Vol 27, No 3 (2025)

Background. Endocrinopathies are a subset of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICTI) immunotherapy, of which diabetes mellitus (irDM) is one of the most serious.

Aim. To describe peculiarities of DM development against the background of immunotherapy in patients with malignant neoplasms on the example of a series of clinical cases.

Materials and methods. Seven patients with melanoma, non-small-cell lung cancer and renal cancer aged 43 to 69 years, who developed DM against the background of immunotherapy (nivolumab, ipilimumab, pembrolizumab, atezolizumab both as monotherapy and combined treatment) were included in the retrospective study.

Results. Partial response was observed in 1 patient, stabilization – in 6 patients. The median of time before the development of DM was 10.13 months. Complications of DM were observed in 4 patients, and other irAEs developed in 5 patients. Fatal outcome was observed in 2 patients, due to progression of the underlying disease (1 patient) and development of coma due to insulin-dependent DM (1 patient).

Conclusion. IrDM is a rare but extremely serious complication of ICTI therapy that requires clear definition of diagnostic criteria. Identification of premorbid predictors of irDM may allow for targeted treatment trials and earlier detection of this complication of ICTI therapy.

Immune checkpoint inhibitors (ICIs) are widely used in the treatment of patients with solid tumors and lymphoproliferative diseases. However, these agents may cause immune-mediated adverse events, including the myelodysplastic syndrome (MDS) as a rare but serious hematologic side effect. The development of MDS during ICI therapy is usually associated with hyperactivation of the immune system, leading to autoimmune damage to the bone marrow. A clinical case of MDS (refractory anemia without sideroblasts) during ICI therapy is presented. In a 77-year-old patient with stage IV melanoma without a primary site, a persistent decrease in hemoglobin was noted during combination immunotherapy (ipilimumab 1 mg/kg + + nivolumab 3 mg/kg). During the examination, other causes of anemia were excluded – the most common being deficiencies of iron, vitamin B₁₂, and folic acid. A negative Coombs test and normal levels of bilirubin and lactate dehydrogenase ruled out erythrocyte hemolysis. A decrease in the reticulocyte count and the appearance of a significant fraction of immature forms suggested bone marrow dysfunction. Prednisolone and erythropoietin therapy led to only a slight increase in hemoglobin levels, precluding continuation of ICI immunotherapy. Due to the lack of response to supportive therapy, the diagnostic evaluation was continued, and an iliac bone marrow biopsy was performed. The morphological study showed refractory anemia without sideroblasts, an MDS variant. Therefore, the anemia was due to a clonal erythropoietic disorder. This case highlights the need for a comprehensive anemia diagnosis in patients receiving ICIs. In the lack of a response to immunosuppression, after excluding other possible causes of anemia in cancer patients, clonal hematopoietic disorders, including MDS, should be considered. The concomitant MDS requires a multidisciplinary approach to balance the efficacy of cancer therapy with hematologic risks.

Modern trends in oncological care are based on the principles of precision medicine, which necessitates the identification of prognostic and predictive molecular genetic markers. The results of genomic profiling of bladder cancer (BC) represent a wide range of genes involved in carcinogenesis, but the functional significance and clinical potential of most of them have not been sufficiently studied. The aim of this study was to summarize modern scientific and practical data on the trends in precision medicine in the field of oncourology in BC. The materials for the study were domestic and foreign scientific databases, in particular the National Library of Medicine (http://www.ncbi.nlm.nih.gov/) using the electronic resource PubMed (https://pubmed.ncbi.nlm.nih.gov/), eLIBRARY.RU (https://www.elibrary.ru/) and Google Scholar (https://scholar.google.ru/schhp?hl=ru), when searching by keywords: BC, urothelial carcinoma, NGS, molecular profiling, genes, FGFR3, TERT, PIK3CA, TP53, mutations, expression. An analytical review concerning clinical, pathomorphological and molecular genetic data on the problems of diagnosis and treatment of BC included reports on preclinical experimental and clinical studies, meta-analyses, systematic reviews, cohort randomized studies for the period 2002–2025. A number of studies have demonstrated the association of molecular genetic changes in genes encoding receptor and intracellular kinases (FGFR2/3, PIK3CA etc.) with early stages of BC carcinogenesis, provided that the multifactorial prognostic significance is variable, taking into account the availability of modern molecular-targeted drugs. In particular, a pan-FGFR inhibitor, erdafitinib, which has demonstrated its effectiveness, is currently approved for the treatment of common forms of BC. Taking into account the pathogenetic mechanisms, an important further prospect for the use of receptor and intracellular kinase inhibitors in BC is the development and introduction into clinical practice of highly selective systemic and locally delivered forms with the possibility of their use in clinically heterogeneous groups of patients, including those with early stages of the disease. In turn, alterations in genes responsible for DNA repair (TP53, etc.) are associated with an aggressive course of the disease and a corresponding less favorable prognosis. In this direction, the key point of application of personalized therapy is the development and use of agents capable of modulating the activity of proteins of the reparation system at various stages of carcinogenesis. Thus, the mutational and functional status of genes involved in key oncogenic and reparation pathways in BC plays an important role in the context of developing a prognostic model, and also serves as a predictive target for therapeutic intervention.

