Aim . To assess the efficacy and safety of lenvatinib and pembrolizumab for the treatment of mismatch repair-proficient endometrial cancer (EC) in routine clinical practice in Russia. Materials and methods . This multicenter, retrospective, cohort study included patients with recurrent and metastatic EC from 37 cancer centers in Russia treated between May 2020 and April 2023. Patients with histologically verified EC without microsatellite instability who received ≥1 course of pembrolizumab/lenvatinib therapy were included in the study. The primary endpoint was progression-free survival; the clinical characteristics of the patients were additionally analyzed, the objective response rate and the toxicity profile of therapy were assessed. Results . The study included 100 patients. Median age was 65 (30–83) years. The most common histologic tumor subtype was endometrioid adenocarcinoma (68 %); serous adenocarcinoma was diagnosed in 22 % of cases, other types of tumor – 10 % of cases. All patients had pMMR/microsatellite-stable tumors. The median progression-free survival was 7.75 months (95 % confidence interval 0.7–33.8), and a partial response to therapy was observed in 24 % of patients. Almost half of the patients (44 %) required dose reduction due to adverse events. The most common adverse events included fatigue (n = 26; 26 %), hypertension (n = 20; 20 %), and hypothyroidism (n = 14; 14 %). Conclusion . This study confirms the clinical efficacy of lenvatinib and pembrolizumab in patients with recurrent and metastatic EC without mismatch repair system deficiency (pMMR-tumors) in routine clinical practice.

Introduction. One of the key issues associated with the off-label use of antitumor drugs is safety. Typically, the advantages of such prescriptions in oncology are linked to the potential clinical benefits outweighing the risks of complications.Aim. To assess the safety of the off-label antitumor drug therapy in comparison with the on-label drug administration in the context of real clinical practice among oncologists in the Tula region.Materials and methods. The study was conducted at the Tula Regional Clinical Oncology Center, Russia. Over a six-month period in 2019, clinical data, provided by the regional information system, were analyzed for 919 completed treatment cases of 201 patients over 18 years of age who received antitumor drug therapy for malignant neoplasms. The study enrolled patients who had at least one hospitalization and got off-label antitumor drug therapy, as well as those receiving on-label drug treatment. The study assessed the safety of the off-label antitumor drug therapy in comparison with that of the on-label treatment, estimating the frequency of adverse events (AEs), spectrum of adverse events, severity of adverse events, fatal outcomes, treatment delays and discontinuations, and hospitalizations due to toxicity. A comparative analysis involved the results of using off-label and on-label antitumor drug therapy in terms of the aforementioned parameters. Results and discussion. No unforeseen adverse events were revealed in the study. The spectrum of adverse events encompassed 40 clinical and laboratory abnormalities with varying frequencies across the studied groups. Adverse events were observed in the majority of patients across both studied groups (83% and 86%). A predominance of grade I and II toxicity was noted. In some instances, therapy was discontinued and treatment was suspended; however, the frequency of these occurrences was significantly lower compared to current literature data. One fatal outcome due to complications from the administered therapy was recorded. All adverse events were reported in both studied groups with similar frequencies. The most commonly observed adverse events in both groups included hepatotoxicity, anemia, thrombocytopenia, nephropathy, cephalalgia, leukocytosis, skin toxicity, dyslipidemia, hypertension, bone pain syndrome, and dizziness. Other adverse events occurred sporadically with similar frequency. The most severe presentations were noted in the following adverse events: thrombocytopenia, gastrointestinal toxicity, leukocytosis, hyperglycemia, and immune-mediated diabetes mellitus with ketoacidotic coma.Conclusion. In real clinical practice, the safety of off-label and on-label antitumor drug therapy reveals no significant difference.

Background. Endometrial cancer (EC) treatment outcomes need to be improved. Immunotargeted therapy lead to long-term and delayed effects compared to chemotherapy. Estimation of long-term efficacy and quality of life are crucial when we are talking about efficacy in whole.Aim. To evaluate the long-term clinical efficacy of lenvatinib plus pembrolizumab therapy in patients with EC.Materials and methods. The study included 43 patients with stages I-IV EC with mismatch repair-proficient tumors and treatment duration of more than 9 months. We evaluated median progression-free survival, objective response, duration of treatment depending on the line of therapy, prevalence and type of adverse events, and correction regimens. Results. Lenvatinib plus pembrolizumab treatment was safe and efficacious in recurrent EC. Median of progression-free survival (patients with response or stabilization more than 9 months) is 10.2 months (95 % confidence interval 9.1-13.0), median of follow up is 9.7 (1.4-33.8) months. There were no complete responses, partial response was in 12 (28 %) patients, disease stabilization was in 31 (72 %) patients. Regarding safety, the overall rate of any-grade adverse events was 56.3 %. The most common treatment-related adverse events were fatigue (32.6 %), hypertension (23.3 %), and hypothyroidism (18.6 %). Dose reduction was performed in 22 (51.2 %) patients.Conclusion. The combination of lenvatinib plus pembrolizumab has long-term efficacy and manageable profile of safety. The presence of a significant pool of patients with durable response allows improving the survival rate of such patients in Russia.

