e21602 Background: Risk stratification of primary cutaneous melanoma based on Breslow thickness remains clinically imperfect, particularly in thin tumors (≤1 mm), where a subset progresses unexpectedly. Previously, targeted RT-PCR analyses of established tissue RNA markers demonstrated prognostic utility mainly in thick melanoma, with no robust markers identified for thin tumors, prompting an unbiased RNA sequencing approach to address this gap.Objectives: Identify RNA expression signatures associated with prognosis in thin (≤1 mm) and thick (≥4 mm) primary cutaneous melanoma. Methods: RNA-seq was performed on primary tumor tissue from 51 thin and 65 thick melanomas after hybrid-capture library preparation and deep sequencing (NovaSeq 6000, S4). Expression was quantified for 18,146 genes, including full coding regions of 17,702 protein-coding genes (54,142 transcripts), using a standardized four-step pipeline with stringent filtering. Analyses were performed by clinical outcome (regional recurrence and/or distant metastases and/or death) and to build classifiers distinguishing thin vs thick melanoma. Results: In thin melanoma, 69 genes were differentially expressed by outcome; a 10-marker panel (BAIAP2L1, DMRT3, ENSG00000305404, HOXA11-AS, MGP, MIR1183, MUC6, NBPF17P, NANOS3, TMEM191C) showed the best prognostic performance (AUROC 0.835). In thick melanoma, 26 prognostic genes were identified; a 6-marker panel (EEF1A1P16, HSPA8P5, IBSP, MEX3B, MMP3, VAMP2) achieved AUROC 0.93. A shared 4-marker signature (MMP3, RGS1, SPP1, VAMP2) performed consistently across thin and thick tumors (AUROC 0.80). A 5-marker classifier (ALOX12, COL22A1, KRT10-AS1, S100B, SPP1) distinguished thin vs thick melanomas (AUROC 0.96), supporting distinct transcriptional programs linked to thickness and progression biology. Conclusions: RNA profiling reveals substantial prognostic heterogeneity within thin melanoma and identifies multigene signatures that may refine risk stratification beyond Breslow thickness. Divergent prognostic panels in thin vs thick tumors suggest distinct mechanisms of progression and support development of clinically deployable RNA-based assays for risk-adapted management.These signatures identify biologically aggressive subsets within thin melanoma that may warrant intensified surveillance or consideration of adjuvant strategies.

e21519 Background: While anti-PD-1 is the first-line (1L) standard for BRAFwt advanced melanoma (aM), disease progression (PD) occurs in over half of patients, requiring second-line (2L) strategies. The ipilimumab/nivolumab (Ipi/nivo), though frequently used in 2L, is limited by toxicity and financial burden, and its ability to overcome resistance to prior immunotherapy is unclear. We aimed to assess different 2L options and the potential of Ipi/nivo based on prior anti-PD-1 response. Methods: A retrospective observational study approved by the IRB was conducted at two Russian centers: N.N. Blokhin NMRCO and Moscow Oncology City Hospital 62. We included all pts aged ≥18 yrs with BRAFwt aM who progressed on anti-PD-1 and were treated or consulted in these centers in 2023. We assessed the PFS from the start of 2L to PD, OS from the start of 1L (OS1) and 2L (OS2) to death from all pts and PFS, OS1 and OS2 in the Ipi/nivo group regardless of previous best response to anti-PD-1: complete and partial response (CR and PR), stable disease (SD), PD. Results: A total of 86 pts were included, 38 (44,2%) male and 48 (55,8%) female, with a mean age of 61,2 yrs. The 2L options are presented in the Table below. 