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Background. The use of the modern targeted drugs in patients with non-small-cell lung cancer (NSCLC) with certain somatic alterations (genetic alterations in EGFR, ALK, ROS1, BRAF, RET genes, etc.) provides a significant increase in overall and disease-free survival with an acceptable toxicity profile. The use of RET inhibitors, such as selpercatinib, has significantly improved prognosis in NSCLC patients with RET gene translocation, since chemotherapy and immunotherapy in this cohort of patients are ineffective options. The RET gene translocation occurs rarely (2–3 % of cases among lung adenocarcinoma), but detection of this genetic alteration with subsequent administration of targeted therapy significantly improves the prognosis of the disease. Case report. We present a clinical case of the efficacy of targeted therapy with selpercatinib in a 60-year-old patient with RET-positive NSCLC. Methods to eliminate toxicity after selpercatinib therapy and therapy response are described. Results. Second-line selpercatinib therapy resulted in partial response in our patient with lung adenocarcinoma and the presence of translocation in RET gene. Adverse effects from targeted therapy were minimized or eliminated by the use of concomitant therapy, temporary cancellation of targeted therapy with subsequent dose reduction and gradual return to full therapeutic doses. Conclusion. This case demonstrates the high significance and importance of genetic testing in patients with lung adenocarcinoma not only for the most common mutations, but also for rarer somatic alterations, such as translocation in the RET gene. Detection of this translocation and subsequent administration of appropriate targeted therapy significantly improves the prognosis of patients.

Lung cancer remains one of the most dangerous and most common cancers, requiring constant improvement of diagnostic and treatment methods. The genetic heterogeneity of lung cancer forces us to search for new therapeutic targets in an attempt to achieve greater effectiveness for certain groups of patients. The purpose of the study was to update current knowledge about lung adenocarcinoma with a mutation in the KRAS gene, to consider new opportunities for personalized treatment of KRAS-mutated NSCLC and to form an image of a Russian patient who is potentially indicated for targeted therapy. Material and methods. A search of available literature sources published in the Pubmed, Cochrane Library, Elibrary database was carried out, publications covering the period from 2008 to 2023 were included. Results. The article discussed molecular genetic testing, including NGS next generation sequencing, and its role in determining the presence of KRAS gene mutations in patients with lung cancer. the effectiveness of targeted drugs, such as Sotorasib and Adagrasib was also discussed. The mechanism of action is aimed at suppressing the activity of the mutant KRAS G12C protein, which can significantly improve patient survival prognosis. We obtained data on the results of testing 935 patients with non-squamous non-small cell lung cancer from various medical centers in Russia. The KRAS gene mutation was identified in 160 (17.1 %) patients, of whom 96 (10.3 %) had KRAS G12C variant. The KRAS mutation was determined by PCR in 44 patients and by NGS (including on the FoundationOne platform) in 111 patients. Clinical characteristics, such as gender, age, smoking status, PD-L1 expression level, presence of co-mutations (TP53, STK11, KEAP1, were largely similar between patients from real-world clinical practice and patients included in the CodeBreak100 study. Conclusion. The research results confirm the high effectiveness of Sotorasib and Adagrasib for patients with the KRAS G12C mutation and open up new prospects in the treatment of lung cancer. The clinical data obtained from Russian patients demonstrate consistency with the patient profile from registration studies of these drugs. This once again demonstrates the need to expand the range of molecular genetic testing for timely identification of this group of patients and prescribing the most effective treatment for them.

Aim of the study: to evaluate prognostic value of baseline lung immune prognostic index (LIPI) and its modification (mLIPI) for metastatic non-small cell lung cancer (mNSCLC) patients treated with immune checkpoint inhibitors (ICI).Material and methods. Baseline neutrophil-to-lymphocyte ratio, lactate dehydrogenase, hemoglobin, platelets, and fibrinogen level were collected from 133 patients treated with ICI in monotherapy or combination between July 2015 and July 2022 in N.N. Blokhin NMRCO. According to evaluating factors patients were divided into three groups of “good” (LIPI 0/mLIPI 0–1), “intermediate” (LIPI 1/mLIPI 2–3) and “poor” prognosis (LIPI 2/mLIPI 4–5). The primary endpoint was progression free survival (PFS).Results. The median PFS for the LIPI groups were 9.7 months (1.4–17.9; 95 % CI), 7.9 months (5.9–9.9; CI 95 %) and 6.0 months (4.07–7.93; 95 % CI) in the “good”, “intermediate” and “poor” prognosis groups, respectively; the hazard ratio (HR) for patients in the “poor” prognosis group (17 patients) was 2.02 (1.06–3.84; 95 % CI) compared with the “good” LIPI group (p=0.03). The median PFS for mLIPI groups were 9.0 months (4.53–13.47; 95 % CI), 8.0 months (5.4–10.6; CI 95 %) and 2.0 months. (1.33–2.67; 95 % CI) in the “good”, “intermediate” and “poor” prognosis groups, respectively. The HR for patients in the “poor” prognosis group (n=12) was 3.12 (1.51–6.46; 95 % CI) compared with the “good” mLIPI group (p=0.002).Conclusion. Baseline LIPI and mLIPI predicts potential resistance to ICI treatment in mNSCLC patients.

Non-small cell lung cancer is a very heterogeneous group of diseases. When choosing an effective patient management strategy, an oncologist focuses on the stage of the disease, the morphological form of the tumor, as well as its molecular genetic markers. Most of the targeted mutations in lung cancer today are in adenocarcinoma. The standard for detecting this type of cancer in 2022 is the determination of mutations in the EGFR genes (18-21 exons) and BRAF (V600E), translocations of the ALK and ROS1 genes, and determination of PD-L1 status regardless of gender, age, and history of smoking. Often, lung cancer is detected in the advanced stages, but the detection of ALK gene translocation can give the patient a high chance of a longer life expectancy and long-term control of the disease. In this article, on the example of a clinical case of a patient with ALK-positive lung adenocarcinoma, a multidisciplinary approach to the management of cancer patients, long-term control of the disease with the use of the second-generation targeted medication alectinib, as well as treatment options for disease progression are demonstrated.