Safety is recognized as a crucial issue of off-label use of anticancer drugs. The potential benefits of such prescriptions in oncology are associated with prevailing the expected clinical benefits over the risks of complications. However, in certain clinical situations with uncertain benefit/risk ratio, an off-label use of drugs may threaten the life and health of the patient. The present paper explores the safety of off-label anticancer drug therapy in real clinical practice. Health care and routine clinical practice are given particular emphasis on systematic recording and careful monitoring of adverse events associated with the off-label use of medicinal products. The creation of a unified registration system for off-label use of drug therapy in oncology along with the creation of large databases (on the sites of institutions with an option to combine the data obtained at the level of districts, regions and the country) enables a significant amount of information on the safety and effectiveness of this approach to be gathered. As a result, a predictable nature of treatment and manageable toxic effects are potentially provided. The study into reasons behind off-label use of drugs in oncology, as well as the study into spectrum and severity of adverse events resulting from the implementation of these prescriptions, will provide detailed information on the safety of off-label use of anticancer agents in patients with malignant neoplasms at different stages of oncological treatment.

Objective: to re-evaluate the efficacy and safety of lenvatinib with pembrolizumab in unselected Russian renal cell carcinoma (RCC) patients, included in the phase IV study, in a median follow-up extended to 17.1 months. The primary end point was progression-free survival (PFS), secondary end points were overall survival (OS), objective response rate (ORR) and duration of response (DOR), disease control rate (DCR) and its duration, as well as safety. Materials and methods. The study included medical data of 165 patients with verified advanced RCC who received lenvatinib with pembrolizumab in 36 centers of the Russian Federation from 05.02.2018 to 25.07.2024. The median age was 60 (20-76) years, the male to female ratio was 2.3:1. The majority of patients had Karnofsky performance status >= 80 % (74.6 %), clear cell RCC (93.3 %) without sarcomatoid differentiation (93.3 %), metachronous metastases (50.9 %) localized in >1 organ (75.2 %), were nephrectomized (63.0 %) and did not receive antitumor therapy (91.0 %). At the time of lenvatinib with pembrolizumab therapy start 40 patients (24.2 %) were classified into International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable prognostic group, 92 (55.8 %) in the intermediate prognostic group, and 33 (20.0 %) in the poor prognostic group. The median follow-up was 17.1 (1.5-72.9) months. Results. The median PFS achieved 24.0 (18.7-29.3) months, 17-month PFS- 60.5%. The median OS was 48.9 (18.5- 79.2) months, 17-month OS - 76.1 %. Objective response was registered in 46.0 % of patients including 2.4 % complete responders; the DCR was 92.1 %. The median DOR was 16.6 (2.1-72.9) months, duration of disease control - 14.3 (2.1-72.9) months. Confirmed dynamics of change in the sum of tumor foci diameters was recorded in 152 patients, while the median change was -25 % (from -100 % to +29 %). Any decrease in the sum of tumor foci diameters occurred in 69.1 % of cases. The incidence of any adverse events (AE) was 78.2 %, severe AE - 24.2 %, and serious AE - 9.7 %. Immune-mediated AEs developed in 17.0 % of cases and AE grades 3-4 in 6.7 % of cases. Mortality from AEs was 1.2 %. Conclusion. Compared with the registration study, in real-world clinical practice in patients with advanced RCC the lenvatinib with pembrolizumab provides a lower ORR with comparable PFS and OS rates and demonstrates a satisfactory safety profile.

