RU2715567C1 - Method of treating disseminated renal cell carcinoma - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and aims at treating renal cell carcinoma. Nivolumab is administered intravenously drop-by-drop into the preparation in dose of 3 mg/kg of body once every two weeks. Computed tomography is performed every 8 weeks. If observing X-ray signs of disease progression, the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4) and absolute concentration of natural killers with T-lymphocyte receptors (CD3+CD16+56+, X5). Discriminant functions F1 and F2 are calculated from obtained values. If F1>F2, pseudo-progression is established in the patient and treatment is continued in the previous mode, and if F2>F1 – treatment is carried out with the preparation Everolimus, which is administered in dose of 10 mg per day orally in form of eight-week cycles until progressing.

EFFECT: invention enables improving survival rates in patients with renal cell carcinoma.

1 cl, 12 tbl, 2 ex

Description

The invention relates to medicine, more specifically to oncology, and may find application in the treatment of malignant neoplasms.

Renal cell cancer (RCC) is, according to various authors, 2-4% of all adult tumors. Every year, 338,000 new cases are detected in the world, and 114,000 patients die from this disease. 70-85% of tumors have a histological structure of clear cell cancer. In 30% of patients with initial treatment, distant metastases are detected. In another 30%, they occur during the first year after a radical operation. Metastases are the cause of death in 40% of cases. In the general population of patients with renal cell carcinoma, the five-year survival rate in patients with locally advanced forms is on average 67%, and in the presence of distant metastases - 12%. In specialized centers, where it is possible to use all available options for surgical and drug treatment, as well as very clearly observed intervals of instrumental evaluation of effectiveness, this figure reaches 23%.

Currently, various options for surgical treatment, radiation, drug and cell therapy are used to treat patients with RCC.

The basis for the treatment of patients with local and locally advanced forms of tumors is various surgical options, including open and endoscopic operations, interventional radiological procedures, local hyperthermia and cryoablation. Drug therapy is used only as an auxiliary method in the presence of contraindications for surgical treatment.

In patients with disseminated forms, the surgical treatment is important only as a cytoreduction method to increase the likelihood of a clinical effect when using targeted and immunotherapy. Surgical interventions are also used to stop life-threatening complications arising from the growth of tumor mass.

Currently, the following methods of pathogenetic treatment of patients with disseminated RCC are known:

1. Targeted therapy.

1.1. Tyrosine kinase inhibitors (Sunitinib, Sorafenib, Pazopanib).

1.2. Inhibitors of mTOR (Temsirolimus, Everolimus).

1.3. Angiogenesis Inhibitors (Bevacizumab).

2. Immunotherapy.

2.1. Blockers of co-inhibitory molecules (Nivolumab).

2.2. Cytokines (IL-2, IFN-α).

2.3. Cell therapy.

2.4. Vaccine therapy.

The modern treatment strategy for patients with disseminated RCC includes the consistent use of several lines of drugs. In the first line, they are used that have demonstrated high efficacy of previously untreated patients, in the second - means that have proven to be more effective compared to analogues in previously treated patients. Starting from the third line, there are no clear instructions on the choice of the drug. Either previously unused drugs or those at different phases of clinical trials are used here. The choice of tactics in this case is completely determined by the attending physician based on the clinical situation. In this case, the basic principle is to use the drug with a different mechanism of action when changing the line of therapy.

The design of clinical trials that determine the use of the drug in a particular line necessarily includes randomization according to the prognosis and histological type of the tumor. To assess the prognosis in patients with disseminated RCC, most studies use a scale developed by Motzer R.J. et al. in 1999 (MSKCC - Memorial Sloan-Kettering Cancer Center scale). It includes 5 parameters: lactate dehydrogenase, hemoglobin, adjusted calcium, Karnovsky status, previous nephrectomy. A favorable prognosis is determined by the absence of risk factors, 1-2 factors - an intermediate forecast, 3 or more - unfavorable. All prognostic systems, including MSKCC, are designed for clear cell cancer, which, according to various authors, accounts for 60% to 90% of kidney tumors. For other histological variants (papillary carcinoma (7% -14%), chromophobic (6% -11%), oncocytoma (7% -10%), tumor of the collecting tubes (<1%)), prognostic factors have not been studied.

Most professional associations include tyrosine kinase inhibitors (Sunitinib, Sorafenib, Pazopanib), an angiogenesis inhibitor (Bevacizumab) in combination with interferon-α, and an mTOR inhibitor (Temsirolimus) as the first line.

Sunitinib underwent clinical trials in patients with clear cell cancer with a favorable and intermediate prognosis. As part of phase III, in the group of 375 patients, the median time to progression was 11 months, in the comparison group (IFN-α) - 5 months. (N. Engl. J. Med. 2007; 356: 115-124).

Sorafenib underwent clinical trials in patients with clear cell cancer with a favorable and intermediate prognosis. As part of phase III, in the group of 451 patients, the median time to progression was 5.5 months, in the comparison group (placebo) - 2.8 months. (J. Clin. Oncol. 2009; 27 (20): 3312-3318).

Pazopanib, a second-generation tyrosine kinase inhibitor, also showed improved long-term treatment outcomes when compared with placebo, inferior to Sunitinib. When compared with placebo in patients with clear cell carcinoma (favorable and intermediate prognosis) in the group of 153 patients, the median time to progression was 11.1 months, in the placebo group - 2.8 months. When compared with Sunitinib, the median time to progression was 8.5 months, and in the comparison group - 9.5 months. (Eur. J. Cancer. 2013; 49 (6): 1287-1296. N. Engl. J. Med. 2013; 369 (8): 722-731).

Temsirolimus is a first-generation mTOR inhibitor. mTOR is a component of the universal intracellular signaling pathway PI3K / AKT / mTOR, which regulates proliferation processes, and apoptosis metabolism. Temsirolimus was clinically tested in patients with a poor prognosis. As part of phase III, in the group of 209 patients, the median time to progression was 3.8 months, in the comparison group (IFN-α) - 1.9 months. (N. Engl. J. Med. 2007; 356 (22): 2271-2281).

Bevacizumab has been shown to be effective in combination with IFN-α. As part of phase III, in the group of 369 patients, the median time to progression was 8.5 months, in the comparison group (IFN-α plus placebo) - 5.2 months. (J. Clin. Oncol. 2010; 28 (13): 2137-2143).

In the second line of treatment in most countries, professional associations have recommended the use of two tyrosine kinase inhibitors: Cabosantinib and Lenvatinib; mTOR inhibitor Everolimus and blocker of co-inhibitory molecules Nivolumab.

Everolimus is a second-generation mTOR inhibitor. Historically, it was the first drug used in the second line. In most studies, it is currently used as a comparison drug. As part of phase III, in a group of 272 patients, the median time to progression was 4.6 months, and the median overall survival was 14.8 months. In the comparison group (placebo) - 1.8 and 14.4 months. respectively (Cancer. 2010; 116: 4256-4265).

Cabozantinib is a second generation tyrosine kinase inhibitor. As part of phase III, in the group of 330 patients, the median time to progression was 7.4 months, in the comparison group (Everolimus) - 5.1 months. (Lancet. Oncol. 2016; 17: 917-927).

The effectiveness of the combination of Lenvatinib + Everolimus was evaluated in the study E7080-G000-205 (phase II). The frequency of an objective response (the sum of full and partial responses to treatment) was 35% for the combination, 0% for Everolimus and 39% for Lenvatinib. The median time to progression is 12.8 months, 5.6 months. and 9.0 months respectively (Lancet. Oncol. 2015; 16: 1473-1482).

Nivolumab is the first representative of a new class of drugs (blockers of co-inhibitory molecules, checkpoint inhibitors), the mechanism of action of which is associated with a disruption in the interaction between the co-inhibitory molecule and its ligand (PD-1 / PD-L1). Currently, Nivolumab is the only drug in its class that has successfully passed the III phase of clinical trials in patients with locally advanced and disseminated renal cell carcinoma. In a ChekMate 025 study (N. Engl. J. Med. 2015; 373: 1803-1813), which compared the efficacy of Everolimus and Nivolumab, experts recognized that the latter should be considered as the second-line drug of choice. Despite the fact that there were no significant differences in the median time to progression in both groups (4.6 months of Nivolumab and 4.4 months of Everolimus), the median overall survival was significantly greater in the group with Nivolumab (25 months and 19 months. respectively).

Vaccine therapy and various options for cell therapy are currently used only in clinical trials and are not widely used in practice.

A known method of treating RCC by cytokine therapy (J. Immunother. Cancer. 2019; 7: 1-7). The most widely used in the clinic are drugs based on interleukin-2 (IL-2) and interferon-α (IFN-α). IL-2 is currently recommended for use in the third and subsequent lines of therapy in high-dose mode, when others are exhausted. treatment options in specialized institutions where it is possible to stop side effects that inevitably occur at high doses. IFN-α is currently used in combination with angiogenesis inhibitors.

Significant advantages of modern drugs used in the treatment of patients with disseminated RCC are the ability to improve long-term treatment results and the low incidence of serious side effects. However, a significant drawback is the lack of a method for accurately determining the moment of change of therapy lines in order to obtain the optimal result.