HCC is considered refractory when it comes to progression during treatment with TKIs (sorafenib, lenvatinib). The combined immunotherapy of nivolumab with ipilimumab was studied in the one cohort of CheckMate-040 study, excluding immunotherapy-naive patients. The question of choosing an immunotherapy option in the presence of several options remains open. Like separate issue remains the prospect of using immunotherapeutic combinations after progression on immunotherapy. We present a long history of treatment of a patient with advanced HCC, which has been observed for 8 years at the Blokhin National Medical Research Center of Oncology. The example of this clinical observation shows the result of a multidisciplinary individual approach to the treatment of advanced HCC with the background of hepatitis C virus without liver cirrhosis (Child -Pugh A), stage BCLC-C. During this period of time, the patient received 5 lines of antitumor therapy, which were repeatedly supplemented with TACE procedures, radiation therapy and surgical treatment, with oligometastatic progression. The longest period of therapy without progression was recorded with the use of Nivolumab 240 mg in the 3rd line for 18 months, without clinically significant toxicity. The disease progressed with damage of the brain substance, one-stage microsurgical removal of metastases was performed, followed by EBRT. 4-line TKI therapy was not long-term. Due to the lack of a potential therapy option, it was recommended to resume therapy with anti-PD-1 with the addition of anti-CTLA-4, which gave its objective effect. Since November 2021 patient received 4 courses of Nivolumab 1 mg/kg + ipilimumab 3 mg/kg once every 3 weeks, and a partial effect was achieved (-42% according to RECIST 1.1). Then we performed nivolumab 240 mg IV every 2 weeks — which the patient continues to the present time.

Lung cancer is one of the most common malignant tumors with the highest mortality, with about 85% of cases of the disease being non-small cell lung cancer. To date, adjuvant chemotherapy based on platinum preparations remains the standard of treatment for patients with radically operated stage II or III non-small cell lung cancer. However, a large proportion of patients still have a risk of developing a recurrence of lung cancer even after complete resection of the tumor. That is why there is a need to search for new methods of treatment of early stages of NSCLC, which will minimize the likelihood of postoperative relapses and improve survival in a potentially curable group of patients. Already today, clinical trials are beginning to advance the treatment of non-small cell lung cancer in the early stages beyond the standard cytotoxic chemotherapy. Immunotherapy, represented by immune checkpoint inhibitors, is being investigated in an increasing number of clinical trials in patients with operable NSCLC at early stages, gradually enriching existing treatment methods. At the same time, some issues related to adjuvant immunotherapy have yet to be considered. The choice of the drug, the use of monotherapy or combined treatment regimens remain unclear. This review examines the progress of research aimed at improving adjuvant therapy through the inclusion of immune checkpoint inhibitors in the treatment of early stages of resectable non-small cell lung cancer. Adjuvant immunotherapy can improve relapse-free survival in individual patients with resectable lung cancer, and current or planned studies using biomarkers and immunotherapy may also ultimately lead to an improvement in the overall survival of this group of patients.

The purpose of the study: to conduct a systematic literature review on the effectiveness and feasibility of using information on the presence of KRAS gene mutations (in different codons), TP 53 (KP), ST K11/LKB1 (KL), and KEAP mutations and the association of KRAS m with PD -L1 status in patients with non-small cell lung cancer (NSCLC ) as a predictor of the effectiveness of immunotherapy with immune checkpoint inhibitors.Material and Methods. The review includes data from randomized clinical trials and meta-analyses on the predictive value of KRAS mutation status for response to immunotherapy in patients with NSCLC over the past 10 years.Results. The presence of KRAS mutations in NSCLC patients could be a predictive factor for their response to immunotherapy, as several studies have demonstrated benefit from immunotherapy in these patients. The combination of KRAS mutation with TP 53 (KP) co-mutation predicts a better response to immunotherapy, while a combination with ST K11/LKB1 (KL) and KEAP 1 predicts a worse response (reduced response rate and overall and disease-free survival). In PD -L1-positive patients, the presence of KRAS mutation is associated with a better prognosis after treatment with immunotherapy. Moreover, the presence of KRAS mutation is associated with a worse response to first-line and subsequent-line chemotherapy, thus indicating a more promising use of immunotherapy in these patients.Conclusion. Identification of TP 53 (KP), ST K11/LKB1 (KL), and KEAP 1 co-mutations and the presence of KRAS mutation in addition to determination PD -L expression enable selection of patients who will obtain the greatest benefit from immunotherapy. In addition, the ability to determine KRAS mutation and co-mutation status using a liquid biopsy (with acceptable specificity and sensitivity) makes it possible to use this method for determining sensitivity to immunotherapy when it is not possible to obtain tumor sample (to determine PD 1-L1 expression).

Introduction. Fibrolamellar hepatocellular carcinoma (FLC), which develops most often in the younger population. In FLC, variable histoarchitectonics are noted, possibly the presence of a sclerosing component, foci of necrosis and dystrophy of tumor cells.Objective. Assessment of the influence of the proportion of the sclerosing component in fibrolamellar carcinoma (FLC) of the liver on the course and prognosis of the disease. Determination of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion.Materials and methods. A retrospective study included 34 patients with a diagnosis of FLC, who underwent radical surgical treatment at the first stage. A histological assessment of the proportion (%) of the sclerosing component in FLC was made. The effect of the proportion of the sclerosing component on overall (OS) and relapse-free (DFS) survival was assessed. The analysis of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion was carried out.Results. Significantly worse RFS was achieved in the groups of patients with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5% (p = 0.0010; p = 0.024; log – rank test). Median DDS in group 1 is 107 (95% CI, 22–192) months; at 2 – 11 (95% CI, 8–14) months; in 3 – 21 (95% CI, 8–33). The frequency of histologically confirmed microvascular invasion in the compared groups was 29, 74, 87.5%, respectively. OS was significantly worse in 2 groups (27 patients in total) with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5%. Median OS in group 1 120 (95% CI, 60–180) months; at 2 – 41 (95% CI, 15–92) months; in 3 – 69 (95% CI, 35–103). A direct relationship was found between an increase in the proportion of the sclerosing component in a tumor and an increase in the frequency of microvascular invasion.Conclusions. We can assume that the severity of the sclerosing component in the FLK tumor can serve as an effective morphological marker of a less favorable prognosis for this HCC subtype and correlate with the frequency of microvascular invasion.