The integration of precision diagnostics and therapy into the routine practice of oncologists, the active use of immune checkpoint inhibitors for the treatment of malignant tumors, and the improvement of diagnostic methods for rare forms of malignant tumors potentially increase the risk of the number of agnostic use of “off-label” anticancer drugs. The existence of these trends in the context of an increasing number of registrations of new antitumor agents and indications requires an active study of the reasons for the prescription of off-label antitumor drugs by oncologists. The study of the reasons for the use of off-label drugs in oncology will provide detailed information on the feasibility and safety of such prescriptions in patients with malignant tumors at different stages of the treatment of the tumor process. This article is devoted to understanding the reasons for prescribing off-label anticancer drugs in oncology

The implementation of adjuvant antitumor drug therapy, covering all patients who are prescribed this type of treatment according to a set of formal group criteria, provides a benefit for a separate category of patients, unjustifiably subjecting to therapy those who are cured and do not need this treatment, as well as a cohort of patients progressing against the background of adjuvant drug therapy. This article highlights the problems of uncertainty in the analysis of the potential benefits and harms of adjuvant therapy, as well as provides an overview of current research studying the use of molecular methods for deeper risk stratification and determining indications for adjuvant treatment in localized forms of malignant tumors.

The off-label use of anticancer drugs is widespread in modern oncology. The potential advantages of such prescriptions are associated with exceeding the expected clinical benefi ts over the risks of complications. The off-label use of anticancer drugs demonstrates the inconsistent efficacy of this approach depending on the type of malignancy, the reasons for prescribing these agents and their belonging to a particular pharmacological group. In a number of situations, the clinical benefits of off-label drugs are more convincing than in case of authorized indications. Currently, prescribing the “old” registered anticancer drugs, used in everyday clinical practice, is seen routine. However, labeling does not reflect the full range of indications with strong evidence of safety and efficacy. The paradigm shift toward molecularly targeted therapy and immunotherapy in various malignancies may increase the off-label use of the specified agents. Lack of treatment options for rare forms of malignancies and exhaustion of the possibilities for registered therapy are the major reasons for off-label prescribing targeted drugs based on the identifi ed molecular genetic disorders. In such cases, the concept of precision therapy is oft en implemented by using agents, the clinical efficacy of which is confi rmed by data with a low level of evidence or with no evidence. Studying the eff ectiveness of the off-label use of anticancer agents is necessary to systematize information and develop algorithms for making decisions about the prescription of these drugs in routine clinical practice.

Objective: to compare the efficacy and toxicity of aflibercept and bevacizumab in combination with fOLfIRI in secondline therapy for patients with metastatic colon cancer.Materials and methods. we performed a retrospective analysis of data on patients with metastatic colon cancer treated in 9 clinics in the Russian federation. The inclusion criteria were as follows: metastatic or locally advanced colon cancer; treatment with bevacizumab or aflibercept plus fOLfIRI in the second-line therapy. The primary outcome measure was progression-free survival (PfS). Secondary outcome measures included objective response rate and incidence of adverse events.Results. A total of 271 patients with metastatic colon cancer who received second-line therapy with bevacizumab (n = 81) or aflibercept (n = 190) between 2014 and 2018 were selected for this study. Study groups were matched for main prognostic signs. The objective response rate was 18.1 % in the bevacizumab group and 20.5 % in the aflibercept group (p = 0.7). The median PfS was 5 months (95 % confidence interval 3.8–6.1) in the aflibercept group and 7 months (95 % confidence interval 0.81–2.1) in the bevacizumab group (hazard ratio 1.4; 95 % confidence interval 0.99–2.1; p = 0.04). multivariate regression analysis demonstrated that the type of the targeted drug independently had no effect on PfS (hazard ratio 1.3; 95 % confidence interval 0.9–1.9; p = 0.2). we observed no statistically significant differences in the incidence of complications of any grades between the groups (58 % vs 72 %, p = 0.1). Patients receiving aflibercept were more likely to develop grade III–Iv arterial hypertension (2 % vs 9.5 %) and diarrhea (0 % vs 5.4 %), whereas thrombotic complications were more common in the bevacizumab group (10 % vs 1.8 %).Conclusion. we observed no significant differences in objective response rate and PfS between patients with metastatic colon cancer receiving bevacizumab or aflibercept in combination with fOLfIRI as second-line therapy. The toxicity profiles were different. Our findings can be used for choosing an optimal targeted drug for second-line treatment.

The off-label use of medicines is a routine clinical practice of oncology, especially in malignant-tumour patients with no treatment alternatives left when registered-drug options have been exhausted or standard therapies reveal contraindications. The recent shift from single-gene assays to multigene panels powered by full-exome or -genome sequencing expands the capacity of precision therapy, leading to a wider agnostic off-label use of targeted drugs for detecting a particular molecular genetic disorder. Studies of the off-label drug use in oncology will clarify the feasibility and safety of such prescriptions in patients with rare forms of malignancy when registered therapies have been exhausted or standard treatment reveals contraindications. This article examines the prevalence and landscape of off-label drug use in cancer patients and elaborates on the off-label principle. The paper presents a critical reflection on the off-label use of medicines in oncology.