Most researchers studying the clinical use of targeted and immunosuppressive drugs acknowledge that current methods for assessing the immediate outcome of treatment do not allow an accurate assessment of the moment of disease progression. In this regard, in the literature for several years the issue of the need to continue treatment in the previous mode, despite the observation of progression, has been debated. But if in the first works, where similar tactics were used in patients receiving tyrosine kinase inhibitors, they only managed to increase the median survival, then with the advent of new generation immunopreparations, it was noted that continued treatment after progression also leads to a decrease in the volume of tumor lesion (PLOS ONE. 2014; 9 (5, e96316): 1-8). The term "pseudo-progression" has appeared in the literature. Pseudo-progression is a phenomenon in which, with treatment, there are signs of disease progression, confirmed by instrumental methods, and with continued treatment without changing drugs, a partial or complete response is observed (World. J. Urol. 2018; 36: 1703-1709. J. Clin. Oncol . 2015; 33 (31): 3541-3543).

An exact explanation of the pseudo-progression phenomenon does not currently exist. There are several hypotheses in the literature based on the characteristics of the interaction of the tumor and the immune system during treatment. The first is based on the fact that the immune system needs a lot of time to rebuild against the background of stimulation or reduction of suppressor effects. This leads to clinical effects that are realized later than the interval between periods of the examination. The second hypothesis is based on the assumption that, at the first stage, for the realization of the clinical effect, hyperinfiltration of tumor foci by immune cells is necessary. In computed tomography, this is perceived as progression. This hypothesis is confirmed in several studies where a biopsy of metastases during progression was performed.

According to various authors, the frequency of pseudo-progression in patients with RCC is from 7 to 15%. The maximum number of observations of this phenomenon was noted in studies of the efficacy and safety of Nivolumab in patients with RCC.

Accurate differential diagnosis of true and pseudo-progression is a key moment in improving the treatment of disseminated forms of RCC. If this phenomenon is not taken into account, then a statement of the fact of progression by radiological criteria indicates the need to change the line of therapy, and if this is pseudo-progression, the patient stops taking the drug that was effective. If you ignore the fact of x-ray progression and continue taking the drug, then the patient in this case continues to receive ineffective treatment. An increase in the volume of the tumor mass during this period potentially reduces the likelihood of a positive clinical effect when changing the line of therapy. Therefore, both options will lead to a deterioration in the long-term results of treatment.

The literature traces three strategies to overcome the negative effects of pseudo-progression on long-term treatment outcomes:

1. Continuation of treatment, regardless of the nature of the progression.

2. Improving the algorithms of x-ray diagnostics.

3. Search for molecular biological indicators that would confirm the data of x-ray studies.

The first strategy is fully implemented in the study of the effectiveness and safety of Nivolumab in the framework of I, II and III phases of clinical trials. As part of phase I, one person noted a decrease in the size of all foci, except for the pancreas. Continued treatment with him led to a partial response in this focus. The data obtained allowed the use of a similar strategy in the development of treatment protocols in the framework of phase II and III of clinical trials.

A significant drawback of this approach, in our opinion, is that patients who have progression confirmed after a follow-up examination continue to receive a drug that has already lost their effectiveness for a long time. During this period, the growth of the tumor mass occurs, and the potential benefit that can be obtained by using the drugs of the next line decreases.

The second strategy for leveling the negative consequences of pseudo-progression is associated with the modification of the radiological criteria for the response of the tumor to treatment.

To evaluate the response of a tumor to treatment in 1981, the World Health Organization (WHO) proposed criteria that included four response options: complete response (CR) - complete disappearance of all foci for a period of at least 4 weeks; partial response (PR) - reduction of all or individual tumor foci by more than 50% in the absence of progression of the rest; disease stabilization (SD) - a decrease of less than 50% or an increase of less than 25% in the absence of new lesions; progression (PD) - an increase of more than 25% in one or more lesions, or the appearance of new ones.

In 2000, in connection with the introduction of widespread clinical practice of computed tomography (CT), RECIST (Response Evaluation Criteria in Solid Tumors) criteria were proposed, the concepts of measurable, non-measurable and marker foci were introduced (J. Natl. Cancer Inst. 2000; 92 : 205-216).

Measured foci - foci having an axial plane size greater than or equal to 10 cm with spiral computed tomography with a section thickness of 5 mm or more during reconstruction, or equal to 20 mm with step computed tomography with a section thickness of 10 mm.

Non-measurable foci: small (up to 10 mm), bone metastases, leptomeningeal metastases, pericardial and pleural effusions, foci with cystic or necrotic transformation, lymphogenous carcinomatosis of the skin and lungs.

Marker (targeted, target) foci - foci of the largest diameter (up to 5 per organ, up to 10 in total), suitable for accurate repeated measurement. The rest are non-marker. Response criteria according to RECIST: complete response (CR) - complete disappearance of all marker foci; partial response (PR) - reduction of more than 30% of the sum of the maximum sizes of foci; disease stabilization (SD) - a decrease of less than 30% or an increase of less than 20% in the absence of new lesions; progression (PD) - the appearance of a new lesion or an increase in the sum of the largest sizes by more than 20%.

With the advent of targeted drugs, the nature of the dynamics of the tumor during treatment has changed. In 2009, a modified version of the response criteria appeared - RECIST v 1.1, where for the first time the appearance of new foci was not considered as a sign of disease progression. With the advent of the new generation of immunotropic drugs, a number of modified scales have been proposed for assessing the tumor response to treatment: irRC (immune-related response criteria), irRECIST (immune-related RECIST), iRECIST (immune RECIST), imRECIST (immune-modified RECIST). The principal differences between them are the nature of the measurement of foci (linear dimensions or two mutually perpendicular), the basic size of the foci (5 × 5 mm or more or equal to 10 mm), the number of targeted target lesions in each organ (5 in irRC and 10 in the rest) . But all of these scales require confirmation of progression in a subsequent study of 4-8 weeks (Ann. Oncol. 2019; 30: 385-396).

The advantage of these modified regimes for assessing the immediate clinical effect is that the appearance of new foci is not considered an unambiguous sign of progression. The need for repeated examinations to confirm the increase in the size of the foci allows us to differentiate patients with pseudoprogression. A significant drawback is the inability to quickly diagnose true progression. As a result, patients continue to receive treatment that has lost its effectiveness, which negatively affects the prognosis of the disease.

The third strategy involves the search for molecular biomarkers that would help, with greater accuracy than radiological methods, differentiate true and pseudo-progression.

In the literature, there are indications of many molecular biological components, with the help of which it would be possible to monitor the treatment of cancer patients. They are associated with the assessment of histological, serological markers, circulating immune cells, as well as the use of “liquid biopsy” methods, in which circulating DNA and / or circulating tumor cells are evaluated.

Most publications are related to the theoretical justification for the use of certain markers in cancer patients. Four research directions are fundamentally considered: 1) assessment of the biological potential of a tumor: genomic, functional markers, markers of subpopulations of tumor-infiltrating lymphocytes; 2) a quantitative assessment of circulating tumor and immunocompetent cells; 3) phenotypic and functional assessment of circulating tumor and immunocompetent cells; 4) antigen-specific monitoring of T-lymphocytes: binding, clonal activation, characterization of the T-cell receptor (Mol. Med. 2012; 18: 1499-508).

Most studies relate to monitoring various treatment options, as well as the predictive and predictive potential of biomarkers. Only a few studies are devoted to differential diagnosis of true and pseudo-progression. And most of them were carried out with the participation of patients with melanoma and the use of liquid biopsy methods that evaluate circulating tumor DNA (J. Clin. Oncol. 2015; 32: 579-586).

Currently, the available literature does not indicate methods that would accurately differentiate between true and pseudo-progression in patients with RCC and thus determine the time to stop treatment with drugs that have lost their effectiveness and start treatment with the next line of drugs.

Closest to the proposed one is the method proposed by a group of authors who analyzed the treatment effectiveness of patients with RCC by Nivolumab in the framework of phase III (Eur. Urol. 2017; 72: 368-376).

The essence of the proposed auto-method is that, in contrast to the standard treatment approach for RCC, which involves changing the drug against the background of progression, patients continued to receive Nivolumab in the previous regimen: 3 mg / kg of the mass by intravenous drip once every two weeks in cycles of 8 weeks with subsequent computed tomographic research and evaluation of direct results according to the criteria of RECISTv 1.1. The rationale for this tactic was the data obtained during the first and second phases of clinical trials of the effectiveness and safety of Nivolumab in patients with RCC (table 1: the frequency of pseudo-progression in patients with disseminated RCC using Nivolumab (JAMA. Oncol. 2016; 2 (9): 1179-1186 Eur. Urol. 2017; 72: 368-376)).