Introduction. Lorlatinib is a third generation ALK tyrosine kinase inhibitor. Back in 2018, the drug underwent accelerated FDA approval and was recommended for the treatment of patients with ALK-positive non-small cell lung cancer after progression on crizotinib and another ALK inhibitor. For a long time, the use of the drug in Russia was possible only in clinical trials or expanded access program. However, now this drug is becoming available in our country.Purpose. To analyze the overall and intracranial response during lorlatinib therapy, as well as the tolerability of lorlatinib therapy in patients with ALK-positive non-small cell lung cancer who previously received crizotinib and one or more lines of cytostatic therapy.Materials and methods. The study included 39 patients aged 28 to 76 years, diagnosed with non-small cell lung cancer. In 36 cases, a translocation in the ALK gene was detected, in three, a ROS1 translocation. All patients received targeted therapy with crizotinib and one or more lines of chemotherapy before starting lorlatinib therapy. All patients received 100 mg lorlatinib therapy until disease progression or intolerable toxicity.Results. During the observation period for the moment of September 2021, an objective response was achieved in 28 patients (71.7%), in 10 patients (25.6%) – stabilization of the disease, in one patient (2.6%) – progression. The median duration of the drug was just over 40 months. The drug intake was characterized by a predictable and manageable toxicity profile.Conclusions. These data indicate a high direct efficacy of lorlatinib in patients with ALK/ROS1 translocations. The data obtained do not contradict the results obtained in the course of clinical trials. The drug lorlatinib has currently received registration in Russia for the treatment of non-small cell lung cancer in cases of the development of progression while taking secondgeneration ALK inhibitors or several lines of therapy with ALK inhibitors.

The optimal hepatocellular cancer (HCC) therapy remains a challenge. Due to checkpoint inhibitors patients with intolerance to the targeted therapy and or those with the impaired liver function can get an appropriate drug therapy. This clinical observation illustrates the long-term effect of pembrolizumab as the 2-line therapy in a patient diagnosed with. Sorafenib in standard doses as first line therapy led to severe toxicity and necessitated the withdrawal of therapy. Although subsequently the doses were reduced and concomitant medications used, sorafenib therapy was discontinued due to pronounced side effects typical of kinase inhibitors. From August 2017 to September 2019, as a part of a clinical study, the patient received 35 courses of immunotherapy with pembrolizumab 200 mg i.v. every 3 weeks, with satisfactory tolerance. The best response - partial tumor regression – was achieved at 84 weeks of therapy and continues to this day. Favorable toxicity profile makes checkpoints inhibitors a good treatment option in patients with impaired liver function (Child-Pugh 7–8 points) or with intolerable toxicity of kinase inhibitors.

Introduction. Lung cancer remains the one of the most common and fatal cancers in the world. For a long time, chemotherapy was the only treatment option for metastatic lung cancer. Currently, immunotherapy became the one of the preferred options of treatment.The purpose of our work was to evaluate the long-term results of using the PD-1 inhibitor nivolumab in real-world settings.Materials and methods. 108 pretreated patients with metastatic NSCLC were included in this non-randomized, observational study. The median follow-up time was 54.5 months.Results. Median overall survival was 8.8 months (6-12, 95% CI). The five-year overall survival rate was 19.4%. Median progressionfree survival was 3.9 months (3-5, 95% CI). The five-year progression-free survival rate was 7.7%. Overall response rate (ORR) was 18%. In patients with ORR, the median overall survival was not achieved. Prolongation of immunotherapy after disease progression had a positive effect on the overall survival of patients. Clinically significant immuno-related adverse events developed in 21% of patients, but only 7.3% showed the development of adverse events grade 3-4 that required discontinuation of immunotherapy. A rare complication that we met was a case of encephalopathy, to which the patient achieved durable complete response despite discontinuation of immonotherapy.Conclusion. Received survival, efficacy and safety data may inform treatment decisions for patients with metastatic NSCLC in real world settings.

Personalized therapy is starting to play an increasing role in modern approaches to the treatment of oncological diseases. The previously existing uniform standard for each malignant disease is expanded with new options and treatment possibilities, depending on each specific clinical situation. That increases the effectiveness of therapy and helps to control the disease. A separate niche in the individual approach to anti-tumor treatment is occupied by targeted therapy of malignancies. There are a lot of mutations that can lead to the emergence of malignant neoplasms. So of all that multitude of choices the individual approach to a patient helps to select the mutations that are most likely to be found in a given patient. The research in the area of the c-MET mutation has allowed it to occupy its niche as a therapeutic target. The identification of this mutation is not included in the routine set of analyses performed for a patient with diagnosed lung adenocarcinoma. But expanding the panel of molecular testing would increase the detectability of this mutation and, as a result, improve the quality of treatment for this category of patients. This clinical case describes the experience of treatment of an elderly patient with lung adenocarcinoma, in whose tumor tissue a MET mutation was detected.

The abscopal effect was described more than 50 years ago and is a phenomenon in which radiation therapy promotes the regression of metastatic foci remote from the site of radiation. For decades, this effect has been described as a rare, unexplained phenomenon in patients receiving radiation therapy. Today, the abscopal effect is still an exceptional phenomenon: the mechanism underlying it is still not fully understood. It is believed that the abscopal effect is most likely associated with systemic immune responses that occur under the influence of radiation therapy.We present the case of a 63-year-old patient with advanced peripheral cancer of the upper lobe of the left lung, disease progression in the form of metastatic brain lesions and regression of tumor foci in the lungs after radiation therapy to the brain, while the patient did not receive additional treatment in the form of immunotherapy.The article examines the history of the abscopal effect, an attempt is made to understand the mechanisms of its occurrence, which can help to further improve the results of treatment of patients with NSCLC using radiation therapy and modern approaches to complex cancer treatment.

