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Journal of B.U.ON. : Official Journal... 2021In this study, we aimed to compare the data of sunitinib and pazopanib used in the first-line treatment of metastatic renal cell carcinoma (RCC) cases and to evaluate... (Comparative Study)
Comparative Study
PURPOSE
In this study, we aimed to compare the data of sunitinib and pazopanib used in the first-line treatment of metastatic renal cell carcinoma (RCC) cases and to evaluate the effective factors in terms of survival.
METHODS
The records of 125 patients with metastatic RCC admitted between January 2005 and February 2018 were retrospectively analyzed and 63 patients who received pazopanib or sunitinib were included in the study while 62 patients were excluded due to insufficient data. Clinical and histological characteristics, treatment responses, progression-free survival (PFS), and overall survival (OS) of the patients were compared.
RESULTS
Patients with metastatic RCC who received pazopanib or sunitinib as tyrosine kinase inhibitors (TKI) in first-line treatment were analyzed; 45 (71.4%) were male while 18 (28.6%) were female, and the median age was 60. 43 (68.3%) patients were treated with sunitinib and 20 (31.7%) with pazopanib. PFS of pazopanib and sunitinib were 10.6 and 7.2 months, respectively. Median OS was 14.5 months in patients receiving pazopanib and 13.6 months in those receiving sunitinib. There was no statistical difference in PFS and OS between both treatments. The median OS of clear-cell RCC was 15.2 months, while of non-clear-cell RCC was 7.7months.
CONCLUSIONS
High ECOG score, non-clear-cell histology, presence of liver metastasis in metastatic RCC patients were found to be associated with shorter OS and PFS. Sunitinib and pazopanib produced similar OS and PFS rates in first-line treatment of metastatic RCC.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome
PubMed: 34565028
DOI: No ID Found -
Journal of Proteomics Jan 2018Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy....
UNLABELLED
Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.
SIGNIFICANCE
Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.
Topics: Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Humans; Indazoles; Neoplasm Proteins; Neoplasms; Phosphoproteins; Pyrimidines; Signal Transduction; Sulfonamides
PubMed: 28842319
DOI: 10.1016/j.jprot.2017.08.015 -
Oncology Reports Nov 2015Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid...
Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. We highlight the importance of pharmacodynamic assessment of the ERK pathway for patients enrolled in trials involving MKIs.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Indazoles; MAP Kinase Signaling System; Mice, Nude; Pyridones; Pyrimidines; Pyrimidinones; Sulfonamides; Thyroid Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 26324075
DOI: 10.3892/or.2015.4225 -
Cost-Effectiveness of the First Line Treatment Options For Metastatic Renal Cell Carcinoma in India.JCO Global Oncology Feb 2023Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and...
PURPOSE
Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and nivolumab have shown significant improvement in the median progression-free survival and overall survival among patients with mRCC. In this study, we aimed to determine the cost-effectiveness of the first-line treatment options for the patients with mRCC in India.
METHODS
A Markov state-transition model was used to measure the lifetime costs and health outcomes associated with sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab among patients with first-line mRCC. Incremental cost per quality-adjusted life-year (QALY) gained with a given treatment option was compared against the next best alternative and assessed for cost-effectiveness using a willingness to pay threshold of one-time per capita gross-domestic product of India. The parameter uncertainty was analyzed using the probabilistic sensitivity analysis.
RESULTS
We estimated the total lifetime cost per patient of ₹ 0.27 million ($3,706 US dollars [USD]), ₹ 0.35 million ($4,716 USD), ₹ 9.7 million ($131,858 USD), and ₹ 6.7 million ($90,481 USD) for the sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab arms, respectively. Similarly, the mean QALYs lived per patient were 1.91, 1.86, 2.75, and 1.97, respectively. Sunitinib incurs an average cost of ₹ 143,269 ($1,939 USD) per QALY lived. Therefore, sunitinib at current reimbursement rates (₹ 10,000 per cycle) has a 94.6% probability of being cost-effective at a willingness to pay threshold of 1-time per capita gross-domestic product (₹ 168,300) in the Indian context.
CONCLUSION
Our findings support the current inclusion of sunitinib under India's publicly financed health insurance scheme.
Topics: Humans; Carcinoma, Renal Cell; Sunitinib; Cost-Benefit Analysis; Kidney Neoplasms; Nivolumab; Ipilimumab
PubMed: 36795991
DOI: 10.1200/GO.22.00246 -
Cancer Chemotherapy and Pharmacology Aug 2018This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth...
PURPOSE
This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.
EXPERIMENTAL DESIGN
Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.
RESULTS
The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.
CONCLUSIONS
The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.
Topics: Administration, Metronomic; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Pyrimidines; Sulfonamides
PubMed: 29943192
DOI: 10.1007/s00280-018-3624-6 -
Journal of Hematology & Oncology May 2018The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations.
METHODS
Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off).
RESULTS
Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%).
CONCLUSIONS
A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Carcinoma, Renal Cell; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pyrimidines; Sulfonamides; Sunitinib; White People; Young Adult
PubMed: 29788981
DOI: 10.1186/s13045-018-0617-1 -
Indian Journal of Cancer 2021In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is...
BACKGROUND
In metastatic soft tissue sarcoma (M-STS), pazopanib has demonstrated promising activity; however, there is dearth of data from lower and middle income countries. It is important to explore the feasibility (toxicity, acceptance), efficacy (response rates, survival), and optimal dose requirement of pazopanib in M-STS in India.