In the framework of Phase I, in one 72-year-old man with multiple metastases, a decrease in the size of all foci except the pancreas was noted after the treatment cycle. Continued treatment with him led to a partial response in this focus. Remission lasted 16 months. As part of phase II, there were already 35 patients (out of 168) who continued treatment in the same mode after ascertaining radiological progression. In 25 (71%) patients, a partial response was obtained after primary progression. Of the 406 patients included in the study in the framework of the III phase, 316 (78%) according to the control CT study revealed progression of the disease, and 90 (22%) had stabilization, a partial or complete response. Of 316 patients with progression, in 153 (48%) Nivolumab therapy was continued, and in 163 (52%) it was discontinued. The median duration of treatment with Nivolumab from the time until the course was interrupted was 8.8 months. In the subgroup where the use of Nivolumab was discontinued, 55 patients (34%) subsequently received Everolimus (III line of therapy), 55 patients (34%) received other targeted drugs and cytokines, and 53 patients (32%) received symptomatic therapy . In the prototype, the authors included in the study group of patients who received Nivolumab for at least 4 weeks after radiological progression.

In both studied subgroups (receiving Nivolumab after progression and not receiving), demographic (gender and age) and clinical characteristics (number of targeted lesions, number of previous treatment lines) at the time of randomization were similar, with the exception of Karnovsky status. In the subgroup where treatment with Nivolumab was continued, the number of patients with an indicator of more than 90% was significantly higher (table 2 demographic and clinical characteristics of the studied groups at the time of randomization).

At the time of initial progression, the median time during which patients received Nivolumab was 2.7 months. for the group where treatment was continued, and 2.4 months. - for the group where the line of therapy has changed. At the time of progression, the group where treatment was continued in the previous regimen was already significantly different from the control. And the most significant differences were associated with the time during which it was possible to obtain a clinical effect, the duration of this effect, the nature of progression and the dynamics of the general status according to Karnovsky. Treatment with Nivolumab continued mainly in those patients who were able to quickly achieve a clinical response (median - 1.9 months). The duration of this effect was significantly lower compared with the control group: median - 5, 6 and 7 months. respectively. In addition, in the study group, the general status according to Karnovsky was less likely to change during treatment, and progression was more often detected by the increase in previously existing metastatic lesions (table 3: clinical characteristics of the studied groups at the time of primary progression).

Against the background of Nivolumab therapy, after primary progression, 20 (13%) patients received a partial response to treatment: the sum of the maximum diameters of targeted lesions decreased by more than 30%. In 133 patients (87%), the best overall response (the best result from the start of treatment to progression) was stabilization or progression. After the initial progression, the median time during which patients continued treatment with Nivolumab was 3.4 months. Intra-group analysis also showed that the median survival calculated from the moment the group was analyzed (four weeks after the initial progression) to death was 20.4 months. for the group where the best overall response is represented by a partial response, 12.2 months. with other options. The median survival from the time of randomization to death in the same subgroups was 28.1 and 15.3 months. respectively (table 4: comparative characteristics of subgroups of patients with different best general responses in the group where treatment with Nivolumab was continued after primary progression).

In the analyzed subgroups, two indicators reliably differed: the frequency of a favorable prognosis by MSKCC and the presence of pulmonary metastases.

An analysis of the results allowed the authors to conclude that the most promising candidates for continuing treatment with Nivolumab after progression are patients with a favorable prognosis for MSKCC, lack of bone metastases and a short period until the clinical effect is achieved at the beginning of therapy. The authors also came to the conclusion that in order to optimize the choice of treatment tactics, it is necessary to improve methods for assessing the response of the tumor to treatment and to develop molecular biological criteria that would predict the possibility of achieving an effect when continuing treatment in the same mode after the initial progression.

The advantage of this method of treatment compared with known analogues is the possibility of increasing the life expectancy of patients due to the longer use of Nivolumab and the full realization of the potential of this drug.

The disadvantage, in our opinion, is that the authors did not propose a method according to the results of the study, which made it possible to clearly distinguish a group of patients who can obtain a clinical effect when continuing treatment in the previous mode after progression. In this regard, in 87% (133 people) of patients failed to achieve significant tumor regression.

In our opinion, the proposed method has another significant drawback associated with the duration of treatment after progression. According to the design proposed by the authors, after initial progression, treatment is carried out until the progression is repeated. In the future, the patient is recommended to stop therapy, and use the next line of drugs. According to our observations, a positive clinical effect in the form of stabilization or a partial response can be obtained only after several cycles of progression. In addition, the use of immunopreparations increases the median of overall survival, even in cases where there is a slow progression of the disease.

The technical result of the present invention is to increase the life expectancy of patients with RCC due to the accurate differential diagnosis of true and pseudo-progression and optimization of treatment regimens.

This result is achieved by the fact that in the known method for the treatment of disseminated renal cell carcinoma with the drug Nivolumab at a dose of 3 mg / kg of the mass once every two weeks in eight-week cycles with a CT scan after each cycle, according to the invention, in the presence of radiological signs of disease progression the patient determines the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4) and absolute concentration tion of natural killer receptors of T - lymphocytes (CD3 + CD16 + 56 + X5) of the obtained values was calculated discriminant functions:

• F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4-0.0043 × X5-21.6346,

• F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5-3.9664, and for F1> F2, pseudo progression is established in the patient and treatment continues the previous regimen, and with F2> F1, the treatment is carried out with the drug Everolimus, which is administered at a dose of 10 mg per day orally in the form of eight-week cycles until progression.

Having been professionally treating patients with RCC for several years, we studied various immunotherapy options, as well as the fundamental and clinical aspects of the interaction of the tumor and the immune system.

At the first stage, we preliminarily evaluated the dynamics of immunological parameters with various immediate results of treatment in patients who received immunotherapy in the first line. The main patterns were identified by analysis of this group of patients. In 2016, Nivolumab, the first drug from a new group of co-inhibitory molecule blockers, appeared in clinical practice. According to the recommendations of the developers, it was used in patients with RCC in the second line of therapy. In the process of studying the effectiveness of this drug, we came to the conclusion that the patterns of dynamics of immunological parameters in these patients are the same as in the group of patients receiving various chemoimmunotherapy options in line I. This is explained, apparently, by general biological laws that are not associated with any drugs and depend only on the characteristics of the interaction of the tumor and the immune system. Thus, the development of a method for differential diagnosis of true and pseudo-progression was carried out by us on groups of patients with chemoimmunotherapy in I and Nivolumab in Pliny.

In the process of research, we developed and studied various treatment regimens for patients with RCC, including cytokines (recombinant IL-2, recombinant tumor necrosis factor α, recombinant interferon-α), chemotherapy drugs in immunomodulating modes (Xeloda, 5-fluorouracil, cyclophosphamide) and inhibitors angiogenesis (Neovastet).

We have studied the following drugs used as part of combination treatment:

- Roncoleukin (recombinant IL-2) was administered as a long IV infusion, subcutaneously (s / c) and inhaled using a compression nebulizer. We have studied low-dose (2-4 mg per administration) and medium-dose (6-8 mg per administration) modes of use of the drug.

- Recombinant IFN-α (Interal, Intron A, Alfarona) was administered intramuscularly (IM) in various dosages (from 3,000,000 to 18,000,000 ME for a single injection).

- Recombinant tumor necrosis factor - thymosin α1 (Refnot) was administered sc in doses from 100,000 units to 800,000 units.

- Cyclophosphamide (Cyclophosphamide, Endoxan) was administered iv and orally in doses of 50, 100 and 200 mg daily and every other day, 400 and 600 mg every other day, 1000 mg once every 5 days.

- Xeloda - 1000 mg / m twice daily orally.

- Neovastet in doses of 90 and 240 ml per day orally.

In the period from 1998 to 2010, 248 patients with disseminated RCC received various combinations of these drugs in the first line. The basic treatment option was a four-component regimen including Roncoleukin, interferon-α, Xeloda and antimetabolite (cyclophosphamide). The component composition and number of chemoimmunotherapy cycles are shown in Table 5 (component composition and number of chemoimmunotherapy cycles in patients of the studied group).

To assess the prognosis of the disease in this group of patients, the MSKCC scale adopted in most studies was used (Table 6: risk factors, MSKCC scale).

The median survival in the group as a whole was 20 months. In the subgroup with a favorable prognosis - 42, with an intermediate - 16, and with no favorable - 9 months.

In the second stage, starting in 2010, we modified the immunotherapy regimen used in line I. The most effective combination, in our opinion, turned out to be the combination: the recombinant tumor necrosis factor-α - thymosin α1 (Refnot) - 200,000 units s / c - twice a week, the recombinant interferon-α (Alpharone) - 12,000,000 I / m three times per week, alternating with Refnot and cyclophosphamide (Endoxan), 50 mg orally daily. From 2010 to 2013, such treatment was performed in 32 patients with RCC. A total of 86 cycles were conducted.

The median survival in the group as a whole was 27 months. In the subgroup with a favorable prognosis - 47, with an intermediate - 24, and with no favorable - 8 months.

Since 2015, in Pliny, after progressing against the background of chemoimmunotherapy, angiogenesis inhibitors, or tyrosine kinases, we began to use the drug Nivolumab at a dose of 3 mg / kg body weight once every two weeks according to the manufacturer's recommendations. Data from 12 patients were used to develop a method for differential diagnosis of true and pseudo-progression. Validation of the developed method was carried out on groups of patients who received Refnot, Alfaron with Endoxan in the first line and Nivolumab in the second (table 7 development and validation of the method of differential diagnosis of true and pseudo-progression).

It is important to note that since 1998 in all patients with disseminated RCC, we studied the immune status in order to assess the prognostic, predictive significance of various parameters, as well as to identify differences in the dynamics of immunological parameters after disease progression. In patients with blood, the content of lymphocytes, their subpopulations and cytokines was evaluated. Analyzes were carried out in the immunological laboratory of FGUZ VTsERM im. A.M. Nikiforova EMERCOM of Russia on a Cytomics FC 500 laser flow cytometer (BECKMAN COULTER Inc., USA) using monoclonal antibodies and consumables from BECKMAN COULTER Inc., IMMUNOTECH S.A.S., Protein circuit LLC and Cytokin LLC. The spectrum of the studied parameters and their reference intervals are shown in tables 8 (subpopulations of peripheral blood lymphocytes) and 9 (parameters of the cytokine profile).

The level of lymphocytes and their subpopulations was evaluated in peripheral blood. Analysis of the cytokine profile was carried out in two stages. At the first stage, serum concentration was determined. In the second, a study was conducted in cell culture, where their potential was determined by evaluating the spontaneous and induced production of cytokines. Assessment of lymphocytes, their subpopulations and cytokine profile was carried out at the same time of the day to avoid the influence of circadian oscillations.

The algorithm for developing the differential diagnostic method included three stages. At the first stage, a one-way analysis was carried out, where all immunological parameters were included as variables (tables 8, 9), the relationship of individual components with true or pseudo-progression was revealed. At the second stage, a multivariate analysis was carried out in which mutually affecting components were excluded. The results of univariate and multivariate analysis are shown in table 10 (immunological parameters that determine progression and pseudoprogression). The discriminant analysis was carried out using the parameters identified in multivariate.

Spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4), absolute concentration of natural killer cells with T-lymphocyte receptors (CD3 + CD16 + 56+, X5) were used as variables for discriminant analysis. Based on the data obtained, linear classification functions were created:

F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4-0.0043 × X5-21.6346.

F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5-3.9664.

F1 corresponds to pseudo progression, F2 to true progression. When F1> F2, treatment is continued as before. With F2> F1, true progression is confirmed, and the patient continues treatment using the next-line drug, Everolimus.

In the group of patients receiving Nivolumab, after differential diagnosis of true and pseudoprogression, carried out by calculating discriminant functions according to the developed method, the best general response in the form of progression was obtained in 11 (26%), stabilization in 23 (53%), and partial response in 9 (21%) patients, (table 11: demographic and clinical characteristics of the subgroups of patients with different best overall response during treatment with Nivolumab).

In most patients in all subgroups, metastatic lesions were localized mainly in the lungs and lymph nodes. In the subgroup with a partial response, the number of patients with a favorable prognosis according to MSKCC and status according to Karnovsky more than 90% is significantly higher in comparison with other groups. Most patients in the subgroups with a favorable and intermediate prognosis are currently alive: the median survival in the group as a whole, calculated from the fourth week after pseudoprogression, has not been achieved. Moreover, all patients with a partial response after pseudo-progression are alive, and the average life expectancy of deceased patients in the subgroups with stabilization and progression is 26 and 21 months, respectively, which significantly exceeds the results achieved in the prototype and other known analogues.

The above studies have allowed us to develop and recommend for medical use the proposed treatment method described in the claims.

The essence of the method is as follows.

A patient with a histologically confirmed diagnosis of RCC is subjected to a general clinical examination, including osteoscinigraphy and CT examination of the pelvic organs, abdominal cavity and lungs with contrast enhancement, as a result of which the stage of the disease is established. A patient with disseminated RCC for 8 weeks is treated with Nivolumab at a dose of 3 mg / kg intravenously (iv) drip once every two weeks. After 8 weeks, a follow-up examination is performed, including CT of the pelvic organs, abdominal cavity and lungs with contrast enhancement. Assessing the effectiveness of treatment is carried out using the criteria RECIST v 1.1 (Eur. J. Cancer. 2009; 45: 228-247), according to which, when analyzing CT, targeted foci are isolated - foci of the largest diameter, suitable for accurate repeated measurement. In total, up to five foci are allocated (no more than two per organ). Target foci should be at least 10 mm in diameter in the organs, at least 10 mm in length for lesions of the bones (lytic or mixed foci) and at least 15 mm for lesions of the lymph nodes. The remaining foci are non-targeted. To assess the size of metastases in the parenchymal organs and bones, the largest focal diameter in the axial plane is used, and for the lymph nodes, the focal size along the short axis.

After an eight-week course of treatment, an assessment is made: 1) of all previously selected targeted lesions (even if their size has ceased to be the largest); 2) all previously selected non-targeted outbreaks; 3) new foci.

Categories of the general response to treatment: complete response (CR), partial response (PR), stabilization (SD), progression (PD), evaluation impossible (NE).

Assessment of the dynamics of targeted lesions is carried out by calculating the sum of their maximum diameters (and the smallest diameter in case of damage to the lymph nodes):

1. The complete answer (CR) is the disappearance of all extralymphatic target lesions; reduction of all pathological lymph nodes to a size along the short axis of less than 10 mm.

2. Partial response (PR) - a decrease in the sum of the maximum diameter of the lesions by at least 30% compared with the initial study.

3. Progression (PD) - an increase in the sum of maximum diameters by at least 20% compared with the smallest sum of maximum diameters (nadir) calculated for any of the studies (including primary). The sum of the maximum diameters should increase by at least 5 mm.

4. Stabilization (SD) - the absence of dynamics of the sum of the maximum diameters, as well as its increase or decrease, which does not meet the criteria of PR or PD.

Assessment of non-targeted lesions:

1. The complete answer (CR) is the disappearance of all extralymphatic non-targeted lesions. Reduction of all pathological lymph nodes to a size along the short axis of less than 10 mm. Normalization of tumor markers.

2. Incomplete response / lack of progression - preservation of at least one non-targeted focus or preservation of tumor markers above normal.

3. Progression (PD) - reliable progression of existing non-targeted lesions.

The overall response to treatment is assessed by comparing the dynamics of targeted and non-targeted lesions (table 12: overall response to treatment in patients with measurable lesions in the initial examination).

To identify metastatic foci in the bones, osteoscintigraphy is performed no more than once every 6 months.

If there are signs of disease progression, the patient is immunologically examined to determine the levels of spontaneous production of IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), and induced production of TNF-α (X4) in the patient’s blood. , and the absolute concentration of natural killer cells with T-lymphocyte receptors (CD3 + CD16 + 56 +, X5). Based on the obtained values, discriminant functions are calculated:

F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4-0.0043 × X5-21.6346;

F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5-3.9664.

In the case when F1> F2, the patient continues treatment in the previous mode, and for F2> F1, the treatment is carried out with the drug Everolimus, which is administered at a dose of 10 mg per day orally in the form of eight-week progression cycles.

The essence of the method is illustrated by examples.

Example 1

Patient K., born in 1956

10/20/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation. No active complaints. General condition is satisfactory. From the anamnesis it is known that a left-sided nephrectomy was performed in the Oncological Dispensary No. 2 of the Ministry of Health of the Krasnodar Territory (Sochi) on November 19, 2014. Histologically - clear cell renal cell carcinoma (from 11.27.2014). After surgery, he was under the supervision of the Oncology Center No. 2. 06/22/2015 according to CT studies revealed two lesions in the right lung with dimensions of 15 mm and 18 mm in diameter. According to osteoscintigraphy from 07/07/2015, hyperfixation of the radiopharmaceutical 90% in the sixth rib on the left was revealed. According to magnetic resonance imaging dated July 6, 2015, a destruction zone with a length of about two centimeters is identified in the sixth rib on the left. 07/22/2015 the sixth rib was resected on the left in the City Hospital No. 4 of Sochi. From September 2015 to August 2017, the patient received Sutent (Sunitinib) as a first line of therapy at a dose of 50 mg per day orally in the form of eight-week cycles with a break of two weeks according to the instructions. As a result of treatment, stabilization of the disease was achieved. A follow-up examination according to CT data dated 08/30/2017 showed signs of disease progression in the form of the appearance of new foci in the left lung with a diameter of 12 and 22 mm. In this regard, the patient turned to the Federal State Budgetary Institution "Scientific Center for Chemistry and Health" of the Ministry of Health of the Russian Federation.

The examination revealed the following changes.

10.24.2017. Osteoscintigraphy - without pathology.

10.24.2017. Isotopic renography, a function of the right kidney, is within normal limits. On the left is the function curve.

10/30/2017. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two foci measuring 16 × 18 × 19 mm and 20 × 22 × 22 mm. In the right lung there are two foci of 16 × 16 × 18 mm and 24 × 25 × 25 mm in size.

