scholarly journals Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 5 (4) ◽  
pp. 1-5 ◽  
Author(s):  
Sharon Del Vecchio ◽  
Robert J Ellis
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Current Treatment ◽  
Phase Iii ◽  
Solid Organ ◽  
Cell Renal Cell Carcinoma ◽  
Randomised Controlled

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.

scholarly journals In silico modeling of combination systemic therapy for advanced renal cell carcinoma

2021 ◽  
Vol 9 (12) ◽  
pp. e004059
Author(s):  
Ritesh R Kotecha ◽  
Dennis J Hsu ◽  
Chung-Han Lee ◽  
Sujata Patil ◽  
Martin H Voss
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
In Silico ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Phase Iii ◽  
Advanced Renal Cell Carcinoma

Therapeutic combinations of VEGFR tyrosine kinase inhibitor plus immune checkpoint blockade now represent a standard in the first-line management of patients with advanced renal cell carcinoma. Tumor molecular profiling has shown notable heterogeneity when it comes to activation states of relevant pathways, and it is not clear that concurrent pursuit of two mechanisms of action is needed in all patients. Here, we applied an in silico drug model to simulate combination therapy by integrating previously reported findings from individual monotherapy studies. Clinical data was collected from prospective clinical trials of axitinib, cabozantinib, pembrolizumab and nivolumab. Efficacy of two-drug combination regimens (cabozantinib plus nivolumab, and axitinib plus pembrolizumab) was then modeled assuming independent effects of each partner. Reduction in target lesions, objective response rates (ORR), and progression-free survival (PFS) were projected based on previously reported activity of each agent, randomly pairing efficacy data from two source trials for individual patients and including only the superior effect of each pair in the model. In silico results were then contextualized to register phase III studies of these combinations with similar ORR, PFS, and best tumor response. As increasingly complex therapeutic strategies emerge, computational tools like this could help define benchmarks for trial designs and precision medicine efforts. Summary statement: In silico drug modeling provides meaningful insights into the effects of combination immunotherapy for patients with advanced kidney cancer.

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Long-term outcomes in first-line patients (pts)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5096-5096 ◽  
Author(s):  
C. W. Ryan ◽  
R. M. Bukowski ◽  
R. A. Figlin ◽  
J. J. Knox ◽  
T. E. Hutson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Treatment Protocol ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
The Us ◽  
Phase Iii Study

5096 Background: Sorafenib (SOR) doubled median progression-free survival (PFS) versus placebo in a phase III study (TARGETs) for previously treated pts with clear cell renal cell carcinoma (RCC). We report on pts who had not received any prior systemic anti- cancer therapy (1st line) for advanced RCC from the ARCCS program in the US and Canada, which enrolled a broad range of pts. Methods: Pts received SOR 400 mg bid in the ARCCS open-label, nonrandomized treatment protocol if they were =15 years old with advanced (unresectable, recurrent or metastatic) RCC and had ECOG PS 0–2. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with 1st line pts being eligible for an additional 6-mo follow-up in an extension protocol (EP); Canadian enrollment completed in 8/06. Response evaluation (baseline and =1 post-baseline radiologic assessment) was conducted every 4 wks in the main study and every 8 wks during the EP. Pts without a confirmatory scan were classified as unconfirmed PR. The primary efficacy analysis on PFS was pre-specified to be performed only on the EP-enrolled pts. Results: Of the 2,488 pts valid for safety in ARCCS, nearly 50% were 1st line (n=1239) of which 69% were male with median age 65 yrs; 77% had prior nephrectomy and 29% had prior radiotherapy. Time from diagnoses to treatment was <1 yr for 52% and =1 yr 36% in these 1st line pts. Grade 3 and 4 adverse events with >2% incidence included hand-foot skin reaction 7.7%, fatigue 4.7%, hypertension 3.8%, rash/desquamation 5.2%, dehydration 2.9, diarrhea and dyspnea 2.6%. Confirmed responses are reported in the table ; 15% had unconfirmed PRs. For the 224 1st line pts enrolled in the EP, median PFS was 35.1 wks (95% CI; 32.7, 41.9). Conclusions: SOR toxicity in 1st line pts appeared similar to that in both overall and 2nd line populations previously reported in the phase III study. The PFS among patients enrolled in the EP is encouraging, but may be biased by low enrollment and selection for non-progressors. [Table: see text] [Table: see text]

scholarly journals Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial

2013 ◽  
Vol 31 (30) ◽  
pp. 3791-3799 ◽  
Author(s):  
Robert J. Motzer ◽  
Dmitry Nosov ◽  
Timothy Eisen ◽  
Igor Bondarenko ◽  
Vladimir Lesovoy ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Metastatic Rcc

PurposeTivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC).Patients and MethodsPatients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review.ResultsA total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%).ConclusionTivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.

DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 346-346
Author(s):  
Wei Zhai ◽  
Junyun Wang ◽  
Ning He ◽  
Jiale Zhou ◽  
Jianfei Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
Damage Repair ◽  
Endothelial Growth Factor

346 Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.

scholarly journals NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

2022 ◽  
Author(s):  
Daniel Serie ◽  
Amanda A Myers ◽  
Daniela A Haehn ◽  
Alexander Parker ◽  
Essa Bajalia ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Differential Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Progression Free Survival ◽  
P Value ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Kaplan Meier

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001). Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

scholarly journals Exceptional Response of Metastatic Chromophobe Renal Cell Carcinoma to Vascular Endothelial Growth Factor (VEGF) Inhibitors: Should Increased VEGF-C Expression Be Used to Guide Treatment?

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Jacob W. Bruinius ◽  
Karl J. Dykema ◽  
Sabrina L. Noyes ◽  
Bin Tean Teh ◽  
Brian R. Lane
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Locally Advanced ◽  
Chromophobe Renal Cell Carcinoma ◽  
Molecular Profile ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma

There is sparse literature demonstrating effective treatments for metastatic chromophobe renal cell carcinoma (ChRCC). The tyrosine kinase inhibitor (TKI) sunitinib selectively inhibits the VEGF pathway and it is a standard care for metastatic clear cell renal cell carcinoma (ccRCC), although data supporting its use in ChRCC is much more limited. A 56-year-old underwent palliative nephrectomy for locally-advanced ChRCC with sarcomatoid differentiation. Tumor gene expression profiling using Affymetrix HG-U133 Plus 2.0 GeneChip platform demonstrated significantly elevated VEGF-C expression compared to normal renal tissue n=12 and other types RCC n=158. Adjuvant sunitinib was used to treat his residual unresectable retroperitoneal lymph nodes. He demonstrated an exceptional response and underwent complete surgical resection four months later. He has been managed with TKIs for nearly nine years with only minimal disease progression. Additional studies exploring treatment options for patients with non-clear cell RCC are needed; in their absence, we would recommend TKIs for patients whose tumors bear a similar molecular profile.

Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism

2013 ◽  
Vol 64 (4) ◽  
pp. 484-493 ◽  
Author(s):  
Toyonori Tsuzuki ◽  
Naoto Sassa ◽  
Yoshie Shimoyama ◽  
Takamitsu Morikawa ◽  
Ryoichi Shiroki ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

scholarly journals Pazopanib for the Treatment of Patients with Advanced Renal Cell Carcinoma

2010 ◽  
Vol 4 ◽  
pp. CMO.S4088 ◽  
Author(s):  
Joshua M. Lang ◽  
Michael R. Harrison
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Tyrosine Kinases ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Pharmacokinetic Profile ◽  
Phase Iii ◽  
Advanced Renal Cell Carcinoma ◽  
National Meeting ◽  
Level I

Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies. Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010 national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.

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