Introduction. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.Aim. We sought to describe treatment patterns of eribulin and clinical outcomes of metastatic HER2-positive breast cancer treated with eribulin plus trastuzumab combination in academic institutions and community oncology practices across the Russian Federation.Materials and methods. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.Results. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.Conclusions. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients.

Objective: to identify factors associated with efficacy of an aflibercept-chemotherapy combination in patients with metastatic colon cancer. Materials and methods. This retrospective multicenter study was conducted in 20 clinics from 15 regions of the Russian Federation. The main efficacy outcome was progression-free survival (PFS). We performed univariate and multivariate analysis to assess the impact of various factors of PFS. Results. Two hundred and fifty-seven patients received aflibercept-containing chemotherapy; of them, 175 participants (68.1 %) received it as a second-line therapy. The objective response rate and median PFS were 18.7% and 5 months (95% confidence interval (CI) 4.2—5.8) respec -tively. The following factors were found to have a positive effect of PFS at multivariate analysis: grade I—II adverse events to aflibercept therapy (hazard ratio (HR) 0.58; 95 % CI 0.38—0.89; p = 0.01), therapy for concomitant diseases (HR 0.47; 95 % CI 0.29—0.76; p = 0.002), and ECOG performance status of 0 (HR 0.53; 95 % CI 0.34—0.81; p = 0.004). Patient with all 3 factors present had median PFS of 9 months, whereas patients without them demonstrated PFS of only 3 months (HR 1.9; 95 % CI 1.5—2.6; p <0.001). Conclusions. Satisfactory performance status, adequate therapy for concomitant diseases, and adverse events to aflibercept therapy were associated with better PFS in patients receiving aflibercept-containing chemotherapy.

Objective: to identify factors associated with efficacy of an aflibercept-chemotherapy combination in patients with metastatic colon cancer.Materials and methods. This retrospective multicenter study was conducted in 20 clinics from 15 regions of the Russian Federation. The main efficacy outcome was progression-free survival (PFS). We performed univariate and multivariate analysis to assess the impact of various factors of PFS.Results. Two hundred and fifty-seven patients received aflibercept-containing chemotherapy; of them, 175 participants (68.1 %) received it as a second-line therapy. The objective response rate and median PFS were 18.7% and 5 months (95% confidence interval (CI) 4.2—5.8) respec -tively. The following factors were found to have a positive effect of PFS at multivariate analysis: grade I—II adverse events to aflibercept therapy (hazard ratio (HR) 0.58; 95 % CI 0.38—0.89; p = 0.01), therapy for concomitant diseases (HR 0.47; 95 % CI 0.29—0.76; p = 0.002), and ECOG performance status of 0 (HR 0.53; 95 % CI 0.34—0.81; p = 0.004). Patient with all 3 factors present had median PFS of 9 months, whereas patients without them demonstrated PFS of only 3 months (HR 1.9; 95 % CI 1.5—2.6; p <0.001).Conclusions. Satisfactory performance status, adequate therapy for concomitant diseases, and adverse events to aflibercept therapy were associated with better PFS in patients receiving aflibercept-containing chemotherapy.

Aim. The aim of the study is to examine the efficacy and safety of eribulin in HER2-negative metastatic breast cancer (BC) in Russian clinical practice. Materials and methods. The analysis included 459 patients with advanced BC from 44 federal and municipal medical clinics in Russia and received at least 2 courses of treatment with eribulin in accordance with the registered indications for drug. The average age of women was 56 years (between 29 and 81 years), 83% of patients had HER2-negative tumor subtype (49.9% - luminal BC and 33.1% - triple-negative BC) HER2-positive biological tumor subtype was registered in 17% of patients. Visceral metastases were diagnosed in 73% of patients and three-zone and multiple zone metastases were diagnosed in 41.6% of cases. The median number of prior lines of therapy in patients with disseminated disease was 2; anthracycline and taxane chemotherapy was applied in 94.3% of patients, and 38.1% of patients were recived CT plus capecitabine. Standard treatment regimen with eribulin was cotinuing (1.4 mg/m² as a 2-5-minute intravenous infusion administrated on days 1, 8 of a 21-day cycle) until disease progression, unacceptable toxic effects, or impossibility of the drug administration for any other reason. We estimated the efficacy and safety of treatment with eribulin in Russian patients with HER2-negative BC. Results. Objective response rate was achieved in 20.5% of cases, complete response rate was in 3.2%, partial - 17.3%, and the stable disease rate was marked in 52.7% of women, and in 19.7% of these cases was prolonged more than 6 months. The frequency of objective response was higher in luminal BC group compared with triple-negative BC: 23.5% vs 15.8%; tumor growth control 76.9% vs. 67.8%, respectively; p