11/03/2017 Patient on an outpatient appointment at the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation

As a result of the examination, the diagnosis was established: renal cell carcinoma of the left kidney TxN0M0. 11/19/2014 - left-sided nephrectomy. Progression: metastases in the left lung from 06/22/2014, metastases in the VI rib to the left of 07/06/2015. Resection of the VI rib on the left 07/22/2015. Stabilization 09.2015 - 08.2017 (Sunitinib rate). Progression from 10.30.2017: an increase in the size of foci in the left lung, new foci in the right lung.

Target foci:

1. The left lung: a) 16 × 18 × 19 mm; b) 20 × 22 × 22 mm.

2. The right lung: a) 16 × 16 × 18 mm; b) 24 × 25 × 25 mm.

The sum of the maximum diameters: 19 mm + 22 mm + 18 mm + 25 mm = 84 mm.

Due to the fact that the patient showed signs of disease progression against the background of the first line of therapy with a tyrosine kinase inhibitor Sunitinib, treatment with the second-line drug Nivolumab was continued.

The weight of the patient is 67 kg. Dose for single administration: 67 × 3 = 201 mg (2 vials of 10 ml - 200 mg).

11/14/2017, 11/28/2017, 12/12/2017, 12/26/2017 Nivolumab was administered on an outpatient basis in a dose of 200 mg (2 vials of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl.

01/11/2018. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two foci measuring 22 × 24 × 22 mm and 24 × 24 × 24 mm. In the right lung there are two foci measuring 27 × 25 × 25 mm and 32 × 34 × 32 mm.

01/16/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

At the time of the inspection, he did not show any active complaints. General condition is satisfactory. The course of treatment was satisfactory. There were no side effects.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 22 × 24 × 22 mm; b) 24 × 24 × 24 mm.

2. The right lung: a) 27 × 25 × 25 mm; b) 32 × 34 × 32 mm.

The sum of the maximum diameters: 24 mm + 24 mm + 27 mm + 34 mm = 109 mm.

In a previous study, the sum of the maximum diameters is 84 mm. An increase of + 29.8%, which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

01/23/2018. The immunogram. IL-10 (spontaneous production) - 32 pg / ml, IL-8 (induced production) - 2450 pg / ml, IL-4 (spontaneous production) - 54 pg / ml, TNF-α (induced production) - 1085 pg / ml, CD3 + CD16 + 56 + -890 / mm ³ .

01/26/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 32 + 0.026 × 2450 + 0.0246 × 54 + 0.0019 × 1085-0.0043 × 890-21.6346 = 43.5;

• F2 = 0.0144 × 32 + 0.0006 × 2450 + 0.0012 × 54 + 0.0004 × 1085 + 0.0161 × 890-3.9664 = 12.8.

F1> F2, which met the criteria for pseudo progression.

Treatment continued as before. 01/30/2018, 02/13/2018, 02/27/2018, 03/13/2018 on an outpatient basis, the drug Nivolumab was administered at a dose of 200 mg (2 bottles of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl.

03/26/2018. Osteoscintigraphy - without pathology.

03/30/2018. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two foci measuring 22 × 22 × 22 mm and 24 × 24 × 24 mm. In the right lung there are two foci measuring 26 × 25 × 25 mm and 32 × 32 × 32 mm.

04/04/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

At the time of the inspection, he did not show any active complaints. General condition is satisfactory. The course of treatment was satisfactory. There were no side effects.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 22 × 22 × 22 mm; b) 24 × 24 × 24 mm.

2. The right lung: a) 26 × 25 × 25 mm; b) 32 × 32 × 32 mm.

The sum of the maximum diameters: 22 mm + 24 mm + 26 mm + 32 mm = 104 mm. Compared with the previous study, a decrease in the sum of the maximum focal diameters was noted from 104 to 95 mm (8.7%). Compared with nadir (the smallest value of the sum of maximum diameters for the study period) dated 10/30/2017 (84 mm), an increase in the sum of maximum diameters by 23.8% was noted, which met the criteria for progression.

Given the fact that according to the CT scan revealed signs of disease progression, the patient underwent immunological examination.

04/05/2018. Immungram. IL-10 (spontaneous production) - 19 pg / ml, IL-8 (induced production) - 2056 pg / ml, IL-4 (spontaneous production) - 25 pg / ml, TNF-α (induced production) - 654 pg / ml, CD3 + CD16 + 56 + -72 / mm ³ .

04/11/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

F1 = 0.0588 × 19 + 0.026 × 2056 + 0.0246 × 25 + 0.0019 × 654-0.0043 × 72-21.6346 = 34.5;

F2 = 0.0144 × 19 + 0.0006 × 2056 + 0.0012 × 25 + 0.0004 × 654 + 0.0161 × 72-3.9664 = -1.

F1> F2, which met the criteria for pseudo progression.

Treatment continued as before. 04/26/2018, 05/10/2018, 05/24/2018, 06/06/2018, Nivolumab was administered on an outpatient basis at a dose of 200 mg (2 vials of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl .

06/21/2018. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two foci measuring 16 × 18 × 18 mm and 21 × 22 × 22 mm. In the right lung there are two foci measuring 28 × 26 × 26 mm and 29 × 32 × 32 mm.

06/25/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

At the time of the inspection, he did not show any active complaints. General condition is satisfactory. The course of treatment was satisfactory. Periodically, nausea arose, stopping without the use of medications. No dose adjustment or drug withdrawal was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 16 × 18 × 18 mm; b) 21 × 22 × 22 mm.

2. The right lung: a) 28 × 26 × 26 mm; b) 29 × 32 × 32 mm.

The sum of the maximum diameters: 18 mm + 22 mm + 28 mm + 32 mm = 100 mm. Compared with the previous study, multidirectional dynamics of the sizes of metastases was noted: one of the foci in the right lung increased, the rest decreased. The sum of the maximum diameters of the lesions decreased by 3.8%. Compared with nadir (10/30/2017, 84 mm), an increase in the sum of maximum diameters by 19% was noted, which met the stabilization criteria.

Given that the patient has a stabilization of the disease, treatment is continued in the previous mode.

07/07/2018, 07/17/2018, 07/31/2018, 08/14/2018 Nivolumab was administered on an outpatient basis in a dose of 200 mg (2 vials of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl.

08/27/2018. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology.

Abdominal organs - without pathology. In the left lung there are two lesions with dimensions of 16 × 16 × 16 mm and 15 × 16 × 16 mm. In the right lung there are two foci measuring 28 × 26 × 26 mm and 28 × 28 × 32 mm.

08/30/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Russian Ministry of Health.

At the time of the inspection, he did not show any active complaints. General condition is satisfactory. The course of treatment was satisfactory. Periodically, nausea appeared, stopped with the use of cerucal. No dose adjustment or drug withdrawal was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 16 × 16 × 16 mm; b) 15 × 16 × 16 mm.

2. The right lung: a) 28 × 26 × 26 mm; b) 28 × 28 × 32 mm.

The sum of the maximum diameters: 16 mm + 16 mm + 28 mm + 32 mm = 92 mm. Compared with the previous study, a decrease in the size of foci was noted. The sum of the maximum diameters decreased by 8%. Compared with nadir (10/30/2017, 84 mm), an increase in the sum of maximum diameters by 9.5% was noted, which met the stabilization criteria.

Given that the patient has a stabilization of the disease, treatment is continued in the previous mode.

September 5, 2018, September 19, 2018, October 3, 2018, October 17, 2018 Nivolumab was administered on an outpatient basis at a dose of 200 mg (2 vials of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl.

10/30/2018. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two lesions with dimensions of 15 × 16 × 16 mm and 15 × 15 × 15 mm. In the right lung there are two foci measuring 26 × 26 × 26 mm and 23 × 24 × 23 mm.

11.11.2018. Osteoscintigraphy - without pathology.

11/2/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

The patient noted increased fatigue. General condition is satisfactory. The course of treatment was satisfactory. Periodically, nausea arose, stopping without the use of medications. No dose adjustment or drug withdrawal was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 15 × 16 × 16 mm; b) 15 × 15 × 15 mm.

2. The right lung: a) 26 × 26 × 26 mm; b) 23 × 24 × 23 mm.

Sum of maximum diameters: 16 mm + 15 mm + 26 mm + 24 mm = 81 mm. Compared with the previous study, a decrease in the size of foci was noted. The sum of the maximum diameters decreased by 12%. Compared with nadir (10/30/2017, 84 mm), a decrease in the sum of maximum diameters by 3.6% was noted, which met the stabilization criteria.

Given that the patient has a stabilization of the disease, treatment is continued in the previous mode.

On November 8, 2018, November 22, 2018, December 6, 2018, December 20, 2018, Nivolumab was administered on an outpatient basis at a dose of 200 mg (2 vials of 10 ml) as a 60-minute iv infusion, dissolving in 400 ml of 0.9% NaCl.

01/09/2019. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a rounded focus with a diameter of 8 mm. In the left lung there are three foci measuring 16 × 16 × 16 mm, 17 × 17 × 15 mm and 10 × 12 × 12 mm. In the right lung there are two foci measuring 26 × 26 × 26 mm and 24 × 24 × 24 mm.