Background. For a personalized approach and the choice of treatment for patients with breast cancer (BC), the correct staging of the tumor process, including the assessment of the status of regional lymph nodes (LN), remains an important task. After the introduction of the sentinel lymph node (SLN) concept into clinical practice, it became possible to remove only one LN through which lymph drainage from the mammary gland occurs and to assess its status during urgent and planned histological examination. At the current stage of oncology and radiological diagnostic method development, SLNs are primarily detected using isotopic and fluorescent drugs. The most promising areas include the use of the SLN detection technique with an ultrasonic sulfur hexafluoride contrast medium. This technique is being gradually integrated into clinical practice due to its high diagnostic value; however, it is necessary to detail its diagnostic capabilities, develop utilization algorithms, and establish specific indications for its use.

Aim. To study the possibilities of using an ultrasound contrast medium, sulfur hexafluoride, in the SLN detection, to identify the main enhancement patterns, and to determine the contrast uptake features of SLN with metastatic lesions in patients with BC.

Materials and methods. The prospective study was conducted at the Department of Breast Pathology and the Imaging Department of the Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology from May to October 2024. This part of the study included 144 patients (91 with stage I surgery and 53 after neoadjuvant chemotherapy) with primary resectable stage I-IIIa BC (cT_1-3N_0-1M₀), the average age was 52.4 years. The detection technique using ultrasonic imaging was performed with paraareolar and intradermal injections of the sulfur hexafluoride contrast medium on the affected side. Imaging with contrast enhancement was performed on the Mindray Resona 7 Diagnostic Ultrasound System (PRC) with contrast function.

Results. The study detected SLN in 137 cases (out of 144), resulting in a detection rate of 95.1%. In most cases, 1 SLN was detected; in 24 (17.5%) patients, 2 SLNs were detected. In 7 (4.9%) cases, no SLN was detected (false negative results). There were 6 types (patterns) of contrast medium uptake: Type I (homogeneous, intensive), Type II (homogeneous, low-intensity), Type III (heterogeneous distribution of ultrasonic contrast medium with perfusion defects of <50% of the LN volume), Type IV (heterogeneous contrast enhancement with perfusion defects of >50% of the LN volume), Type V (annular), Type VI (contrast-enhanced lymphatic duct, without ultrasonic contrast medium uptake in the LN; LN structures are visualized in B mode). The most common patterns in metastatic disease were IV, V, and VI. Patterns I, II, and III were typical for LN with no signs of metastasis.

Conclusion. Detection of SLN using ultrasound contrast-enhancement technique is an easily available and reproducible method in clinical practice in patients with BC, and the assessment of the intensity of the accumulation and distribution of contrast medium with ranking by selected patterns may indicate the presence of metastases in the LN.

Background. Metastatic and unresectable melanoma is considered as one of the most aggressive oncological diseases with a high mortality rate. In Russia, two first line immunotherapy combinations have been approved: nivolumab plus ipilimumab (NIVO+IPI) and prolgolimab plus nurulimab (PROLGO+NURU). Both regimens use dual immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). However, the lack of direct randomized comparisons between these regimens makes it difficult to choose the optimal first-line therapy.

Aim. This analysis evaluated the relative efficacy and safety of PROLGO+NURU versus NIVO 1 mg/kg + IPI 3 mg/kg (NIVO 1 + IPI 3) and NIVO 3 mg/kg + IPI 1 mg/kg (NIVO 3 + IPI 1) in patients with metastatic and unresectable melanoma using matching-adjusted indirect comparisons (MAICs).