4 patients were re-administered anti-PD-1 in the 2L after PD and local treatment for PD. mPFS was higher in the Pem/Len group but no statistically significant differences (SSD) were observed between all groups for either PFS, OS1 or OS2. Among pts in the Ipi/nivo group nearly half progressed on anti-PD-1 at the first CT/MRI assessment (see the Table). Only 6,2% had an objective response to anti-PD-1 earlier (CR+PR). Generally, the PD group had the lowest survival rates (the exception of the PR group of 2 pts), although no SSD were found between groups in PFS, OS1, and OS2. Conclusions: Ipi/nivo remains the primary 2L option for BRAFwt aM. No SSD between subgroups were found. The highest PFS in the Pem/Len may be attributed to the mechanism of action of this combination. Previous responses to anti-PD-1 in 1L may influence the effect of Ipi/nivo. These results need to be interpreted with caution given its retrospective nature and small number of pts in groups. Total n=86 (100%) Ipi/nivon=65 (75,6%) CTX10 (11,6%) Pem/Len5 (5,8%) Anti-PD-14 (4,7%) Trame (NRAS+)2 (2,3%) mPFS, mo 3,5 (3,0 - 6,2) 2,63 (2,3 - Na) 11,7 (3,6 - Na) 4,65 (3,5 - Na) 1,15 (1,0 - Na) mOS2, mo 21,8 (17,5 - 34,3) 8,8 (4,7 - Na) 11,5 (Na - Na) 13,7 (10,9 - Na) 1,3 (Na - Na) mOS1, mo 36,2 (28,1 - 55,4) 13,8 (12,3 - Na) Na 58,4 (21,8 - Na) Na (21,9 - Na) Survival in Ipi/nivo (n=65) Best response on anti-PD-1 in 1L CR2 (3,1%) PR2 (3,1%) SD20 (30,8%) PD32 (49,2%) Unk9 (13,8%) mPFS, mo 3,8 (3,8 - Na) 5,9 (5,8 - Na) 5,1 (2,8 - 10,2) 3,0 (2,6 - 6,2) 3,9 (2,8 - Na) mOS2, mo 34,3 (34,3 - Na) 6,7 (6,7 - Na) 32,1 (17,9 - Na) 18,2 (13,43 - 31,6) 39,1 (9,8 - Na) mOS1, mo 65,9 (65,9 - Na) 23,4 (23,4 - Na) 48,1 (30,8 - Na) 24,6 (20,9 - 36,9) 55,4 (31,8 - Na)

9548 Background: Metastatic uveal melanoma (mUM) remains a rare and aggressive malignancy. Immune checkpoint inhibitors (ICI) demonstrate modest activity, and real-world evidence comparing dual (nivolumab + ipilimumab) versus anti-PD-1 monotherapy, as well as the additive role of local therapy is limited. Methods: Multicenter retrospective observational study conducted in Russia (IRB-approved at participating centers). Outcomes assessed: median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and grade ≥3 immune-related adverse events (irAEs). Stratified by treatment line, ICI type, and local therapy use. Univariable Cox proportional hazards regression was performed. Results: Patients with metastatic uveal melanoma treated between 2019 and 2025 were included (n=262). Of these, 25 patients (9.5%) who did not receive systemic treatment or received only palliative care were excluded. Among the full cohort: 158 (60.3%) were female, median age at primary diagnosis was 55.9 years, median time to metastatic disease was 2.42 years. Liver metastases were present in 90.8%. After exclusion, 237 patients were analyzed for survival. Results are presented in Table 1. Univariable Cox regression (after exclusion n=237): Dual ICI exposure (yes vs no): HR 0.60 (95% CI 0.44–0.84, p=0.003); Any ICI exposure (yes vs no): HR ≈0.72 (p=0.102) — non-significant trend. Conclusions: Dual ICI (nivolumab + ipilimumab) was associated with improved overall survival (HR 0.60, p=0.003), particularly with combination with local therapy (predominantly IHP, STRT, and TACE), which substantially enhanced