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. 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). 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. 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. 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.
Background. Cervical cancer (CC) is among the four most common malignancies among the female population. For a long time, platinum-based chemotherapy was the standard of care and practically the only option available. However, treatment outcomes for patients with metastatic and recurrent CC remained poor. The use of immune checkpoint inhibitors significantly increased progression-free survival and overall survival in this group of patients. Currently, pembrolizumab is a priority option in treating patients with metastatic, persistent, recurrent CC with CPS ≥ 1 and is included in international and Russian clinical guidelines. Aim. To evaluate the efficacy and safety of a pembrolizumab biosimilar (Pembroria®) in patients with metastatic, persistent and recurrent CC in the interim analysis of the PERFECTION observational study. Materials and methods. The study included a group of 51 patients diagnosed with stage IV CC. The treatment efficacy was analyzed using the Fleming method with the objective response rate criterion according to RECIST 1.1. Safety was assessed by the incidence of adverse events (AEs) and serious AEs according to the CTCAE 5.0 toxicity scale. Results. At stage g2, an objective response was reported in 24 (47.1%) patients, which exceeded the target threshold (22 responses). 5 (9.8%) patients experienced immune-mediated AEs, a total of 6 cases, including 1 case of grade 3 AE. The overall objective response rate was consistent with KEYNOTE-826, but the AE rate was lower (34.5% in KEYNOTE-826). Conclusion. Pembroria® has demonstrated efficacy comparable to that of the original pembrolizumab product and an acceptable safety profile. Differences in the incidence of immune-mediated AEs associated with Pembroria® require further study, considering the duration of observation and sample size. The results support using Pembroria® in routine clinical practice.
5536 Background: Here we present the final results of single-arm phase II CAESURA (NCT03912402) study of prolgolimab (anti-PD-1 antibody) with platinum doublet and bevacizumab in subjects with advanced cervical cancer (CC). Methods: 58 patients (pts) with metastatic or recurrent/persistent CC with measurable disease received prolgolimab (3 mg/kg) Q3W together with paclitaxel, platinum drug (cis- or carboplatin) and bevacizumab for 6 cycles and then therapy with prolgolimab and bevacizumab until disease progression or toxicity. Objective response rate (ORR) was assessed by central radiology review per RECIST 1.1 (primary endpoint) and iRECIST criteria. CT scans were performed after 9 and 18 weeks of treatment and in case of suspicion on disease progression. Results: Distant metastases at screening had 42 pts, 16 had recurrent or persistent CC. The median age of pts was 48 [38; 58] years old. Squamous cell carcinoma was diagnosed in 50 of 58 subjects. PD-L1 CPS ≥ 1 (22C3) was found in 45 pts, CPS < 1 in 6 cases. ORR per RECIST 1.1 was 63.8% (37 of 58 pts) and included 2 complete, 35 partial responses. ORR per iRECIST was 70.7% (41 of 58 pts) with 2 complete and 39 partial responses. At the cut-off date (12 months) PFS (secondary endpoint) per RECIST 1.1 criteria counted 8.5 (95% CI 5.7; 10.9) months, per iRECIST criteria it reached 13.1 (95% CI 8.1; 13.6) months. Median overall survival was not reached. Any grade adverse events (AEs) occurred in 98% (57/58) of pts, of them in 69% (40/58) they were related to study treatment, including 12 cases of severe events (gr. 3 or higher). Immune-related AEs (irAEs) occurred in 38% (22/58) of pts. The most common irAEs were gr. 1–2 endocrine disorders (26%), including thyroid disorders and one case of gr. 2 adrenal insufficiency. Other important irAEs included 2 cases of enterocolitis (gr. 3 and 4), 1 case of dermatitis (gr. 3), several cases of gr. 2–3 transaminase elevation (9%). In 15 pts at least one component of study treatment was discontinued due to AE, of them 4 events were related to study treatment (including immune-related enterocolitis and adrenal insufficiency). Conclusions: Prolgolimab in combination with chemotherapy and bevacizumab demonstrated promising efficacy, known and acceptable safety profile in pts with advanced CC. Phase III placebo-controlled trial evaluating prolgolimab with chemotherapy and bevacizumab (NCT03912415) as first-line therapy option in subjects with CC is ongoing. Clinical trial information: NCT03912402 .
BACKGROUND: Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disease. SMA is caused by a deficiency of the functional survival motor neuron protein (SMN) as a result of a mutation in the SMN1 gene. BIOCAD is developing a domestic gene therapy drug for the treatment of SMA based on recombinant adeno-associated virus serotype 9 (rAAV9) carrying the SMN1 gene (ANB4). In vitro evaluation of the functional activity of ANB4 will allow a more complete characterization of the drug. AIM: Development of an accurate and reproducible in vitro functional test that reflects the clinical mechanism of action of ANB4. METHODS: To model SMA, the SMN1 gene was knocked down by transfection with small interfering RNA. Amount of the SMN protein was measured by enzyme-linked immunosorbent assay. The functional activity of the drug was evaluated by analysis of Gemin2 protein level using the western blot analysis. RESULTS: Analytical method has been developed to assess the functional activity of the ANB4 drug for the treatment of SMA type 1 (rAAV9 carrying the SMN1 gene). The developed technique made it possible to obtain accurate and reproducible results. Production of Gemin2 after knockdown of SMN1 and the introduction of exogenous SMN1 gene was restored to control values, comparable with the restoration of the level of the SMN protein. CONCLUSION: The developed technique closely reflects the clinical mechanism of action of the ANB4 drug for the treatment of SMA. By evaluating the functional activity in vitro, accurate and reproducible results were obtained in accordance with the required standards, including the principles of 3R.
In this paper, we describe the development of a novel statistical potential for the prediction of antibody-antigen complexes (docking), which play key role in in silico immunotherapy discovery. The developed statistical potential is then used to improve the accuracy of an existing docking algorithm. We also present a new dataset for the development and comparison of different statistical potentials and docking algorithms. One of the key features of the developed dataset is that it can be obtained almost automatically, with few optional manual steps, using the pipeline introduced in this paper.