Materials and methods. A systematic literature review was performed in Embase and PubMed databases. Three phase III randomized controlled trials (RCTs) were included: OCTAVA (PROLGO+NURU, n=135), CheckMate 067 (NIVO 1 mg/kg + IPI 3 mg/kg, n=314), and CheckMate 511 (two regimens: NIVO 1 mg/kg + IPI 3 mg/kg, n=178; NIVO 3 mg/kg + IPI 1 mg/kg, n=180). Individual patient data (IPD) on outcomes and baseline characteristics for PROLGO+NURU were obtained from the OCTAVA trial. For the NIVO + IPI arms, IPD on overall survival (OS) and progression-free survival (PFS) were reconstructed using Guyot’s algorithm from the published Kaplan–Meier curves, and aggregated baseline-characteristic data were extracted. Pairwise unanchored MAICs were performed, weighting on key prognostic factors and effect modifiers: baseline lactate dehydrogenase levels, TNM-defined presence of distant metastasis (M-stage), Eastern Cooperative Oncology Group (ECOG) performance status, BRAF-mutation status, PD-L1 expression <5%, age, and sum of longest diameters of target lesions. To address partial population non-overlap – specifically, the absence of mucosal melanoma and of asymptomatic central-nervous-system metastases (after local control) in OCTAVA – a simulation-based modelling was applied. Efficacy outcomes were analyzed with Cox proportional-hazards regression, and safety outcomes with logistic regression.

Results. OS was statistically significantly higher in the PROLGO+NURU arm than in either NIVO 1 + IPI 3 or NIVO 3 + IPI 1 arms: hazard ratio (HR) 0.69 (95% CI 0.47–0.96; p=0.026) in the CheckMate 067 population, HR 0.64 (0.42–0.91; p=0.011) and HR 0.63 (0.41–0.89; p=0.008) – in the CheckMate 511 population versus NIVO 1 + IPI 3 and NIVO 3 + IPI 1 regimens, respectively. Differences in PFS were statistically insignificant. The PROLGO+NURU regimen also demonstrated a more favorable safety profile, with a lower incidence of treatment-related adverse events, including Grade 3–4 events and events led to treatment discontinuation.

Conclusion. MAICs results showed that the PROLGO+NURU regimen achieved statistically significant superiority in OS compared with the approved NIVO+IPI regimens in Russia (as of 2025). The PROLGO+NURU combination also displayed a more favorable safety profile, with fewer treatment-related adverse events, including Grade 3–4 events and events led to treatment discontinuation. It should be emphasized that the comparison is indirect and the horizon of the comparison was limited (by about 50 months in CheckMate 511 population and 65 months in CheckMate 067 population). Consequently, the findings should be interpreted cautiously. Further updates incorporating data for the longer follow-up, including real-world data, are recommended.

The treatment strategy for patients with locally advanced and disseminated renal cell carcinoma (RCC) has undergone significant changes over the past 10 years. The emergence of effective antitumor immune response checkpoint inhibitors and high-affinity multikinase inhibitors of the second generation, the introduction of prognostic factors to personalize treatment, as well as the optimization of the sequence and combinations of drug regimens, have significantly increased the survival rates of patients with advanced RCC. Cabozantinib is one of the high-affinity multikinase inhibitors of the second generation with proven antitumor activity and safety in patients with advanced RCC. The results of registration studies contributed to the introduction of cabozantinib, both as monotherapy and in combination with nivolumab, into international and Russian clinical guidelines for the treatment of RCC patients across a wide range of indications. The launch of Cabozantinib-Promomed on the Russian market expands access to this treatment option for patients with RCC. The article presents the results of clinical studies of cabozantinib in patients with locally advanced and disseminated RCC, as well as bioequivalence studies of Cabozantinib.

Background. A Russian phase IV observational study was initiated to evaluate the efficacy and safety of lenvatinib with pembrolizumab (Len-Pembro) in patients with advanced renal cell carcinoma (RCC) receiving therapy in real-world practice. This article is based on the results of the third analysis conducted with a median follow-up of 23.1 months and reflects data on the efficacy and safety of Len-Pembro in Russian patients.

Aim. To evaluate the real-world efficacy and safety of Len-Pembro in patients with advanced RCC with a median follow-up increased to 23.1 months. The primary outcome of the study was progression-free survival (PFS), the secondary outcomes included overall survival (OS), progression-free survival on next-line therapy (PFS2), objective response rate (ORR), duration of response, as well as safety.

Materials and methods. The study included data from 165 patients with verified advanced RCC who received Len-Pembro at 36 centers in the Russian Federation from February 05, 2018 to July 30, 2025. The median age was 60 (20–76) years, and 70.3% of the participants were male. Most patients (74.6%) presented with Karnofsky performance score of ≥80%, metachronous metastases (50.9%) of clear cell RCC (93.3%) in >1 organ (75.2%), and had not received any anticancer treatment (91.0%). The IMDC favorable prognosis group included 40 (24.2%), intermediate – 92 (55.8%), and unfavorable prognosis – 33 (20.0%) patients. The median follow-up reached 23.1 (0.5–72.9) months. A total of 110 (66.7%) patients completed Len-Pembro therapy, and 51 (30.9%) patients received next-line treatment.

Results. Median PFS reached 25.8 (95% confidence interval – CI 17.0–34.5) months, 23-month PFS – 52.6%; median OS was 39.9 (95% CI 26.9–52.8) months, 23-month OS – 73.1%; median PFS2 was 33.2 (95% CI 23.4–41.1) months, 23-month PFS2 – 66.9%. The ORR was 49.1%, including 3.0% of complete responses, and the disease control rate was 89.1%. The median duration of response reached 29.7 (95% CI 24.9–34.6) months. The incidence of any adverse events (AEs) was 78.8%, severe AEs occurred in 29.1%, fatal AES – in 1.2%, immune-related AEs – 17.0%, severe immune-related AEs – 6.7%.

Conclusion. In real-world practice, with increased follow-up duration, the values of PFS, OS, and PFS2 were comparable to those obtained in the registrational study, with a lower ORR and a satisfactory safety profile of the combination of Len-Pembro in advanced RCC.

Background. Locally advanced (laBCC) and metastatic basal cell carcinoma of the skin (mBCC) have a poor prognosis. Hedgehog (Hh) pathway inhibitors, such as vismodegib and sonidegib, are highly effective in treatment of advanced forms of BCC.

Aim. To evaluate the efficacy and safety of sonidegib in the investigator-initiated observational study B-SURE (Basal cell carcinoma – Sonidegib Use in Real-world Evidence) in patients with laBCC and mBCC in real-world clinical practice in the Russian Federation as first-line therapy (in patients with no history of treatment with Hh inhibitors), as well as in patients with a history of treatment with vismodegib (another Hh pathway inhibitor).

Materials and methods. The study included 10 patients, 9 with laBCC and 1 with mBCC. Patients visited clinical center in accordance with routine clinical practice and underwent standard procedures and examinations in accordance with clinical guidelines and the physician’s decision. Visit intervals were 3–4 months. Data on patients’ use of sonidegib was collected during visits to the clinical site, and the efficacy of sonidegib therapy was assessed according to RECIST 1.1 criteria. The patients also completed the EORTC QLQ-C30, version 3, and the EQ-5D-5L, version 1.2, before starting sonidegib therapy and every 3 months thereafter during routine visits to clinic.

Results. At the time of data analysis (September 2025), the efficacy of sonidegib therapy was evaluated in 9 patients, while tolerability and safety were evaluated in all 10 patients. Three patients had a history of vismodegib therapy, which was discontinued due to disease progression (n=1), intolerance (n=1), and intolerance with a complete clinical response (n=1). The median time from diagnosis to the development of laBCC and mBCC was 67.5 months. In patients with no prior vismodegib treatment, objective responses were observed in 4 of 7 patients (2 complete, 2 partial responses), yielding an objective response rate (ORR) of 57%. In patients with a history of vismodegib treatment, an objective response was reported in 1 of 3 (complete response in 1), yielding an ORR of 33.3%. The safety profile of sonidegib included adverse events (AEs) in 7 (70%) of 10 patients, mainly of Grade 1-2, which did not require a change in the dose regimen. Severe AEs (Grade 3-4) leading to discontinuation were reported in 1 patient (10%). It is noteworthy that in three patients with severe AEs during previous vismodegib therapy, sonidegib treatment was not associated with such complications, suggesting different safety profiles of these agents.

Conclusion. For the first time, the efficacy of sonidegib, with an ORR of 57%, was demonstrated in a Russian population of Hh inhibitor-naive patients with laBCC and mBCC. Sonidegib demonstrated an acceptable safety profile, with a low discontinuation rate (10%) due to AEs. Particular attention should be given to the favorable tolerability of sonidegib in patients with a history of severe toxicity during vismodegib therapy, which expands the therapeutic options in case of intolerance to another Hh-inhibitor.