sirolimus and cabozantinib

The network meta-analysis was conducted to compare the short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma (RCC). We initially searched databases for randomized controlled trials (RCTs) on different single-drug targeted therapies in treating RCC. The meta-analysis combined the direct and indirect evidence to calculate the pooled odds ratios (OR) and draw surface under the cumulative ranking curves (SUCRA). A total of 14 eligible RCTs were ultimately selected. The partial response (PR) of Cabozantinib in the treatment of RCC was better than Sunitinib (OR = 2.7, 95%CI = 1.0-7.8), Everolimus (OR = 8.1, 95%CI = 3.1-25.0), and Temsirolimus (OR = 4.8, 95%CI = 1.0-31.0); the overall response rate (ORR) of Cabozantinib was better than Sorafenib, Sunitinib, Everolimus, and Temsirolimus (OR = 5.5, 95%CI = 1.1-27.0; OR = 2.6, 95%CI = 1.1-6.6; OR = 8.3, 95%CI = 3.5-20.0; OR = 5.7, 95%CI = 1.3-28.0 respectively). In addition, as for complete response (CR), PR, stable disease (SD), progressive disease (PD), ORR, and disease control rate (DCR), Cabozantinib had the best short-term efficacy among nine single-drug targeted therapies in the treatment of RCC (CR: 50.3%; PR: 93.6%; SD: 75.1%; PD: 68.0%; ORR: 95.5%; DCR: 73.2%); while Everolimus had the worst short-term efficacy (CR: 33.6%; PR: 22.3%; SD: 78.0%; PD: 35.9%; ORR: 22.9%; DCR: 19.9%). Our network meta-analysis indicated that Cabozantinib might have better short-term efficacy than other regimens in the treatment of RCC, while Everolimus might have poor short-term efficacy.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Network Meta-Analysis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; Treatment Outcome

While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.. To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.. Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.. The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.. This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.. We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

Topics: Anilides; Antineoplastic Agents; Axitinib; Benzimidazoles; Bevacizumab; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Pyrrolidinones; Quinolines; Quinolones; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Clear cell renal cell carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL loss drives tumor angiogenesis and accounts for the clinical activity of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), the first-line standard of care for advanced RCC. Within the last year, three new second-line treatments have received FDA approval for use after anti-angiogenic therapy: the immune checkpoint inhibitor nivolumab, the TKI cabozantinib, and the combination of the TKI lenvatinib and the mTOR inhibitor everolimus. Cabozantinib inhibits VEGFRs, MET, and AXL, kinases that promote tumorigenesis, angiogenesis, metastasis, and drug resistance. Compared with everolimus, cabozantinib has shown statistically significant improvements in the three key efficacy endpoints of overall survival, progression-free survival, and objective response rate in patients with RCC who were previously treated with a VEGFR TKI. Herein, we summarize the translational research and clinical development that led to approval of cabozantinib as second-line therapy in RCC.

Topics: Anilides; Antibodies, Monoclonal; Carcinoma, Renal Cell; Everolimus; Humans; Nivolumab; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Translational Research, Biomedical; Von Hippel-Lindau Tumor Suppressor Protein

Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients.. Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies.. Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Nivolumab; Protein Kinase Inhibitors; Pyridines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; TOR Serine-Threonine Kinases

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA-Binding Proteins; Everolimus; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; MicroRNAs; Molecular Targeted Therapy; Mutation; Niacinamide; Nivolumab; Nuclear Proteins; Phenylurea Compounds; Precision Medicine; Prognosis; Pyridines; Pyrimidines; Pyrroles; Quinolines; Receptors, CCR4; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.. We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.. Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.. Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Pyridines; Quality of Life; Sirolimus; Survival Analysis

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Topics: Anilides; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Humans; Liver Neoplasms; Pyridines; Sirolimus; Xenograft Model Antitumor Assays

Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive.. We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets. Candidate genes should be both significantly prognostic and related to drug sensitivity or resistance, and were then validated in vitro.. ADCYAP1 loss and GNAS gain were associated with sensitivity and resistance and to Cabozantinib, respectively. ACRBP gain and CTBP1 loss were associated with sensitivity and resistance and to Pazopanib, respectively. CDKN2A loss and SULT1A3 gain were associated with sensitivity and resistance and to Temsirolimus, respectively. CCNE1 gain was associated with resistance to Axitinib and LRP10 loss was associated with resistance to Sunitinib. Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest.. Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC. Further validation and functional analyses are therefore needed.

Topics: Anilides; Antineoplastic Agents; Arylsulfotransferase; Axitinib; Carcinoma, Renal Cell; Carrier Proteins; Cell Line, Tumor; Chromogranins; Computer Simulation; Cyclin E; DNA Copy Number Variations; Drug Resistance, Neoplasm; GTP-Binding Protein alpha Subunits, Gs; Humans; Indazoles; Kidney Neoplasms; Oncogene Proteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib