Kostroma Research Institute of Agriculture

Abstract Background: BCD-217-2/OCTAVA (NCT05732805) is an international, multi-center, randomized, double-blind, placebo-controlled phase III study conducted to access the efficacy and safety of prolgolimab+nurulimab (BCD-217) combination therapy with continued prolgolimab therapy compared to prolgolimab monotherapy as 1st line treatment for patients (pts) with unresectable or metastatic melanoma (un/mM). BCD-217 is a fixed-dose combination of nurulimab (aCTLA-4, 5 mg/ml) and prolgolimab (aPD-1, 15 mg/ml) was recently approved as the 1st line treatment for un/mM in Russia. Here we present the primary analysis of the study. Methods: Pts with unresectable or metastatic cutaneous melanoma (IIIC-IVM1a-c) with treatment- naïve for unresectable/metastatic disease were randomized in 2 treatment arms: combination drug containing nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) at a dose of 0.2 ml/kg Q3W during the first four blinded infusions (nuru+prolgo arm) and prolgo arm received prolgolimab monotherapy at a dose of 3 mg/kg Q3W during the first four blinded infusions. Then both arms received prolgolimab maintenance up to two years. The primary endpoint of the study was progression-free survival (PFS). Results: 271 pts were randomized to nuru+prolgo (n=135) or prolgo monotherapy (n=136) arms. After the median of 15.8 mo follow-up the median PFS (mPFS) was 15.4 (10.3; ND) mo in the nuru+prolgo group and 10.8 (4.7; ND) mo in the prolgo monotherapy group (95% CI, HR 0.68 (0.482; 0.957), iRECIST). The mPFS benefit of nuru+prolgo arm compared to prolgo arm are maintained in RECIST 1.1 assessment: 9.9 mo vs 2.8 mo, respectively. ORR and DCR were also higher in NURU+PROLGO arm. mOS was not reached in both groups (95% CI, HR 0,88, (0.50; 1.55)). 12-mos OS was 84% in each arm. Grade 3-4 treatment-related AE were reported in 16.3% of pts in nuru+prolgo arm compared to 14.0% - prolgo arm. Immune-related AEs (irAE) of all grades were reported in 52.6% of cases in nuru+prolgo arm and 32.4% of cases - in prolgo arm (p 0.0007). Majority of them were mild. The proportion of gr.≥3 irAEs was 13.3% vs 5.9% in nuru+prolgo arm and prolgo arm, respectively (p 0.04). Treatment discontinuation due to AE was reported in 9.6% of cases for nuru+prolgo vs 4.4% of cases for prolgo arm. Conclusions: OCTAVA trial resuts demonstrated that the fixed-dose combination of nurulimab + prolgolimab is significantly more effective than aPD-1 monotherapy without a serious deterioration of the safety profile in patients with metastatic or unresectable cutaneous melanoma as 1st line therapy. Citation Format: Lev Demidov, Igor Samoylenko, Galina Kharkevich, Kristina Orlova, Vladimir Moiseenko, Igor Utyashev, Daniil Stroyakovskiy, Vadim Kozlov, Anastasia Mochalova, Svetlana Demidova, Marina Lyadova, Andrey Kutkovich, Pavel Skopin, Nadezhda Kovalenko, Sufia Safina, Vitaliy Volkov, Yulia Semiletova, Vera Vaschenko, Nikolaiy Kislov, Artem Poltoratsky, Irina Shumskaya, Sergey Kolomiets, Alexander Sobolev, Igor Belogortsev, Svetlana Odintsova, Sameer Rastogi, Timur Andabekov, Anastasia Zimina, Konstantin Penkov, Anna Semenova, Alexey Obukhov, Vasiliy Belyakovsky, Oleg Gladkov, Rakesh Neve, Natalia Falaleeva, Elena Poddubskaya, Amale Vaibhav, Dmitriy Kirtbaya, Yana Chapko, Maria Smagina, Irina Sorokina, Yulia Linkova, Arina Zinkina-Orikhan, Fedor Kriukov, Anton Lutsky, Evgenia Mikhailova. Proved clinical benefit of low-dose anti-CTLA4 + anti-PD-1 immunotherapy versus mono anti-PD-1 therapy in patients unresectable or metastatic melanoma: Phase III OCTAVA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 653.