01/11/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

Fatigue and nausea persisted. The general condition is satisfactory, stable. No dose adjustment or drug withdrawal was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 16 × 16 × 16 mm; b) 17 × 17 × 15 mm; c) 10 × 12 × 12 mm.

2. The right lung: a) 26 × 26 × 26 mm; b) 24 × 24 × 24 mm.

3. Liver: 8 × 8 × 8 mm.

The sum of the maximum diameters: 16 mm + 17 mm + 12 mm + 26 mm + 24 mm + 8 mm = 103 mm. Compared with the previous study, the appearance of new lesions was noted, which met the criteria for progression. The sum of the maximum diameters increased compared to nadir (10.30.2018, 81 mm) by 27.2%.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

01/15/2019. The immunogram. IL-10 (spontaneous production) - 56 pg / ml, IL-8 (induced production) - 872 pg / ml, IL-4 (spontaneous production) - 12 pg / ml, TNF-α (induced production) - 950 pg / ml, CD3 + CD16 + 56 + -452 / mm ³ .

01/18/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 56 + 0.026 × 872 + 0.0246 × 12 + 0.0019 × 950-0.0043 × 452-21.6346 = 4.49;

• F2 = 0.0144 × 56 + 0.0006 × 872 + 0.0012 × 12 + 0.0004 × 950 + 0.0161 × 452-3.9664 = 5.03.

F2> F1, which met the criteria for progression. Given that according to the CT scan, the patient showed signs of progression, which was confirmed by the values of discriminant functions, the patient continued treatment using the next-line drug - Everolimus.

From January 21, 2019 to March 17, 2019, the patient received Everolimus 10 mg per day orally according to the instructions.

03/19/2019. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a rounded focus with a diameter of 8 mm. In the left lung there are three foci measuring 15 × 14 × 13 mm, 16 × 16 × 15 mm and 10 × 12 × 12 mm. In the right lung there are two foci measuring 24 × 25 × 24 mm and 24 × 24 × 24 mm.

03/22/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Russian Ministry of Health.

The treatment was satisfactory. He did not notice bouts of nausea. Fatigue and palmar-plantar syndrome persisted, stopped by the use of a cream with an antifungal effect. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 15 × 14 × 13 mm; b) 16 × 16 × 15 mm; c) 10 × 12 × 12 mm.

2. The right lung: a) 24 × 25 × 24 mm; b) 24 × 24 × 24 mm.

3. Liver: 8 × 8 × 8 mm.

The sum of the maximum diameters: 15 mm + 16 mm + 12 mm + 25 mm + 24 mm + 8 mm = 100 mm. Compared with the previous study (January 9, 2019, 103 mm), a decrease in the sum of maximum diameters by 2.9% was noted, which met the stabilization criteria.

Considering that stabilization was achieved as a result of therapy, treatment was continued in the previous mode: from March 25, 2019 to May 19, 2019, the patient received Everolimus 10 mg per day orally according to the instructions.

05/23/2019. Osteoscintigraphy - without pathology.

05/27/2019. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a rounded hearth with a diameter of 7 mm. In the left lung there are three foci measuring 14 × 14 × 13 mm, 15 × 15 × 15 mm and 10 × 12 × 12 mm. In the right lung there are two foci with dimensions 22 × 23 × 22 mm and 24 × 24 × 24 mm.

06/04/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

The treatment was satisfactory. Fatigue persisted, which did not require medical correction. Palmar-plantar syndrome - without dynamics. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 14 × 14 × 13 mm; b) 15 × 15 × 15 mm; c) 10 × 12 × 12 mm.

2. The right lung: a) 22 × 23 × 22 mm; b) 24 × 24 × 24 mm.

3. Liver: 7 × 7 × 7 mm.

The sum of the maximum diameters: 14 mm + 15 mm + 12 mm + 23 mm + 24 mm + 7 mm = 95 mm. Compared with nadir (03/19/2019, 100 mm), a decrease in the sum of maximum diameters by 5% was noted, which met the stabilization criteria.

Considering that stabilization was achieved as a result of therapy, treatment was continued in the previous mode: from 10.06.2019 to 08.08.2019, the patient received Everolimus 10 mg per day orally according to the instructions.

08/08/2019. CT scan. In the area of the bed of the left kidney, pathological formations were not detected. The right kidney is without pathology. In the right lobe of the liver there is a rounded hearth with a diameter of 7 mm. In the left lung there are three lesions measuring 12 mm in diameter, 14 mm in diameter and 10 mm in diameter. In the right lung there are two foci measuring 22 mm in diameter and 24 mm in diameter.

08/09/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Russian Ministry of Health.

The treatment was satisfactory. Fatigue persisted, which did not require medical correction. Palmar-plantar syndrome - without dynamics. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTV 1.1 scale.

Target foci:

1. The left lung: a) 12 × 12 × 12 mm; b) 14 × 14 × 14 mm; c) 10 × 10 × 10 mm.

2. The right lung: a) 22 × 22 × 22 mm; b) 24 × 24 × 24 mm.

3. Liver: 7 × 7 × 7 mm.

The sum of the maximum diameters: 12 mm + 14 mm + 10 mm + 22 mm + 24 mm + 7 mm = 89 mm. Compared with nadir (03/19/2019, 100 mm), a decrease in the sum of maximum diameters by 11% was noted, which met the stabilization criteria.

Given that stabilization was achieved as a result of therapy, treatment was continued in the previous mode.

Currently, the patient is alive, is being monitored at the Federal State Budget Scientific Center "Russian Scientific Center for Remediation of Chronicles" of the Ministry of Health of the Russian Federation named after Acad. A.M. Granova and continues treatment. 23 months have passed since the start of treatment with Nivolumab. The time to progression was 14 months.

Example 2

Patient A., born in 1962

06/27/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation. The patient did not show active complaints. General condition is satisfactory.

From the anamnesis, it is known that 06/25/2013 according to CT data revealed a neoplasm of the right kidney measuring 8 × 12 cm. Histologically - clear cell renal cell carcinoma (from 11.27.2014). After surgery, he was under the supervision of the Murmansk Oncology Center. After surgery, once every six months a CT scan of the abdominal organs and lungs was performed. 10/19/2015 according to CT studies revealed a lesion in the left lung with a size of 22 mm in diameter. From 11.2015 to 04.2017, treatment was carried out using the combination of: Avastin (bevacizumab) - 10 mg / kg iv every two weeks and IFN-α 3,000,000 ME intramuscularly twice a week. As a result of treatment, stabilization of the disease was achieved. The size of the lesion in the left lung decreased to 19 mm in diameter. A follow-up examination according to CT data dated 04/26/2017 showed signs of disease progression in the form of a new lesion in the left lung with a diameter of 13 mm. In this regard, the patient turned to the Federal State Budgetary Institution "Scientific Center for Chemistry and Health" of the Ministry of Health of the Russian Federation.

The examination revealed the following changes.

06/30/2017. Osteoscintigraphy - without pathology.

06/30/2017. Isotopic renography, a function of the left kidney, is within normal limits. On the right is the function curve.

07/03/2017. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. In the left lung there are two foci measuring 20 × 20 × 19 mm and 15 × 14 × 14 mm. The right lung - without pathological changes.

07/04/2017 Patient on an outpatient appointment at the Federal State Budgetary Institution "Russian Scientific Center for Chemistry and Health" of the Ministry of Health of the Russian Federation.

As a result of the examination, the diagnosis was established: disseminated renal cell carcinoma of the right kidney T2aN0M0. 07/03/2013 - right-sided nephrectomy. Progression: metastases in the left lung from 10/19/2015. Stabilization 11.2015 - 04.2017 (Avastin course with interferon-α). Progression from 04/26/2017: a new lesion in the left lung.

Target foci:

Left lung: a) 20 × 20 × 19 mm; b) 15 × 14 × 14 mm.

Sum of maximum diameters: 20 mm + 15 mm = 35 mm.

Due to the fact that in the patient against the background of the first line of therapy, Avastin, an angiogenesis inhibitor in combination with interferon-α, showed signs of disease progression, treatment with the second-line drug, Nivolumab, was continued.

The weight of the patient is 80 kg. Dose for single administration: 80 × 3 = 240 mg: 2 vials of 10 ml (200 mg) + 1 vial of 4 ml (40 mg).

07/12/2017, 07/26/2017, 08/09/2017, 08/23/2017 Nivolumab was administered as an outpatient at a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

September 8, 2017. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the level L1 - L2, a chain of lymph nodes with dimensions 55 × 25 mm is determined. In the left lung there are two foci measuring 22 × 20 × 20 mm and 18 × 18 × 16 mm. In the right lung there is a lesion measuring 15 × 15 × 15 mm.

09/12/2017. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. No side effects were noted.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 20 × 20 × 20 mm; b) 18 × 18 × 16 mm.