For more than 10 years, there have been no significant improvements in treatment outcomes for patients with inoperable locally advanced non-small cell lung cancer. At the moment, the standard of treatment for this category of patients is concurrent chemoradiation therapy. At the same time, the 5-year overall survival rate varies in the range of 15–25%. This indicator contributes to the modernization of existing approaches, as well as the search for new ways in the treatment of patients with inoperable stage III non-small cell lung cancer.One of the promising areas is the combination of chemoradiation therapy with immunotherapy. Thus, the use of Imfinzi (durvalumab, AstraZeneca) as a consolidation therapy in the Phase III clinical trial PACIFIC demonstrated a reduction in the risk of death by about one third in comparison with the standard approach.We present a clinical case study of a patient with locally advanced non-small cell lung cancer who received treatment in the framework of concurrent chemoradiation therapy followed by immunotherapy with durvalumab, continuing until now. The result of the therapy is the complete response to the specific treatment, recorded according to PET-CT.Thus, the use of immunotherapy as consolidation therapy represents a promising strategy for improving outcomes after concurrent chemoradiation therapy in patients with inoperable stage III non-small cell lung cancer

Introduction. Nowadays the stereotactic radiotherapy (SRT) of patients with clinical stage I-II lung cancer is the choice of the treatment modality for functionally inoperable patients. It shows safety and high efficiency in reaching the local control. Though there is a range of unsolved issues connected with the prediction of treatment efficiency and frequency of complications, an integration of new technologies in the planning and treatment process allows to widen the search of the predictive factors.Materials and methods. Since 2014, 42 patients (T1N0M0 – 16 patients, T2N0M0 – 26 patients) with clinical stage I-IIa lung cancer have underwent SRT. The majority of patients (38) have been recognized as functionally inoperable due to the concurrent broncho-pulmonary pathology, 4 conditionally operable patients have refused an operation. 11 patients had the primary multiple tumors in their anamneses, 3 patients had a сentral tumor. Used dose fractionation options were: 10 Gy х 5 fractions (n = 29) and 7 Gy х 8 fractions (n = 13) – BED = 100 Gy.Resuts. The median follow-up was 32 months (range 6–56 months). The 3-year local control was 94%. The isolated local recurrences were not registered. Overall 3-year survival rate was 74% (95% CI, 60–90) and a 3-year tumor-specific survival rate – 84% (95% CI, 71–98). During one-factor analysis a reliable influence on the prognosis of the fractionation regimen (р = 0,04) and, close to reliability, the initial SUVmax level influence (р = 0,07) were revealed. Grade 3 pulmonary toxicity was observed in 4 (9%) patients, one patient with a Central tumor died from pulmonary hemorrhage (grade 5 toxicity). Grade 3 chest pain was observed in 3 (7%) patients, two of them had a rib fracture.Conclusions. With modern approaches to SRT treatment planning and delivery there should be a search for additional treatment efficiency and toxicity predictors. The total dose delivery regimen and initial tumor SUVmax can be predictive efficiency factors, while the pulmonary tissue volume can be a predictive toxicity factor.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that has been approved for the treatment of metastatic non-small cell lung cancer (NSCLC) positive for the secondary T790M mutation of EGFR. Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC), resulting in a poor prognosis and limited treatment options. Almost 25% of patients present with accompanying central nervous system (CNS) metastases at the first diagnosis. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood‐brain barrier (BBB), creating a major unmet need for the development of agents with good BBB‐penetrating biopharmaceutical properties. Although the CNS penetration of first‐ and second‐generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR‐TKI treatment has been shown to delay time to CNS progression in patients with both in preventing or delaying the onset of CNS metastases, and in leading to intracranial response of preexisting CNS lesions. This is one of the arguments in favor of starting osimertinib upfront rather than initiating treatment with firstor second-generation EGFR-TKIs.

Fibrolamellar hepatocellular carcinoma (FLC) is a relatively rare primary liver tumor of unknown etiology (chronic infections with hepatitis B or C viruses, chronic alcohol poisoning, cirrhosis of the liver), which occurs mainly in the young population. FLK is more often diagnosed already at common stages due to the absence of pronounced clinical manifestations in patients for a long time. In pathomorphological diagnostics, FLC is a cluster of large polygonal eosinophilic cells with a clearly defined vesicular nucleus, surrounded by abundant growths of lamellar fibrosis. In most cases, collagen fibers are arranged in parallel strands; in metastatic tumors, collagen fibers can be arranged haphazardly (the so-called “tangled fibers”).For many years, attempts have been made to identify reliable markers for the detection and differential diagnosis of FLC and to determine the cause of tumors in young patients, and the molecular mechanisms of FLC carcinogenesis have been studied. In 2014 during the full transcriptome analysis of FLC samples, the chimeric transcript DNAJB1PRKACA was discovered, which is formed as a result of deletion of a section of chromosome 19 with a size of 400 thousand nucleotide pairs and leads to the fusion of two genes, which Is found in most FLC samples. Surgery is the only curative treatment of this tumor type and radical method of treating the disease. Given that lymph node involvement is an important prognostic factor, complete periportal lymphadenectomy should be performed as part of radical surgery for patients with FLK. The role and possibilities of locoregional and drug-based treatment methods are not fully clear, and the search for effective treatment regimens and potential targets specific to this form of HCR is urgent. Studies show conflicting results for different chemotherapy regimens and the use of targeted therapy. The literature describes isolated clinical cases of successful use of immunotherapy in patients with PD-L1-expressing tumors. The most important condition for successful treatment is an in-depth study of the molecular mechanisms of FLC carcinogenesis. This review presents current data on epidemiology, classification, clinico-morphological, molecular and genetic aspects, as well as some diagnostic features and FLC treatment modalities.