METHODS
All patients who received pazopanib for M-STS in 2013-2018 in Tata Memorial Centre were included. Institutional ethics committee approval was obtained. Assessment for response with contrast computed tomography scans was done as per the response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Pazopanib was continued until progression or unacceptable toxicity. Clinical benefit rates and survival were evaluated by Kaplan-Meier method. All statistical calculations were done using SPSS version 21.0.
RESULTS
Seventy-two consecutive patients with a median follow-up of 17 (4-40) months were included in this study. Median lines of prior therapy were 2 (0-2). Among 50 evaluable patients, there were 12/50 (24%) partial responses, 25/50 (50%) stable disease, and 15/50 (30%) progressive disease. Median progression-free survival was 5 (95% confidence interval (CI) 3-6.9) months and median overall survival was 11 (95% CI 6.8-15.2) months. Adverse effects (G2/G3) in patients: hand foot syndrome-28%, hyperbilirubinemia/transaminitis-10%, diarrhea-20%, hypertension-17%, hypothyroidism-15%, anemia-6%, and fatigue-17%. Notably, 40% patient required dose reduction and median dose was 600 (200-800) mg daily.
CONCLUSION
Pazopanib was found a feasible treatment option for M-STS in India with internationally comparable outcomes. However, significant patients required dose modifications, and median tolerated dose was lower than the standard 800 mg dose. This novel finding merits confirmation in larger cohorts for reproducibility.
Topics: Adult; Aged; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis; Young Adult
PubMed: 33753596
DOI: 10.4103/ijc.IJC_314_19 -
Journal of Immunology (Baltimore, Md. :... Aug 2022Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and...
Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and devastated the global economy and health care system. Lung injury is an early disease manifestation believed to be a major contributor to short- and long-term pathological consequences of COVID-19, and thus drug discovery aiming to ameliorate lung injury could be a potential strategy to treat COVID-19 patients. By inducing a severe acute respiratory syndrome-like pulmonary disease model through infecting A/J mice with murine hepatitis virus strain 1 (MHV-1), we show that i.v. administration of pazopanib ameliorates acute lung injuries without affecting MHV-1 replication. Pazopanib reduces cell apoptosis in MHV-1-infected lungs. Furthermore, we also identified that pazopanib has to be given no later than 48 h after the virus infection without compromising the therapeutic effect. Our study provides a potential treatment for coronavirus-induced lung injuries and support for further evaluation of pazopanib in COVID-19 patients.
Topics: Animals; Indazoles; Lung; Lung Injury; Mice; Murine hepatitis virus; Pyrimidines; Sulfonamides; COVID-19 Drug Treatment
PubMed: 35914834
DOI: 10.4049/jimmunol.2100968 -
Molecular Cancer Therapeutics Apr 2010This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor...
This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor tyrosine kinase inhibitor. In vitro (Western blot) and in vivo dose-finding experiments were done following pazopanib therapy in ovarian cancer models. Pazopanib and metronomic (daily) oral topotecan therapy was examined in an orthotopic model of ovarian cancer. Tumor weights, survival, and markers of the tumor microenvironment [angiogenesis (CD31 and pericyte coverage), proliferation (Ki-67), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)] were analyzed by immunostaining following therapy. Pazopanib therapy reduced vascular endothelial growth factor receptor 2 (VEGFR-2) activity in vitro and vivo in a dose-dependent manner. Compared with control mice, pazopanib reduced tumor weight by 28% to 82% (P < 0.01 in the SKOV3ip1 model) and metronomic topotecan reduced tumor weight by 40% to 59% in the HeyA8 (P = 0.13) and SKOV3ip1 (P = 0.07) models. Combination therapy had the greatest effect with 79% to 84% reduction (P < 0.01 for both models). In the SKOV3ip1 and A2780 models, mouse survival was significantly longer (P < 0.001 versus controls) with pazopanib and metronomic topotecan therapy. Pazopanib therapy reduced murine endothelial cell migration in vitro in a dose-dependent manner following VEGF stimulation and decreased tumor microvessel density and pericyte coverage when given in combination with metronomic topotecan. Tumor cell proliferation decreased in all treatment arms compared with controls (P < 0.01 for combination groups) and increased tumor cell apoptosis by 4-fold with combination therapy. Pazopanib therapy in combination with metronomic topotecan therapy showed significant antitumor and antiangiogenic properties in preclinical ovarian cancer models and warrants further investigation as a novel therapeutic regimen in clinical trials. Mol Cancer Ther; 9(4); 985-95. (c)2010 AACR.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biological Therapy; Cell Death; Cell Line, Tumor; Cell Proliferation; Female; Humans; Indazoles; Kaplan-Meier Estimate; Mice; Models, Biological; Neovascularization, Pathologic; Ovarian Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Topotecan; Xenograft Model Antitumor Assays
PubMed: 20371710
DOI: 10.1158/1535-7163.MCT-09-0967 -
Expert Review of Anticancer Therapy Nov 2019: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the... (Review)
Review
: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.
Topics: Drug Resistance, Neoplasm; Humans; Indazoles; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sarcoma; Sulfonamides
PubMed: 31665941
DOI: 10.1080/14737140.2019.1686979