2. The right lung: a) 15 × 15 × 15 mm.

3. Lymph nodes: 55 × 25 mm.

The sum of the maximum diameters: 20 mm + 18 mm + 15 mm + 25 mm = 78 mm. Compared with the previous study, the appearance of new lesions was noted, which met the criteria for progression. The sum of the maximum diameters increased by 123% compared with the previous study.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

09/15/2017. The immunogram. IL-10 (spontaneous production) - 36 pg / ml, IL-8 (induced production) - 1924 pg / ml, IL-4 (spontaneous production) - 22 pg / ml, TNF-α (induced production) - 618 pg / ml, CD3 + CD16 + 56 + -90 / mm ³ .

09/19/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 36 + 0.026 × 1924 + 0.0246 × 22 + 0.0019 × 618-0.0043 × 90-21.6346 = 31.8;

• F2 = 0.0144 × 36 + 0.0006 × 1924 + 0.0012 × 22 + 0.0004 × 618 + 0.0161 × 90-3.9664 = -0.6.

F1> F2, which met the criteria for pseudo progression.

The treatment was carried out as before. 09/27/2017, 10/11/2017, 10/25/2017, 11/08/2017 Nivolumab was administered as an outpatient at a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

11/23/2017. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 25 mm was determined. In the left lung there are two foci measuring 18 × 18 × 17 mm and 18 × 18 × 16 mm. In the right lung there is a lesion measuring 15 × 15 × 15 mm.

11.24.2017. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. No side effects were noted.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 18 × 17 mm; b) 18 × 18 × 16 mm.

2. The right lung: a) 15 × 15 × 15 mm.

3. Lymph nodes: 55 × 25 mm.

The sum of the maximum diameters: 18 mm + 18 mm + 15 mm + 25 mm = 76 mm. Compared with the previous study, a decrease in the size of one of the lesions was noted. The sum of the maximum diameters is increased by 117% compared with the nadir (study dated July 3, 2017, 35 mm), which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

11/29/2017. The immunogram. IL-10 (spontaneous production) - 73 pg / ml, IL-8 (induced production) - 1312 pg / ml, IL-4 (spontaneous production) - 67 pg / ml, TNF-α (induced production) - 752 pg / ml, CD3 + CD16 + 56 + -182 / mm ³ .

12/01/2017. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 73 + 0.026 × 1312 + 0.0246 × 67 + 0.0019 × 752-0.0043 × 182-21.6346 = 19;

• F2 = 0.0144 × 73 + 0.0006 × 1312 + 0.0012 × 67 + 0.0004 × 752 + 0.0161 × 182-3.9664 = 1.2.

F1> F2, which met the criteria for pseudo progression.

The treatment was carried out as before. 12/12/2017, 12/26/2017, 01/01/2018, 01/23/2018 Nivolumab was administered as an outpatient at a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

01/29/2018. Osteoscintigraphy - without pathology.

02/07/2018. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 25 mm was determined. In the left lung there are two foci measuring 16 × 16 × 15 mm and 15 × 15 × 16 mm. In the right lung there is a lesion measuring 12 × 12 × 12 mm.

02/09/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. During the course of treatment noted periodic nausea and diarrhea, which did not require medical correction. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 16 × 16 × 15 mm; b) 15 × 15 × 16 mm.

2. The right lung: a) 12 × 12 × 12 mm.

3. Lymph nodes: 55 × 25 mm.

Sum of maximum diameters: 16 mm + 16 mm + 12 mm + 25 mm = 69 mm. Compared with the previous study, a decrease in the size of foci was noted. The sum of the maximum diameters is increased in comparison with the nadir (study dated July 3, 2017, 35 mm) by 97%, which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

02/15/2018. The immunogram. IL-10 (spontaneous production) - 39 pg / ml, IL-8 (induced production) - 1556 pg / ml, IL-4 (spontaneous production) - 47 pg / ml, TNF-α (induced production) - 1200 pg / ml, CD3 + CD16 + 56 + -393 / mm ³ .

02.17.2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 39 + 0.026 × 1556 + 0.0246 × 47 + 0.0019 × 1200-0.0043 × 393-21.6346 = 22.9;

• F2 = 0.0144 × 39 + 0.0006 × 1556 + 0.0012 × 47 + 0.0004 × 1200 + 0.0161 × 393-3.9664 = 4.4.

F1> F2, which met the criteria for pseudo progression.

The treatment was carried out as before. 02/21/2018, 03/03/2018, 03/21/2018, 04/04/2018 Nivolumab was administered on an outpatient basis at a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

04/19/2018. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the LI - L2 level, a chain of lymph nodes measuring 55 × 20 mm was determined. In the left lung there are two lesions with dimensions of 15 × 15 × 15 mm and 11 × 10 × 10 mm. In the right lung there is a lesion measuring 12 × 12 × 12 mm.

04/20/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. The frequency and severity of nausea and diarrhea are the same. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 15 × 15 × 15 mm; b) 11 × 10 × 10 mm.

2. The right lung: a) 12 × 12 × 12 mm.

3. Lymph nodes: 55 × 20 mm.

The sum of the maximum diameters: 15 mm + 11 mm + 12 mm + 20 mm = 58 mm. Compared with the previous study, a decrease in the size of foci was noted. The sum of the maximum diameters was increased in comparison with the nadir (study dated July 3, 2017, 35 mm) by 65.7%, which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

04/26/2018. The immunogram. IL-10 (spontaneous production) - 37 pg / ml, IL-8 (induced production) - 2365 pg / ml, IL-4 (spontaneous production) - 63 pg / ml, TNF-α (induced production) - 984 pg / ml, CD3 + CD16 + 56 + -236 / mm ³ .

04/27/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 37 + 0.026 × 2365 + 0.0246 × 63 + 0.0019 × 984-0.0043 × 236-21.6346 = 44.4;

• F2 = 0.0144 × 37 + 0.0006 × 2365 + 0.0012 × 63 + 0.0004 × 984 + 0.0161 × 236-3.9664 = 2.3.

F1> F2, which met the criteria for pseudo progression.

The treatment was carried out as before. 05/05/2018, 05/17/2018, 05/31/2018, 06/14/2018 Nivolumab was administered on an outpatient basis in a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

06/29/2018. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 15 mm was determined. In the left lung there is a lesion measuring 14 × 14 × 13 mm and. In the right lung there is a lesion measuring 10 × 10 × 12 mm.

07/07/2018. Osteoscintigraphy - without pathology.

07/03/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. The frequency and severity of nausea and diarrhea without dynamics compared with previous courses. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTV 1.1 scale.

Target foci:

1. The left lung: a) 14 × 14 × 13 mm.

2. The right lung: a) 10 × 10 × 12 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 14 mm + 12 mm + 15 mm = 41 mm. Compared with the previous study, the disappearance of one of the foci, a decrease in the size of metastases in the lungs and lymph nodes was noted. The sum of the maximum diameters increased compared to the nadir (study dated July 3, 2017, 35 mm) by 11.4%, which met the stabilization criteria.

Given that the patient’s stabilization of the disease continued treatment in the previous mode. 07/10/2018, 07/24/2018, 08/08/2018, 08/21/2018 Nivolumab was administered on an outpatient basis at a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

09/06/2018. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 15 mm was determined. In the left lung there is a lesion measuring 14 × 14 × 13 mm and. In the right lung there is a lesion measuring 10 × 10 × 12 mm.

September 7, 2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. The frequency and severity of nausea and diarrhea are the same. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 14 × 14 × 13 mm.

2. The right lung: a) 10 × 10 × 12 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 14 mm + 12 mm + 15 mm = 41 mm. Compared with the previous study, the dynamics of the size of the lesions were not observed. The sum of the maximum diameters was increased compared to the nadir (study dated July 3, 2017, 35 mm) by 17.1%, which met the stabilization criteria.

Given that the patient’s stabilization of the disease continued treatment in the previous mode. 09/12/2018, 09/26/2018, 10/10/2018, 10/24/2018 Nivolumab was administered on an outpatient basis at a dose of 240 mg (2 vials of 10 ml vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0 9% NaCl.

11/08/2018. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 15 mm was determined. In the left lung there is a lesion measuring 16 × 16 × 17 mm and. In the right lung there is a lesion measuring 10 × 10 × 12 mm.

11/9/2018. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. The frequency and severity of nausea and diarrhea without dynamics compared with previous courses. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 16 × 16 × 17 mm.

2. The right lung: a) 10 × 10 × 12 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 17 mm + 12 mm + 15 mm = 44 mm. Compared with the previous study, an increase in the size of one of the lesions was noted. The sum of the maximum diameters was increased in comparison with the nadir (study dated July 3, 2017, 35 mm) by 22.9%, which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

11/15/2018. The immunogram. IL-10 (spontaneous production) - 77 pg / ml, IL-8 (induced production) - 1984 pg / ml, IL-4 (spontaneous production) - 78 pg / ml, TNF-α (induced production) - 948 pg / ml, CD3 + CD16 + 56 + -231 / mm ³ .

11/16/2018. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 77 + 0.026 × 1984 + 0.0246 × 78 + 0.0019 × 948-0.0043 × 231-21.6346 = 37.2;

• F2 = 0.0144 × 77 + 0.0006 × 1984 + 0.0012 × 78 + 0.0004 × 948 + 0.0161 × 231-3.9664 = 2.5.