Introduction. In modern recommendations for the treatment of localized small cell lung cancer (SCLC), preference is given to socalled «early» chemoradiotherapy (CRT), which has a number of limitations due to its pronounced toxicity. With regard to prophylactic brain irradiation (PBI), although there is reliable evidence that it is necessary, PBI cannot be performed on all patients due to the frequent refusals of the patients themselves and the accompanying neurological pathology. The article presents own experience of therapy of patients with localized SCLC with the analysis of accumulated data. Materials and methods. Retrospective assessment of treatment results of patients with localized SCLC was carried out. The analysis included data on 63 patients. 47 patients received simultaneous CRT and 16 patients received consecutive CRT. The results of simultaneous CRT were evaluated first. 27 patients received “early” CRT, while 20 patients received “late” CRT. Results. The PFS median for the group of early CRT was 9.5 months (95% CI 4.2–14.9) and for the group of “late” CRT it was 11.8 months (6.4–17.1). The difference is statistically unreliable. The median of total survival rate was higher in the group of “early” CRT, despite the fact that PFS was lower. The OS median in the group of “early” CRT was 27.9 months (95% CI 2.1–53.7), and in the group of “late” – 24.8 months (95% CI 13.3–36.1). The difference is statistically unreliable. Prophylactic brain irradiation (PBI) in the group of patients with simultaneous CRT was received by 26 patients (55%). The results of overall survival show the crucial importance of PBI in patients with localized SCLC. The OS median in patients who received PBI was 45.9 months (95% CI 21.2–70.5), in patients who did not receive PBI – 21.7 months (95% CI 14.3–29). The difference is statistically significant, p = 0.01. As for complications, 2nd degree esophagitis was recorded more frequently in the group of early CRT – 57% in the group of early CRT and 42% in the group of late CRT, 3rd degree esophagitis was recorded in 1 patient in each group, the difference is not significant. Grade 3–4 hematological toxicity was observed in 5 patients in the group of early CRT and 2 patients in the group of late CRT, the difference is also unreliable. The OS median in the group of patients who received consecutive CRT was 27.1 months (95% CI 18.2–37.6), and the OS median in the group of patients who received simultaneous CRT was 27.9 months (95% CI 18.9–36.9). Conclusions. The obtained data show an unreliable advantage of the “early” CRT over the “late” CRT in terms of overall survival. However, no differences in median time before progression of both local and general ones were obtained. It is extremely important to perform PBI in patients with localized SCLC, as the survival rate in the assessed group of patients doubled.

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

On April 27, 2020, COVID-19 pandemic affected more than 2,5 million of people in more than 200 countries and caused 185 000 deaths. Healthcare systems have come under enormous stress. In COVID-19 pandemic oncological patients face two serious challenges: the risk of severe infectious disease course and the risk of malignant tumor progression. Forced correction of existing oncological standards of care is based on expert and professional community opinions, and daily gaining experience. The issue resumes the data on COVID-19 influence on liver function among the patients with chronic liver diseases and hepatocellular carcinoma. The guidance on HCC management in COVID-19 pandemic are provided. More than 1,5 million of people suffers from the liver pathology caused by chronic virus hepatitis, alcohol consumption, nonalcoholic fatty liver disease. Mild COVID-19 is often followed by transient liver function disorder which do not need specific treatment. Severe COVID-19 lids to the increase of aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), to the decrease of serum albumin in most cases. Regarding the HCC treatment preference should be given to telemedicine, limitation of contacts in health-care facilities, outpatient treatment, including oral medication (tyrosine kinase inhibitors), and if possible delay of invasive procedures with the help of bridge-therapy and active monitoring. Selecting the patients for surgery, ablation or transarterial chemoembolization (TACE) patients with minimal risk of decompensation, with maximum treatment benefit (on the base of prognostic scales), with lack of comorbid should be preferred. Selective and super selective TACE with drug-eluting beads or radioembolization should be used to reduce the risk of immunosuppression and postembolic syndrome. Live organ transplantation should be considered to be postponed. Targeted therapy could be a temporarily alternative to invasive procedures.

Immunotherapy is the most promising method in the treatment of lung cancer, especially in connection with the rapidly growing development of monoclonal antibodies aimed at inhibiting immune checkpoints: anti-CTLA-4, anti-PD-1, anti-PD-L1. Classic immuno-mediated adverse events that occur with this method of treatment can affect several organs, including the lungs. Pneumonitis is a potentially life-threatening complication and often requires rapid treatment with high doses of corticosteroids and antibacterial drugs. We present the case of a 67-year-old patient with primary multiple malignant tumors of the larynx and left lung after combined treatment and incomplete treatment with Nivolumab, complicated by immuno-mediated pneumonitis. This report highlights the importance of treating patients with contraindications to chemotherapy when specific antitumor treatment is required, as well as timely detection of a rare but dangerous adverse event: immuno-mediated pneumonitis that occurs during treatment with immune checkpoint inhibitors. Thus, knowing the frequency of adverse events when using PD-1 and PD-L1 inhibitors, as well as the possible presence of comorbidities in patients, will make it easier for doctors to make informed decisions in the treatment of patients, and understanding the interaction of the tumor and the immune system will help determine the best predictors of response and further improve the results of treatment of patients with NSCLC.

Lung cancer is a leader in the world in terms of morbidity and mortality. Moreover, the number of patients with locally advanced forms of non-small cell lung cancer exceeds 30% of all newly diagnosed cases. The standard of treatment for patients with inoperable stage III lung cancer is chemoradiotherapy. Currently, ways to increase the effectiveness of chemoradiotherapy are being considered, in particular, local escalation of the radiation dose to the tumor, which allows personalizing approaches in the treatment of this category of patients. One of the most common complications of chemoradiotherapy is post-radiation pulmonitis, which requires timely diagnosis and treatment with glucocorticosteroids in severe cases. We present a case report of a patient with locally advanced non-small cell lung cancer who received treatment as part of simultaneous chemoradiotherapy in the hypofraction mode, complicated by post-radiation pulmonitis. Successful treatment of complications led to the restoration of the general condition of the patient; during the follow-up examination, a complete response to the specific treatment was recorded. Thus, a promising method of treating patients with inoperable stage III non-small cell lung cancer is the option of simultaneous chemoradiotherapy with local escalation of the radiation dose to the tumor, while being wary of complications such as pulmonitis, allows for timely diagnosis and treatment of the condition.

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer worldwide. Despite the success over recent years in the treatment of NSCLC it has not yet been able to achieve good long-term survival. The development of immune checkpoint inhibitors has altered the landscape of treatment of advanced cancers, including non-small cell lung cancer (NSCLC). Nivolumab is the PD-1 inhibitor approved for the treatment of NSCLC to show a survival benefit in a randomised phase III trials. The experience of physicians in routine clinical practice is often different from those in a controlled clinical trial setting. The purpose of this analysis is to evaluate nivolumab use in real world setting. Results: The general survival at 76 patients by metastatic NSLC receiving an immunotherapy nivolumab during the period from 2015 to 2019 is analysed. The minimum time of observation was 1.6 months. The median of the general survival made 7.6 months (5.92-9.41. DI 95%). The one-year survival - 35%, at the same time 3-year survival was 25%. At patients with the objective answer the median of the general survival was not reached. Immunomediated adverse events developed in 42% of patients, but only 6.6% showed the development of adverse events of 3-4 degrees, which indicates a favorable toxicity profile. Conclusion: the results received by us correlate with data of clinical trials.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with unmet needs of effective medications. Lenvatinib – a new oral multikinase inhibitor (MKI) proved to be as effective as sorafenib in terms of survival has been added recently to standard first-line treatment of advanced HCC. Regorafenib, another MKI in the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Cabozantinib and ramucirumab have all been shown to extend overall patient survival in sorafenib-refractory HCC patients and appear to have a reasonable safety profile. Immune checkpoint inhibitors therapy with nivolumab or pembrolizumab – monoclonal antibody to PD1-receptor are effective in about 15–18% of HСС patients presenting with long-lasting objective responses. Immunotherapy was safe in terms of viral hepatitis activation, but in comparative trials in first and second-line settings failed to achieve statistical difference in overall survival other sorafenib and placebo, respectively. Due to less toxic profile HCC immunotherapy seems to be a reasonable option to Child-Pugh B patients. Multiple ongoing trials are studying immune checkpoint inhibition alone or in combination with TKIs. The results of these trials will help determine the optimal choice, timing, and sequence of agents. This article reviews current situation in the field of new therapies of HCC from the point of common medical practice in searching for optimal second-line treatment decision in different clinical situations.

Nowadays neoadjuvant immunotherapy is one of the main research areas in oncology. This interest is supported by the success of check-point inhibitors in treatment of advanced and metastatic lung cancer. The postulate that neoadjuvant immunotherapy achieves tumor devitalization before surgery is confirmed by a morphological assessment of surgical material with a gradation of the antitumor effect. In addition to affecting directly to the tumor, it also affects at potential micrometastases. A morphological assessment with a gradation of the antitumor effect (MPR – a major pathomorphological response, CPR – a complete pathomorphological response) provides a unique opportunity to identify predictors of effectiveness and adjust the treatment tactic. A major morphological response (MPR – less than 10% of viable tumor cells in the tumor tissue) is associated with better overall survival. Currently, there is evidence that the appointment of neoadjuvant immunotherapy in mono mode allows you to achieve MPR in 18–45%, and the use of a combination of immunotherapy with chemotherapy increases it to 32–92%. Neoadjuvant immunotherapy or combination with chemotherapy does not postpone surgical treatment but allows us to achieve the better result.

Molecularly targeted therapy with tyrosine kinase inhibitors (TKI) has been recognized as the optimal treatment option for patients with EGFR-positive non-small-cell lung cancer (NSCLC). At present, 5 drugs of this group are available: first generation – erlotinib and gefitinib, second generation – afatinib and dacomitinib (not registered in Russia), and third generation – osimertinib. The drugs have some peculiarities, this refers to their antitumor activity, safety profile, and resistance mechanisms. Knowledge of these differences is necessary to determine a rational treatment plan. Gefitinib and erlotinib increase the time before progression compared to standard chemotherapy, but do not affect the overall survival rate. Afatinib significantly increases the time before progression, and in the cohort of patients with deletion in the 19th exon – the overall survival rate. Dacomitinib was more effective than gefitinib in terms of time before progression and total survival. On average, the disease progresses after a year and a half of successful treatment. The dominant mechanism of resistance development to TKI of the first and second generation consists in accumulation of mutation of the gatekeeper gene T790M. Most often it is determined in patients with deletion in the 19th exon (Del19). Osimertinib has proved to be effective against tumors not only with activating mutations, but also with T790M resistance mutation, and with minimal activity to EGFR «wild» type receptors. The first indication that it was registered was progression on targeted therapy with first and second generation drugs caused by the secondary mutation of T790M. Later, the advantage of osimertinib compared to gefitinib/erlotinib in untreated EGFR-positive patients was proved. Thus, there are at least two main options for treatment tactics: the consistent use of second and third generation drugs or prescription of osimertinib in the first line with subsequent chemotherapy. Evaluation and consideration of known prognostic factors will allow choosing the optimal tactics for a particular patient.

The standard approach for stage IB and IIIIIA non-small cell lung cancer (NSCLC), associated with the high risk of relapse, after total lung resection is adjuvant chemotherapy, nowadays. The 5-year survival benefit for this approach is about 5%, and the risk of relapse reduces from 11 to 15%, depending on the stage. However, the relapse rate within 5 years after surgery and adjuvant chemotherapy in stage IBIIIA NSCLC is up to 70%. This fact requires the search for new solutions. The efficacy and safety profile of targeted drugs in metastatic NSCLC show the possibility to use them as adjuvant therapy in the early stages of the disease. This approach was actively studied in patients with mutations in the EGFR gene, and the most promising were the results of the ADAURA trial, which had been studied the use of Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, as adjuvant therapy. The use of adjuvant targeted therapy in ALK-positive patients is currently less studied and its efficacy will be determined as the results of the ALINA and ALCHEMIST trials are obtained.

