavine prevented the effects of both IH and SH, and pazopanib blocked those of IH but not those of SH. Macitentan had no impact. Thus, IH and SH stimulate hepatic cancer cell proliferation via distinct signaling pathways that may act synergistically in OSA patients with cancer, leading to enhanced tumor progression.
Topics: Humans; Vascular Endothelial Growth Factor A; Hep G2 Cells; Acriflavine; Hypoxia; Sleep Apnea, Obstructive; Hypoxia-Inducible Factor 1; Cell Proliferation; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37108039
DOI: 10.3390/ijms24086875 -
Xenobiotica; the Fate of Foreign... Jun 2019To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization...
To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.
Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Biomarkers; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Indazoles; Liver; Male; Metabolomics; Mice; Mice, Inbred C57BL; Multivariate Analysis; Oxidative Stress; Pyrimidines; Spectrometry, Mass, Electrospray Ionization; Sulfonamides
PubMed: 29897827
DOI: 10.1080/00498254.2018.1489167