cabozantinib and tivozanib

Renal cell carcinoma (RCC) is the most common kidney cancer in adults (approximately 90%), and clear cell RCC (ccRCC) is the most frequent histologic subtype (approximately 75%). We reviewed the safety and efficacy of checkpoint inhibitors (CPIs) in ccRCC, identifying 5927 articles in PubMed, Embase, Cochrane, and Web of Science. Ten randomized control (N = 7765) and 10 non-randomized (N = 572) studies were included. Overall, 4819 patients treated with CPI combinations were compared with everolimus, sunitinib, or placebo. Overall response rates (ORR) were 9-25% with nivolumab (niv), 42% with niv + ipilimumab (ipi), 55.7% with niv + cabozantinib, 56% with niv + tivozanib vs. 5% with everolimus. ORR was 51.5-58% with avelumab + axitinib vs. 25.5% with sunitinib. ORR was 59.3-73% with pembrolizumab + tyrosine kinase inhibitor vs. 25.7% with sunitinib. ORR was 32-36% with atezolizumab + bevacizumab vs. 29-33% with sunitinib. In patients with PD-L1+ve and -ve ccRCC, niv, atezolizumab, ipi, and pembrolizumab were safe and effective alone and when combined with cabozantinib, tivozanib, axitinib, levantinib, and pegilodecakin. Atezolizumab + bevacizumab was safe and effective in ccRCC with high PD-L1 expression. Pembrolizumab was safe and effective in preventing recurrence in ccRCC patients with nephrectomy. Additional randomized, double-blind, multicenter clinical trials are needed to confirm these results.

Topics: Adult; Axitinib; B7-H1 Antigen; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Kidney Neoplasms; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Sunitinib

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.

Topics: Angiogenesis Inhibitors; Anilides; Axitinib; Carcinoma, Renal Cell; Drug Interactions; Humans; Indazoles; Kidney Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib

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

Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip

Topics: Anilides; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Nerve Growth Factors; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinolines; src-Family Kinases; Sulfonamides; Sunitinib