The urgency of the problem of treating patients with lung cancer is caused by a steady increase in the lung cancer incidence and lung cancer mortality rates in population. Most patients with NSCLC initially present with locally advanced or disseminated disease. Currently, simultaneous chemoradiation therapy (CRT) is the standard for the treatment of locally advanced NSCLC, which appears superior to the single chemotherapy or radiation therapy, while the overall survival (OS) rate remains not high enough. Therefore, the search for optimal combinations of chemotherapeutic drugs and radiation therapy (CRT), as well as fractionation regimens is a promising direction in the treatment of such patients. In this article, we will review the on-topic studies data that are currently available, future directions of the therapy and objectives.

Hepatocellular cancer (HCC) is a significant problem of modern Oncology. Until recently, sorafenib was the only drug in the treatment of locally advanced and metastatic HCC. Knowledge of the mechanisms of carcinogenesis and tumor escape from the immune response is the basis for immunotherapy in the treatment of malignant tumors and HCC, in particular. Сlinical trials have shown immunotherapy significantly improves the results of treatment of patients with locally advanced and metastatic HCC with controlled toxicity profile. Currently, nivolumab and pembrolizumab (сheckpoint inhibitors) have been registered as the second line of treatment after progression on sorafenib. Clinical trials are needed to identify optimal combinations of drugs and sequences of their use in different clinical situations.

Now the number of patients receiving immunotherapy with checkpoint inhibitors is growing. At the same time, clinicians increasingly encounter such a clinical phenomenon as pseudoprogression. Nowadays we have no radiological evidences of pseudoprogression. The every such case requires an individual decision.

In the open prospective non-randomized single-center study we recruited patients with advanced NSCLC harboring EGFR mutations. Initially there were two months of treatment by gefitinib 250 mg daily. Then, after a 2-week drug-free period, 3 cycles of paclitaxel 175 mg / m2 and carboplatin AUC5 were administrated at days 71-113. Thereafter, gefitinib was re-started on day 135 and continued until disease progression. The primary endpoint was progressive free survival (PFS) time. One-year PFS in all patients group included in the study at the time of the preliminary analysis was 79.8%, median PFS was 17 months (13.5–23, CI 95%). In the group of integrated chemotherapy one-year PFS was 89.3%, median PFS was 19 months (14–23.5, CI 95%).

Small-cell lung cancer (SCLC) is one of the most prognostically unfavorable malignant tumors for which an effective targeted inhibitor has not yet been found. Cytotoxic therapy for SCLC has not changed in the last thirty years. Immunotherapy is a fundamentally new method of treatment of malignant tumors, which has proven its effectiveness in various solid tumors. Fundamental prerequisites for the efficacy of immunotherapy in SCLC include a high level of mutational load and paraneoplastic syndromes typical for SCLC (Lambert - Eaton syndrome, etc.), leading to immunization against the tumor; factors that may adversely affect the efficacy of immunotherapy are low levels of PD-L1 expression, low content of T-lymphocytes infiltrating the tumor, and loss of histocompatibility of SCLC antigens by tumor cells. The first studies that studied the efficacy of CTLA-4 inhibitors in the first line of therapy of SCLC and PD-L1/PD-1 inhibitors during progression after the first line showed ambiguous results. However, the study to evaluate the efficacy of athezolizumab (antibody to PD-L1 receptor) in combination with chemotherapy in the first line of SCLC, where for the first time in 30 years in the studies of phase 3 at disseminated SCLC a significant increase in the total survival rate was shown. The study of immune control point inhibitors in SCLC, both localized and disseminated, continues, the prospects of immunotherapy in SCLC are already clearly defined, and further development and improvement in one of the most adverse forms of cancer is expected.

Ceritinib is the second ALK tyrosine kinase inhibitor after crizotinib, registered in the Russian Federation for the treatment of ALKpositive patients with non-small cell lung cancer (NSCLC). Later alectinib was registered. Thus, we have the opportunity, firstly, to continue targeted therapy with second-generation drugs after progression on crizotinib, and secondly, the appointment of more active drugs in the first line provides the best results of treatment.

Targeted therapy is the optimal treatment of patients with advanced EGFR-positive NSCLC. The first- and second-generation EGFR tyrosine kinase inhibitors provide a durable antitumor response in most patients during the year. Due to appearance of T790M secondary mutation of resistance at progression of the disease, the administration of osimertinib leads to full control of the tumour for another 10 months. However, this is not the only mechanism of acquired drug resistance. A repeated biopsy of the tumour followed by histological and molecular genetic research makes it possible to clarify the cause of resistance and personalize the further disease management.

At the present time, a small group of patients with oligometastases (who have a solitary metastatic lesion in another organ along with the primary tumour of the lung) is differentiated among the patients with metastatic lung cancer. A total of 14 patients of the study citied in this article underwent a comprehensive treatment of oligometastatic non-small cell lung cancer (ONSCLC), which included systemic therapy and local influence on solitary metastasis. The median overall survival for this group was 20 months (16.0–32.6, CI 95%). The 1-year and 2-year overall survival rates accounted for 84.5 and 65.7%, respectively. The findings of the study demonstrate the possibilities of an aggressive approach to the treatment of patients with ONLDLC.

Choice of the optimal therapy for BCLC-B hepatocellular carcinoma (HCC) is a significant clinical problem. Transarterial chemoembolisation (TACE) is considered to be the method of choice as this approach is reported to produce a direct effect and to have a significant survival rate. However, TACE is not always applicable and produce a survival benefit due to the clinical heterogeneity of BCLC-B HCC. The article includes different approaches for BCLC-B HCC patients, TACE prediction and refractory criteria as well as the results obtained. The necessity of timely sorafenib systemic therapy in BCLC-B and in advanced HCC after TACE is discussed. Practical application of regorafenib as the second line in HCC systemic treatment is discussed.

Pharmaceutical therapy of hepatocellular carcinoma represents a major clinical issue of debate in modern oncology. Until now, Sorafenib remains the only option for the management of locally advanced and metastatic hepatocellular carcinomas, which increases the overall survival of patients. In the absence of alternative treatment, the oncologist understanding of the place, time, the strategic goal and tactical objectives of the pharmaceutical therapy of hepatocellular carcinoma at different stages of cancer is of great importance. The article considers the practical aspects of the Sorafenib therapy of hepatocellular cancer in various clinical situations, and proposes algorithms of accompanying therapy for the underlying liver pathology. It presents the results of Regorafenib therapy, a new multi-kinase inhibitor, which significantly increases survival in the second line therapy of sorafenib-resistant hepatocellular carcinoma. The options of pharmaceutical therapy for hepatocellular carcinoma using cytotoxic and molecular-directed medicines, prospects of modern immunotherapy are discussed.

