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Background. Prior to the introduction of new agents — immune checkpoint inhibitors — for inoperable and/or metastatic melanoma (IMM), chemotherapy outcomes were generally poor. The median (Me) overall survival (OS) in IMM was no more than 6-9 months, and the Me of progression-free survival (PFS) was about 2 months. The introduction of immune checkpoint inhibitors and targeted therapy changed the prognosis for the life of IMM patients dramatically. The development, studies, and approval of a new original PD-1 inhibitor, prolgolimab, in Russia in 2020 prompted the professional community to conduct a prospective observational study in the Russian Federation to assess its real-world efficacy and safety. Aim To evaluate the real-world efficacy and safety of prolgolimab in patients with IMM. Materials and methods. From October 2020 to October 2022, 700 patients with IMM receiving prolgolimab in real clinical settings in oncological institutions of various levels in the Russian Federation were included in the study. The main inclusion criteria were: pathology-confirmed diagnosis of melanoma; metastatic and/or inoperable type; use of prolgolimab outside of clinical trials; and signed informed consent. Objective response rate in the general population and the Intention-to-treat and Per Protocol populations was considered the main criterion for evaluating the efficacy of therapy, and the safety criterion was the incidence of grade 3-4 adverse events (AEs). PFS and OS rates were also assessed. Statistical analysis was performed using the SPSS 25.0 software package. Results. The objective response rate for the Per Protocol population (with radiographic assessment available) was 42% (n=235/559). Disease progression was reported in 26.7% (n=149) of patients, stabilization in 31.3% (n=175), and disease control in 73.3% of patients with IMM, regardless of the line of therapy. At the follow-up Me of 12 months (0-36), PFS for all patients regardless of the line of therapy was 8 months (95% confidence interval [Cl] 6.537-9.463), 6-month PFS was 55%, and 12-month PFS was 41%. OS Me for all included patients was 32 months, 6-month OS was 82%, and 12-month OS was 69%. Depending on the line of therapy, the OS Me was: line 1 - not reached, line 2-30 months (95% Cl 16.007-43.993), line 3 and subsequent- 22 months (95% Cl 14.264-29.736); p=0.736. According to the CTCAE 5.0 general terminology criteria for AEs, a total of 136/693 (19.6%) AEs of varying degrees were reported, in particular: grade 1-2 - 105/693 (15.2%), grade 3-4 - 25/693 (3.6%), unknown grade - 5/693 (0.7%), as well as one fatal case (0.1%) due to thromboembolism in the vascular center with an unclear (according to the investigator's assessment) relation with prolgolimab. Conclusion The results obtained at 12 months of follow-up confirm the high efficacy and satisfactory tolerability of prolgolimab in patients with IMM in real-world practice, regardless of the line of therapy and other characteristics.

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).

Background. Novel agents immune checkpoint inhibitors fundamentally changed the prognosis for life in patients with metastatic and/or inoperable melanoma. The development, studies, and approval of a new original PD1 inhibitor in Russia in 2020 prompted the professional community to conduct a prospective observational study in the Russian Federation to assess the real-world efficacy and safety of prolgolimab, as real-world patients differ from the refined population in clinical trials. Aim. To evaluate the real-world efficacy and safety of prolgolimab in patients with metastatic and/or inoperable melanoma. Materials and methods. From October 2020 to October 2022, the study enrolled 700 patients with metastatic and/or inoperable melanoma receiving prolgolimab in real clinical settings in oncological institutions of various levels in the Russian Federation. The main inclusion criteria were: pathology-confirmed diagnosis of melanoma, metastatic and/or inoperable type, use of prolgolimab outside of clinical trials, and signed informed consent by the patient. Objective response rate (ORR) was considered the main criterion for evaluating the efficacy of therapy, and the safety criterion was the incidence of grade 34 adverse events. Statistical analysis was performed using the SPSS 20.0 software package. Results. The ORR for patients with skin melanoma treated with prolgolimab in the first line therapy (n= 207/337) was 48.3% (n=100), the disease stabilization was reported in 30.4% (n=63), and progression in 21.3% (n=44) of patients. There were no significant differences in response to therapy between patients with/withoutBRAFmutation, although ORR was higher in patients withBRAFmutation: the ORR for patients withBRAFmutation was 57.9% (n=33), and forBRAFnon-mutated patients, 44.4% (n=52;p=0.222). At a median follow-up of 5 months, the median PFS was 10 months (95% confidence interval 7.3512.64). The incidence of grade 34 treatment-related adverse events according to CTCAE 5.0 was 2% (n=12), and 12% (n=82) for grade 12 adverse events. Conclusion. The results confirm the high efficacy and satisfactory tolerability of prolgolimab in patients with metastatic and/or inoperable melanoma in real-world settings. There were no significant differences in ORR between patients with or withoutBRAFmutation.

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