INTRODUCTION: Uveal melanoma (UM) is an oncological disease, which develops metastases mainly to the liver. One of treatments for this pathology is isolated hepatic chemoperfusion (IHCP). The implementation of this method requires surgical isolation of the liver from the systemic circulation and the use of a heart-lung machine. Due to a small number of observations of this treatment method in the world, the optimal vascular access for its implementation has not been determined so far. AIM: To analyze the in-hospital results of IHCP in patients with UM metastases performed from three different vascular accesses. MATERIALS AND METHODS: Over three years, 38 IHCP procedures were performed of the Kostroma Clinical Oncological Dispensary. Depending on the vessels into which the cannula for perfusion with Melphalan was inserted, patients were divided into 3 groups: group 1 with cava-porto-arterial access (perfusion into the inferior vena cava, portal vein, and common hepatic artery), n = 14; group 2 with cava-arterial access (perfusion into the inferior vena cava and common hepatic artery), n = 21; group 3 with a forced access, n = 3. The study took into account major complications: death, bleeding; and minor complications: tumor lysis syndrome, abscess of the left lobe of the liver, peritonitis, a systole, deep vein thrombosis of the lower limbs, hydrothorax, acute liver failure, anasarca, polyserositis, ischemic cholangiopathy, thrombosis of the common hepatic artery, detachment of the common hepatic artery intima. A combined endpoint was the achievement of at least one of the listed complications. In case of several complications in one patient, they were not summed up and were considered as ‘1’. RESULTS: In the postoperative period, the highest number of bleedings including those requiring revision, was noted in groups 1 and 3. The combined endpoint in the total sample made 42.11% and was lowest in group 2. Fatal outcomes were recorded in 3 cases (2 in group 1 and 1 in group 2), and were caused by increasing liver failure. CONCLUSION: The lowest number of complications IHCP was identified with cava-arterial access. Further continuation of the study is necessary to investigate the immediate and remote outcomes of IHCP.

IntroductionCarotid endarterectomy (CEA) is a surgery aimed at removing atherosclerotic plaque from the carotid artery. There are classical and eversion CEA techniques. The eversion technique is the most popular because it does not require the use of implants. Eversion CEA is also associated with a lower risk of restenosis in the late postoperative period. During the surgery, the carotid artery is clamped and blood flow to the brain comes from the contralateral carotid artery and vertebral arteries. However, if the circle of Willis (COW) is not closed, compensatory mechanisms for protecting the brain are reduced, which can lead to the development of an intraoperative stroke.PurposeTo analysis of in-hospital and long-term CEA outcomes in patients with different types of closed and non-closed COW.MethodsThis is a multicenter Russian study. In the period from 2010 to 2020. 641 eversion CEA were performed. Depending on the type of structure of the COW, six groups of patients were formed: Type 1 - Closed posterior part (CRS) - in the presence of the posterior communicating (PCOMA) and P1 segment of the posterior cerebral (PCA) arteries; Type 2 - Intermediate type of structure of the posterior part (ISRP) - with hypoplasia of PCOMA or PCA; Type 3 - Open back part (OBP) - in the absence of PCOMA or PCA; Type 4 - Closed anterior part (CFS) - in the presence of the anterior communicating artery (ACOMA) and the A1 segment of the anterior cerebral artery (ACA); Type 5 - Intermediate type of anterior part structure (IFPS) - with ACOMA or ACA hypoplasia; Type 6 - Open Front Section (OFS) - in the absence of ACOMA or ACA. The long-term follow-up period was 107.3 ± 14.6 months. The end points of the study were death, ischemic stroke, transient ischemic attack (TIA), myocardial infarction (MI), ICA thrombosis, hemodynamically significant restenosis of the internal carotid artery, bleeding, and combined endpoint (death + ischemic stroke + TIA + MI).The type of distribution was determined using the Kolmogorov-Smirnov criterion. Group comparisons were performed using the Kruskal-Wallis and Pearson chi-square tests. Differences were assessed as significant at p < .05. According to clinical and demographic characteristics, the majority of patients were male and elderly. In 20% of cases, patients had a history of MI and/or stroke/TIA. Diabetes mellitus was diagnosed in 10%. There were no significant differences between groups in EuroSCOREII.ResultsIn the long-term postoperative period, the largest number of deaths occurred in groups 5 and 6 (13 (45.1%) and 12 (30.1%)). The majority of strokes were diagnosed in groups 3 (OBP) and 5 (IFPS) (7 (13.5%) and 9 (17.6%)). The highest value of the combined end point (death + stroke/TIA + MI) was obtained in groups 3 (OBP), 5 (IFPS), and 6 (OFS) (23 (44.2%), 26 (50.1%), and 23 (58.9%)).ConclusionThe eversion technique of carotid endarterectomy for carotid artery stenosis is the most preferred. The greatest number of complications of eversion CEA in the hospital and long-term follow-up periods is observed in patients with OBP, IFPS, and OFS. In the presence of an unstable plaque, a temporary shunt can be used, which will exclude the pharmacological increase in blood pressure and the associated risk of embolization.

e21514 Background: Metastatic uveal melanoma (mUM) continues to have a poor prognosis with distinct biology from cutaneous melanoma and limited effective treatment options. The main options include immunotherapy (IT, anti-PD-1+/- anti-CTLA-4, tebentafusp), chemotherapy, targeted therapy and local treatment methods for patients with isolated liver metastasis (isolated hepatic perfusion, transarterial chemoembolization, percutaneous hepatic perfusion, radiofrequency ablation). Methods: We conducted a single-center retrospective observation IRB-approved study of first-line therapy for pts age 18 and older with mUM treated at the N.N. Blokhin National Medical Research Center of Oncology from 2020 to 2023. Our objectives were to evaluate clinical outcomes in real-world settings, as well as treatment patterns, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs). Results: A total of 125 pts included. The mean age was 54 yrs (range: 20-74), and the median time to metastasis from primary tumor was 2 years (range: 0-21). Liver metastases were diagnosed in 92% of patients, lung metastases in 20%, bone metastases in 17%, and soft tissue metastases in 9%. Conclusions: Our data suggest that the combination of systemic and local liver-directed treatment methods may be associated with a survival benefit and higher treatment response to IT in patients with mUM. [Table: see text]