The advances in molecular biology have had a considerable influence on the medicinal treatment of patients with small cell lung cancer (NSCLC). The discovery of targets and development of drugs for molecular-targeted action improved the results of therapy of a specific group of patients. Translocation (rearrangeable) gene ROS-1 is quite rare – only in 1.7 percent of NSCLC patients. In addition to the genetic characteristics of the tumor, there are a number of morphological features that differentiate these patients from the general population. The most important is the fact that ROS-1 positive patients were very sensitive to crizotinib-tyrosine kinase inhibitor of ALK, MET and ROS1. Immediate effectiveness and long-term results of the use of crizotinib in this category of patients was even higher than the ALK translocation in the tumor. Therefore, it is advisable for patients, particularly with adenocarcinoma of the lung, in the absence of EGFR mutation and ALK to conduct molecular-genetic testing to determine ROS1. Individual approach to the choice of treatment strategy, timely correction of undesirable effects can greatly extend the life of NSCLC patients and improve its quality.

Immunotherapy presents a new promising approach to the treatment of disseminated lung cancer. Pemriblisumab (Kitruda®) is one of the antiPD-1 drugs registered in Russia, which is used in both the secondand, in the event of high-level PD-L1 expression (≥50%), the first-line therapy. This paper presents a clinical observation of a highly efficient pemribrolizumab treatment of a patient with metastatic adenocarcinoma.

Introduction. Patients with advanced small cell lung cancer (SCLC) have an extremely poor prognosis on the background of standard chemotherapy combination of etoposide and platinum-based drugs. In a randomized, double-blind of СА184-156 phase III study, the efficacy and safety of ipilimumab (immune checkpoint inhibitor) or placebo in combination with etoposide and platinum drugs were evaluated as the first-line therapy of disseminated SCLC. The article deals with the results of treatment of patients with advanced SCLC, who participated in the international multicenter phase III study CA184-156 in two Russian Research Centers: the Department of chemotherapy (33 patients) and the Department of diagnostic (23 patients) N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. Materials and methods. Randomization of patients was carried out in a ratio of 1:1 in the group of therapy: etoposide + platinum drug (carboplatin or cisplatin) + ipilimumab and etoposide + platinum drug + placebo. Ipilimumab/placebo was administered at a dose of 10 mg/kg every 3 weeks in parallel with the third and fourth cycles of chemotherapy, further two administrations of ipilimumaba/placebo were performed at intervals of 3 weeks. Further, in the absence of progression, the maintenance therapy with ipilimumab/placebo was performed every 12 weeks. The main endpoints of the study were the assessment of progression-free survival (PFS) and overall survival (OS). Results. In the study CA184-156, the median PFS was 4.6 months in the chemotherapy group with ipilimumab (95% CI 4.5-5.0) and 4.4 months in the chemotherapy group with placebo (95% CI 4.4-4.6). There were no statistically significant differences. The analysis of 56 patients in the subgroup in our centers showed similar findings of median PFS: 4.4 and 4.3 months, respectivelyIn the study CA184-156, the median OS was 11 months in the chemotherapy group with ipilimumab (95% CI 10.5-11.3) and 10.9 months in the chemotherapy group with placebo (95% CI 10-11.5). There were no statistically significant differences. The analysis of 56 patients in the subgroup in our centers showed the following results: median OS was 9.7 months (95% CI 7.8-14) and 10.7 months (95% CI 6.5-20.1), respectively. The multifactorial analysis confirmed the significant effect of such factors as: ECOG 1/2 performance status and age on PFS, and ECOG 1/2 performance status and scheme of chemotherapy (etoposide + cisplatin/etoposide + carboplatin) on OS. Unexpected adverse events in the group of chemotherapy with ipilimumab were not noted. Conclusion. The addition of ipilimumab to chemotherapy did not contribute to an increase either in PFS or in OS in comparison with chemotherapy alone for advanced SCLC patients. Unexpected adverse events in the group of chemotherapy with ipilimumab were not noted. The study of the efficacy of ipilimumab in patients with disseminated SCLC in combination with PD1 inhibitors (nivolumab) is ongoing. The results obtained in the analysis of the data in the subgroups of patients, who participated in the study on the basis of the Department of chemotherapy (33 patients) and Department of diagnostic (23 patients) of N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation corresponded to the data received in the entire multicenter study CA184-156.

Targeted therapy has opened a new era in treatment of patients with non-small-cell lung cancer associated with mutations of the epidermal growth factor receptor (EGFR) gene. However, most patients after starting targeted therapy develop progression within 10-12 months. The basic mechanisms of acquired resistance are known, the secondary mutation in exon 20 of EGFR gene is the leading cause in more than a half of the cases. To detect this mutation is important to repeat molecular testing, that, consequently, requiring re-biopsy. Liquid biopsy is considered as an alternative to re-biopsy. Osimertinib is a third generation EGFR-tyrosine kinase inhibitor, possessing antitumor activity, both, in respect of T790M-positive tumors and of tumors with mutations in exons 18, 19 and 21. In the randomized AURA3 trial, the use of osimertinib was effective in 71% of patients, the median progression free survival was 11 months after the progression on1st-line targeted therapy and was statistically significant than in case of chemotherapy application. Patients with brain metastases also show response to osimertinib treatment. In our study, 29 patients received osimertinib after the progression on targeted therapy of the 1st and 2nd generation tyrosine kinase inhibitors. Objective response was reported in 44.8% (complete response - 3.4%), stabilization - 51.7% and progression - 3.5%. We will show the results concerning the time without progression in the near future. The tolerance of treatment is good. Osimertinib has been approved for 1st-line targeted therapy treatment of patients with the T790M mutation upon progression in Russian Federation, thus we have new opportunities to improve the results of the treatment in this group of patients.