Objective – to evaluate efficacy and safety of everolimus in Russian population of unselected patients with advanced renal cell carcinoma progressing after at least 1 line of anti-angiogenic targeted therapy. Materials and methods . In observational multicenter study CRAD001LRU03 from 17.01.2012 to 31.03.2015 in 43 centers 226 patients with advanced renal cell carcinoma with documented progression on the background or after at least 1 line of anti-angiogenic targeted therapy were included. The survey was conducted on all patients according to the practice, everolimus therapy was administered in accordance with instructions to the drug. Results. Objective response rate was 10 %, tumor control was achieved on 69.2 % of patients. Progression-free survival median – 7.8 months. Adverse events occurred in 44.7 % of patients, reached the III–IV severity of 9.3 %, were the reason for the cancellation of everolimus therapy in 2.2 % of cases. The most frequent complications of treatment were pneumonitis (n = 5 (2.2 %)) and anemia (n = 3 (1.3 %)). Conclusion. The observational study confirms efficacy and favorable safety profile of everolimus mTOR inhibitor in the Russian unselected patients with advanced renal cell carcinoma with progression or intolerable toxicity against background of anti-angiogenic therapy.

Objective – to evaluate efficacy and safety of everolimus in Russian population of unselected patients with advanced renal cell carcinoma progressing after at least 1 line of anti-angiogenic targeted therapy.Materials and methods. In observational multicenter study CRAD001LRU03 from 17.01.2012 to 31.03.2015 in 43 centers 226 patients with advanced renal cell carcinoma with documented progression on the background or after at least 1 line of anti-angiogenic targeted therapy were included. The survey was conducted on all patients according to the practice, everolimus therapy was administered in accordance with instructions to the drug.Results. Objective response rate was 10 %, tumor control was achieved on 69.2 % of patients. Progression-free survival median – 7.8 months. Adverse events occurred in 44.7 % of patients, reached the III–IV severity of 9.3 %, were the reason for the cancellation of everolimus therapy in 2.2 % of cases. The most frequent complications of treatment were pneumonitis (n = 5 (2.2 %)) and anemia (n = 3 (1.3 %)).Conclusion. The observational study confirms efficacy and favorable safety profile of everolimus mTOR inhibitor in the Russian unselected patients with advanced renal cell carcinoma with progression or intolerable toxicity against background of anti-angiogenic therapy.

Background. Thorough study of the molecular genetic alterations in patients with hereditary and sporadic renal cell carcinoma (RCC) enabled to reveal potential therapeutic targets -vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), growth factor receptors (VEGFR, PDGFR, EGFR, FGFR), mTOR signaling protein. Advances in targeted therapy treatment in the current therapeutic practice have brought a problem of its rational use and ultimately effective outcomes. The main solution of solving this problem is to establish independent clinical and laboratory prognostic factors and molecular markers which could predict the efficacy of targeted therapy.Objective - optimization of targeted therapy in patients with RCC by using both molecular and genetic prognostic factors as predictors of the treatment efficacy.Materials and methods. We assessed the level of mRNA expression of 13 potential target genes in primary tumor and metastatic site of patients suffering from metastatic RCC (n = 43) and evaluated the influence of the selected genes' expression on the therapeutic efficacy of mTOR inhibitors and VEGFR inhibitors.Conclusion. VEGFR1 mRNA overexpression in metastatic site as well as mTOR and/or PI3K mRNA overexpression could be assessed as potential biomarkers in predicting the treatment efficacy of VEGFR inhibitors and mTOR inhibitors respectively. The higher expression of RAF1 mRNA and mTOR signaling pathway are not typical molecular alterations in patients with mRCC. RAF1 mRNA overexpression in metastatic site as well as activation of the alternative signaling pathway (RAS-RAF-MAPK) in tumor cell are negative prognostic factors of the efficacy of targeted therapy. Activation of the signaling RAS-RAF-MAPK pathway in tumor cells is probably an alternative independent mechanism that "drives" tumor development in certain groups of patients.