Uveal melanoma is a rare malignant neoplasm originating from the uveal tract of the eye. The liver is the most common site of metastasis, occurring in 70—90% of cases and becoming the sole site of metastasis in approximately 50% of observations. This literature review presents modern methods for treating liver metastases from uveal melanoma: immunotherapy, targeted therapy, oncolytic adenovirus therapy, chemoembolization, transarterial chemoembolization, drug-eluting bead therapy, immunoembolization, radioembolization, thermal ablation, isolated hepatic perfusion. The conclusion is drawn about the highest efficacy, safety, and availability of isolated hepatic perfusion compared to other treatment methods.

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923). Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed. Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies. Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone. Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

The use of an artificial circulation and endovascular technologies in the treatment of liver metastases of uveal melanoma is a highly relevant area. Uveal melanoma is a rare cancer from the uveal tract of the eye. The liver is the most common site of metastasis and is affected in 70-90% of cases, being the only site of metastasis in about 50% of cases. Survival ranges from two to three months. This literature review describes the following methods of treatment of liver metastases of uveal melanoma using a heart-lung machine: arterial (arterio-caval), portal (porto-caval), arterio-porto-caval, retrograde arterio-portal. Special attention is paid to the endovascular method of treatment.Literature sources were searched in the following electronic libraries: elibrary.ru, pubmed.ncbi.nlm.nih.gov, researchgate.net.

We have described a variant of the structure of the vertebral artery. In the V3 segment, the vertebral artery bifurcated and then joined again. This building looks like a triangle. Such anatomy has not been previously described in the world literature. By the right of the first description, this anatomical formation was called the «vertebral triangle of Dr A.N. Kazantsev». This discovery was made during stenting of the V4 segment of the left vertebral artery in the most acute period of stroke.

Objective. To analyze the immediate results of carotid endarterectomy (CEE) with selective use of temporary bypass. Material and methods. A multiple-center retrospective study included 4967 patients with internal carotid artery (ICA) stenosis between January 2005 and October 2020. All patients underwent classical carotid endarterectomy with patch repair. Depending on intraoperative bypass, all patients were divided into 3 groups: group 1 (n=1328, 26.7%) — bypass due to low retrograde blood pressure in ICA (&lt;60% of systemic pressure); group 2 (n=1853, 37.3%) — no bypass due to satisfactory retrograde pressure (≥60% of systemic pressure); group 3 (n=1786, 35.9%) — no bypass (retrograde pressure in ICA was not measured). Mean time for installing the shunt in group 1 was 46.2±17.6 s. We describe insertion of a shunt using illustrations and discuss the main nuances of this procedure. The proposed stages of shunt placement can underlie training of residents and young vascular surgeons. Results. In-hospital incidence of lethal outcomes (p=0.62), fatal (p=0.96) and non-fatal myocardial infarctions (MI) (p=0.73), fatal stroke (p=0.54) and non-fatal stroke/transient ischemic attacks (TIA) (p=0.12) was similar. However, the largest number of «mute» stroke was recorded in patients with shunt (group 1: 2.56%, n=34; group 2: 0.5%, n=9; group 3: 0.55%, n=10; p&lt;0.0001). This condition affected the maximum values of the combined endpoint (taking into account «mute» strokes) that was significantly higher in group 1 (group 1: 3.3%, n=44; group 2: 1.02%, n=19; group 3: 1.56%, n=28; p&lt;0.0001). The greatest number of fatal ischemic strokes was recorded in patients with 60—80% stenosis in group 1 (p=0.02), 91—99% stenosis in group 2 (p=0.003) and group 3 (p&lt;0.0001). The majority of non-fatal strokes (1.8%; n=5) were found in group 3 with contralateral ICA stenosis 91—99% (p=0.0008). The largest number of «mute» strokes (4.4%; n=11) was recorded in group 1 with contralateral ICA stenosis 91—99% (p=0.02). Thus, the combined endpoint showed that stroke was significantly more common in patients with contralateral ICA stenosis 91—99% (group 1: 0.4%, n=6; group 2: 0.2%, n=6; group 3: 1, 85%, n=15; p&lt;0.0001). Conclusion. Intraoperative bypass was followed by higher incidence of “mute” strokes, and the combined endpoint was more common in this group. There were no significant differences in the incidence of non-fatal/fatal stroke, TIA, MI, lethal outcomes. Measurement of retrograde pressure did not always correspond to actual compensatory possibilities of collateral circulation. As a result, significant increase in the incidence of stroke was revealed in patients with contralateral ICA stenosis 60—80% despite normal retrograde pressure. In the 3rd group, we observed higher incidence of fatal and non-fatal strokes in patients with contralateral ICA stenosis 91—99%.