Understanding the mechanisms of acquired resistance to tyrosine kinase inhibitors is important for clinicians from the perspective of the possibility of forming more effective options for the second and subsequent treatment of non-small cell lung cancer. The prospects of treatment strategies for patients with non-small cell lung cancer featuring the acquired resistance to tyrosine kinase inhibitors, not associated with the Т790М mutation, are quite vast from a scientific point of view, but in routine clinical practice they are not yet available in full. This article describes the current understanding of the mechanisms of acquired resistance to tyrosine kinase inhibitors not associated with the mutation of T790M, the evolution of views concerning the treatment of non-small cell lung cancer, progressing in the course of the treatment by this group of drugs. The possibilities of effective use of targeted therapy and various combinations of antitumor agents in such cases are also considered. Taking into account the diversity of unresolved issues and directions of further scientific research, we should not forget about the available research results and the ability to use the described options in routine clinical practice in a proper way.

The prospects of treatment strategies for patients with non-small cell lung cancer (NSCLC) featuring the acquired resistance to tyrosine kinase inhibitors, not associated with the Т790М mutation, are quite vast from a scientific point of view, but in routine clinical practice they are not yet available in full. Understanding the mechanisms of acquired resistance to tyrosine kinase inhibitors is important for clinicians from the perspective of the possibility of forming more effective options for the second and subsequent treatment of NSCLC. The most studied and frequent mechanism causing the formation of the acquired resistance is the appearance of the Т790М mutation in 20 exons of the EGFR gene. This article describes the current understanding of the mechanisms of acquired resistance to tyrosine kinase inhibitors not associated with the mutation of T790M, the evolution of views concerning the treatment of NSCLC, progressing in the course of the treatment by this group of drugs. Taking into account the diversity of unresolved issues and directions of further scientific research, we should not forget about the available research results and the ability to use the described options in routine clinical practice in a proper way.

The article presents a pooled experience of the use of eribulin in the real clinical practice of treatment of metastatic breast cancer in Russian oncological institutions. The effectiveness of the drug in monotherapy with HER2‑negative breast cancer was analyzed, groups of patients with most effective use of eribulin were identified depending on the localization of metastases, the most effective lines of therapy. The effectiveness of the drug in combination with trastuzumab in HER2‑positive breast cancer is described, as well as toxic reactions.

A reasonable strategy for drug therapy of non-small-cell lung cancer (NSCLC) with activating mutations of EGFR is the use of tyrosine kinase inhibitors (TKI) in front-line therapy, providing a two-fold increase in life expectancy for patients with metastatic or locally advanced form of the disease. The results of several randomized trials determined and proved the role of Afatinib, the selective irreversible inhibitor of protein kinase receptors of the ErbB family, which consists in the following positions: a verifiable increase in progression-free period (PFP) as front-line metastatic EGFR-mutated NSCLC as compared to chemotherapy, regardless of the EGFR gene mutation type; the advantage in respect of overall survival (OS) as front-line therapy with frequent EGFR gene mutation in NSCLC, with Del19 in particular (OS increase by more than 1 year in comparison with chemotherapy); the advantage in progression-free survival (PFS), treatment time duration (TTD) as well as in objective response rate (ORR) in comparison with Gefitinib against metastatic EGFR-mutated NSCLC; therapeutic efficacy against brain metastasis and many rare mutations; dose adjustment of Afinitib with a view of its tolerability is an effective measure to decrease the drug-induced toxicity rate without affecting its therapeutic efficacy. This article also presents the results of clinical and economic research of the response and benefit of comparable drugs (Afatinib, Gefitinib and Erlotinib) for treatment of patients with NSCLC in the Russian Federation and the results of minor studies demonstrating the new opportunities of Afinitib and its combinations with other «partners». In particular, the efficiency of Afinitib use in the treatment of patients with HER2-mutated lung cancer is provided. In addition, the safety and efficacy of combinations of Afatinib + Bevacizumab and Afatinib + Cetuximab after the formation of acquired resistance to TKI is also noted, which can be used as a therapeutic option in case of Т790М mutation. Current controversial issues concerning the effectiveness of this drug with the new and other rare mutations, the allegedly incomplete cross-resistance against the previous two drugs of this group, lack of information about the therapeutic benefit of Afinitib in case of discordancy of the primary tumor and its metastasis call for further clinical research studies and refinement of diagnostic tests and systems.