The application of targeted and pathogenetically sound medicational approaches could considerably improve the results of therapy in patients with metastatic renal-cell carcinoma (mRCC). To date, VEGF/VEGFR inhibitors continue to remain a basic and most effective drug treatment in patients with mRCC and the choice of a drug for first-line therapy is based on the following factors: disease prognosis, a patient's general somatic state, and the understanding of immediate therapy goals, anticipated toxicity and tolerability.Most patients develop resistance to VEGFR inhibitors within 6-11 months after treatment initiation. The basis for resistance development may be the following mechanisms: activation of alternative proangiogenic signaling pathways, that of angiogenesis-independent progression pathways, a microenvironment-induced phenotypic change of tumor cells to form their resistance to targeted drugs, and pharmacokinetic and pharmacodynamic changes in the drug itself during therapy.To overcome resistance to VEGFR inhibitors, there are 2 possible options: 1) switching to a drug having another mechanism of action (the mTOR inhibitor everolimus); 2) that to a more selective and potent tyrosine kinase inhibitor (axitinib) that selectively affects and suppresses the activity of the same targets-VEGFR (Vascular Endothelial Growth Factor Receptor) 1-3. As before, there is scanty convincing evidence for unique benefits in a particular succession of targeted drugs: a VEGFR inhibitor-a VEGFR inhibitor or a VEGFR inhibitor-an mTOR inhibitor.In a number of cases, the succession of prescribing of targeted drugs may be practically determined by clinical criteria, specifically by the possibility of controlling toxic complications that may be typical for VEFGR inhibitors and may accumulate in case of their successive use. It must be also remembered that VEGFR inhibitors may be successfully reused in patients who have received second-or more line therapy with targeted drugs in different succession.

With the clinical introduction of targeted drugs, the results of therapy in patients with metastatic renal-cell carcinoma (mRCC) of all prognostic groups as witnessed by the data of randomized trials. Nevertheless, there is a group of favorable prognosis patients (MSKCC) that may use first-line immunotherapy equally with a targeted approach without apparently affecting overall survival. As a rule, these are the patients who have no symptoms of the disease with the primary tumor being removed and the disease is being minimally disseminated. At the same time, how long very rare (1 %) complete remissions achieved by targeted drugs last, whether they can transformed into complete recovery, and how this may be observed in 3–4 % of cases when immune therapeutic options are used in favorable prognosis patients remain to be investigated. Due to the fact that nonspecific therapy involving cytokines fails to overcome fully the phenomenon of immunological tumor tolerance and has limited antitumor activity, the clinical trials are actively studying the efficiency of more specific immunotherapeutic approaches, such as anti-CTLA-4, anti-PD1 monoclonal antibodies, as well as different vaccination types. Thus, there is an opportunity to make the immunotherapeutic approach molecular targeted and to integrate it into a drug treatment algorithm for patients with mRCC. Accordingly, the priority for additional clinical trials is to identify predictive markers of response (or resistance) to immunotherapy that can rationalize and individualize this therapeutic approach.

With the clinical introduction of targeted drugs, the results of therapy in patients with metastatic renal-cell carcinoma (mRCC) of all prognostic groups as witnessed by the data of randomized trials. Nevertheless, there is a group of favorable prognosis patients (MSKCC) that may use first-line immunotherapy equally with a targeted approach without apparently affecting overall survival. As a rule, these are the patients who have no symptoms of the disease with the primary tumor being removed and the disease is being minimally disseminated. At the same time, how long very rare (1 %) complete remissions achieved by targeted drugs last, whether they can transformed into complete recovery, and how this may be observed in 3-4 % of cases when immune therapeutic options are used in favorable prognosis patients remain to be investigated. Due to the fact that nonspecific therapy involving cytokines fails to overcome fully the phenomenon of immunological tumor tolerance and has limited antitumor activity, the clinical trials are actively studying the efficiency of more specific immunotherapeutic approaches, such as antiCTLA-4, anti-PD1 monoclonal antibodies, as well as different vaccination types.Thus, there is an opportunity to make the immunotherapeutic approach molecular targeted and to integrate it into a drug treatment algorithm for patients with mRCC. Accordingly, the priority for additional clinical trials is to identify predictive markers of response (or resistance) to immunotherapy that can rationalize and individualize this therapeutic approach.