F1> F2, which met the criteria for pseudo progression.

The treatment was carried out as before. November 22, 2018, December 6, 2018, December 20, 2018, January 9, 2019 Nivolumab was administered on an outpatient basis in a dose of 240 mg (2 vials of 10 ml and 1 vial of 4 ml) as a 60-minute iv infusion, dissolving in 400 ml 0.9% NaCl.

01/15/2019. Osteoscintigraphy - without pathology.

01/24/2019. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the level L1 - L2, a chain of lymph nodes with dimensions 55 × 15 mm is determined. In the left lung there is a lesion measuring 22 × 20 × 20 mm and. In the right lung there is a lesion measuring 15 × 15 × 15 mm.

01/25/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. The frequency and severity of side effects are the same. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 22 × 20 × 20 mm.

2. The right lung: a) 15 × 15 × 15 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 22 mm + 15 mm + 15 mm = 52 mm. Compared with the previous study, an increase in the size of foci in the lungs was noted. Compared with the previous study, the sum of the maximum diameters increased by 20.9%. The sum of the maximum diameters is increased compared to nadir (study dated July 3, 2017, 35 mm) by 48.6%, which met the criteria for progression.

Given that the patient according to CT studies revealed signs of disease progression, an immunological examination was performed.

01/31/2019. The immunogram. IL-10 (spontaneous production) - 54 pg / ml, IL-8 (induced production) - 1000 pg / ml, IL-4 (spontaneous production) - 92 pg / ml, TNF-α (induced production) - 425 pg / ml, CD3 + CD16 + 56 + -654 / mm ³ .

02/01/2019. A patient at an outpatient appointment with the Federal State Budget Scientific Center "Russian Scientific Center for Remediation and Health" of the Ministry of Health of the Russian Federation.

Calculation of discriminant functions:

• F1 = 0.0588 × 54 + 0.026 × 1000 + 0.0246 × 92 + 0.0019 × 425-0.0043 × 654-21.6346 = 7.8;

• F2 = 0.0144 × 54 + 0.0006 × 1000 + 0.0012 × 92 + 0.0004 × 425 + 0.0161 × 654-3.9664 = 8.2.

F2> F1, which met the criteria for progression.

Considering that according to the CT study, the patient showed signs of disease progression, which was confirmed by the values of discriminant functions, treatment was continued using the next-line drug - Everolimus.

From 02/11/2019 to 04/07/2019, Everolimus received 10 mg per day orally according to the instructions.

04/09/2019. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the level L1 - L2, a chain of lymph nodes with dimensions 55 × 15 mm is determined. In the left lung there is a lesion measuring 20 × 20 × 20 mm and. In the right lung there is a lesion measuring 14 × 15 × 15 mm.

04/11/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. Nausea and diarrhea persisted. The frequency and severity were the same as with Nivolumab. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 20 × 20 × 20 mm.

2. The right lung: a) 14 × 15 × 15 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 20 mm + 15 mm + 15 mm = 50 mm. Compared with the previous study - nadir from 01.24.2019, a decrease in the size of foci in the lungs was noted. Compared with the previous study, the sum of the maximum diameters decreased by 4%, but less than 5 mm, which met the stabilization criteria.

Given that stabilization was achieved as a result of therapy, treatment was continued in the previous mode.

From April 15, 2019 to June 9, 2019 he received Everolimus 10 mg per day orally according to the instructions.

06/11/2019. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the level L1 - L2, a chain of lymph nodes with dimensions 55 × 15 mm is determined. In the left lung there is a lesion measuring 18 × 18 × 18 mm and. In the right lung, there is a lesion measuring 13 × 14 × 14 mm.

06/14/2019. Osteoscintigraphy - without pathology.

06/18/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. Nausea and diarrhea persisted. The frequency and severity were the same as when using Nivolumab. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 18 × 18 mm.

2. The right lung: a) 13 × 14 × 14 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 18 mm + 14 mm + 15 mm = 47 mm. Compared with the previous study, there was a decrease in the size of foci in the lungs by 6%, but less than 5 mm. Compared with nadir during the use of Everolimus (study from 01.24.2019, 52 mm), the sum of maximum diameters decreased by 9.6%, which met the stabilization criteria.

Given that stabilization was achieved as a result of therapy, treatment was continued in the previous mode.

From 06/24/2019 to 08/18/2019, Everolimus received 10 mg per day orally according to the instructions.

08/22/2019. CT scan. In the area of the bed of the right kidney, pathological formations were not detected. The left kidney is without pathology. Abdominal organs - without pathology. At the L1 - L2 level, a chain of lymph nodes measuring 55 × 15 mm was determined. In the left lung there is a lesion measuring 18 × 18 × 18 mm and. In the right lung there is a lesion measuring 13 × 13 × 14 mm.

06/18/2019. Patient on an outpatient appointment at the Federal State Budgetary Institution "Scientific Center for Advanced Research" of the Ministry of Health of the Russian Federation.

No complaints at the time of the inspection. General condition is satisfactory. Nausea and diarrhea persisted. The frequency and severity were the same as when using Nivolumab. No dose adjustment was required.

Assessment of the dynamics of metastatic lesions according to the RECISTv 1.1 scale.

Target foci:

1. The left lung: a) 18 × 18 × 18 mm.

2. The right lung: a) 13 × 13 × 14 mm.

3. Lymph nodes: 55 × 15 mm.

Sum of maximum diameters: 18 mm + 14 mm + 15 mm = 47 mm. Compared to the previous study, no dynamics were noted. Compared with nadir during the use of Everolimus (study dated January 24, 2019, 52 mm), the sum of maximum diameters decreased by 9.6%, which met the stabilization criteria.

Given that stabilization was achieved as a result of therapy, treatment was continued in the previous mode.

Currently, the patient is alive, is under the supervision of the FSBI "RSCRHT" MH RF them. Acad. A.M. Granova and continues treatment. 26 months have passed since the start of treatment with Nivolumab. The time to progression was 17 months.

To date, the proposed method has been clinically tested in 43 patients with disseminated RCC who received treatment in the second line against the background of progression after tyrosine kinase inhibitors, angiogenesis or chemoimmunotherapy inhibitors: 16 (37%) patients with favorable, 17 (40%) with intermediate and 10 (23%) with a poor MSKCC forecast. Data from 12 patients were used to develop the method, 31 for validation. In all patients, when radiological signs of disease progression were detected, differential diagnosis was performed between true and pseudo-progression by calculating discriminant functions on average 5 times (from 1 to 12) in the subgroup with the best overall response after progression as a partial response, 6 times (from 2 to 14 ) in the subgroup with stabilization and 2 times (1-2) in the subgroup with progression. The median time from pseudo-progression to true in the stabilization subgroup (the best overall response) was 24.2 months, and the median in the partial response subgroup was not achieved, due to the fact that most patients are currently alive and continuing treatment. All patients with a partial response and more than half of the patients with stabilization in the form of the best overall response are alive, therefore, the median survival, calculated from the moment of pseudo-progression to death, has not been achieved. Moreover, the average life expectancy of deceased patients in the subgroup with stabilization was 26 months, and with progression - 21 months, which significantly exceeds the indicators achieved in the prototype and known analogues.

The method in comparison with known analogues has several significant advantages:

1. Allows you to improve the immediate results of the treatment of patients with disseminated RCC.

2. Allows you to increase the life expectancy of patients.

3. Based on the use of modern advances in molecular biology and cellular immunology.

A method for the treatment of disseminated RCC has been developed in the group of molecular biological prediction and individualization of treatment at the Federal State Budget Scientific Center "Scientific Research Center for Reconstruction and Development of Health" of the Ministry of Health of the Russian Federation named after Acad. A.M. Granova and to date has been clinically tested in 43 patients with a positive result.

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

A method for the treatment of disseminated renal cell carcinoma

Claims (3)

A method of treating disseminated renal cell carcinoma with the drug Nivolumab at a dose of 3 mg / kg of the mass once every two weeks in eight-week cycles with a CT scan of the patient after each cycle, characterized in that, in the presence of radiological signs of disease progression, the patient determines the levels of spontaneous production IL-10 (X1), induced production of IL-8 (X2), spontaneous production of IL-4 (X3), induced production of TNF-α (X4) and the absolute concentration of natural killer receptors T-lymphocytes (CD3 + CD16 + 56 +, X5), discriminant functions are calculated from the obtained values: • F1 = 0.0588 × X1 + 0.026 × X2 + 0.0246 × X3 + 0.0019 × X4-0.0043 × X5-21.6346, • F2 = 0.0144 × X1 + 0.0006 × X2 + 0.0012 × X3 + 0.0004 × X4 + 0.0161 × X5-3.9664 and with F1> F2, pseudo-progression is established in the patient and treatment continues mode, and at F2> F1, treatment is carried out with the drug Everolimus, which is administered at a dose of 10 mg per day orally in the form of eight-week cycles until progression.