ORR, DCR, PFS, and OS across ICI types. Patients who were unable to receive ICI in the first-line setting may be candidates for this option in the second-line; however, this requires further investigation through subgroup comparative analyses. Results. Treatment Line ICI Type Local Therapy n mPFS, mo (95% CI) mOS, mo (95% CI) ORR (%) DCR (%) Gr ≥3 irAEs (%) First-line Dual (nivo+ipi) Without 28 3.5 (3.0–6.6) 18.4 (13.4–33.5) 10.7 28.6 39.3 First-line Dual (nivo+ipi) IHP 60% STRT 35%TACE 5% 20 7.5 (6.2–18.2) 45.7 (23.4–NR) 45.0 80.0 45.0 First-line Mono anti-PD-1 Without 47 3.1 (2.8–3.7) 18.8 (11.9–27.5) 2.1 14.9 2.1 First-line Mono anti-PD-1 STRT 50%IHP 40%TACE 6.7%RFA 3.3% 30 7.53 (4.5–12.3) 27.9 (18.6–NR) 36.7 60.0 16.7 Second-line Dual Without 35 3.3 (2.5–5.5) 13.1 (9.3–18.8) 2.9 31.4 45.7 Second-line Dual STRT 100% 3 9.3 (8.7–NR) 39.1 (9.6–NR) 33.3 100.0 33.3 Second-line Mono anti-PD-1 Without 15 9.0 (5.2–21.6) 21.3 (14.8–NR) 13.3 46.7 0 Second-line Mono anti-PD-1 STRT 50%IHP 25%TACE 25% 8 8.6 (4.7–NR) 17.3 (13.3–NR) 0 75.0 0

9579 Background: In resectable high-risk melanoma, neoadjuvant anti–PD-1 aims to exceed the ~40% MPR benchmark; while combos may deepen response, they add tox, complexity, and cost. Recently reported data for prolgolimab+nurulimab (N = 205) showed pCR 38.5%, near-CR 4.4%, motivating evaluation of prolgolimab mono as a simpler potentially non-inferior approach. Methods: MelPRO-0322 (CRISTINA; NCT06299878) is a prospective single-arm study in resectable stage IIIB–IV melanoma: 3 neoadj doses of prolgolimab followed by radiologic assessment followed by surgery (regional lymphadenectomy or M1a-equivalent metastasectomy). Central pathology used INMC criteria. Interim analysis after full enrollment and pathology assessment. Results: Pt characteristics (N = 82): Median age 61.5 y (range 23.2–87.3); median BMI 28.2 kg/m² (21.0–46.5). Females 47 (57.3%); ECOG 0/1: 56 (68.3%)/26 (31.7%). Primary melanoma: cutaneous or UPO 73 (89.0%), acral 7 (8.5%), mucosal 2 (2.4%). Stage: IIIB 12 (15.8%), IIIC 54 (71.1%), IIID 3 (3.9%), IV 7 (9.2%); stage missing 6 (7.3%). BRAF V600 mut in 43/74 (58.1%). Median neoadj tx duration 28 d (0–108). Median time from start of neoadj tx to surgery 67 d (29–176). LND/resection performed in 66/82 (80.5%). RECIST 1.1 (ITT, N = 82): ORR 23 (28.0%); CR 5 (6.1%), PR 18 (22.0%), SD 27 (32.9%), PD 24 (29.3%); not evaluable 8 (9.8%). Pathologic response (ITT, N = 82): pCR 28 (34.1%), near-pCR 7 (8.5%), MPR 35 (42.7%); pathology not available in 16 (19.5%). Among evaluable (n = 66): pCR 42.4%, MPR 53.0%. Achieving MPR correlated with better radiologic response by RECIST (p < 0.001) and lower nodal tumor burden (fewer positive nodes; p = 0.012). With a median follow-up of 11.8 mo by reverse KM (95% CI 7.5–17.4), EFS in the ITT cohort (N = 82; events = relapse/progression/death) showed 20 events with median EFS 32.2 mo (95% CI not estimable) and RMST 29.8 mo (SE 4.71). In the pathology-evaluable set (n = 66), EFS was longer in pts achieving MPR vs non-MPR/PD (log-rank p = 0.002): median EFS 19.3 mo for non-MPR/PD (n = 31; 10 events) vs not reached for MPR (n = 35; 2 events); RMST 20.3 vs 30.1 mo. In exploratory multivariable Cox models, MPR remained strongly associated with improved EFS (HR 0.043, 95% CI 0.003–0.684; p = 0.026), while higher PLT/LYM ratio (HR 1.029, 95% CI 1.006–1.052; p = 0.015) and male sex (HR 8.74, 95% CI 1.12–68.21; p = 0.039) showed associations with inferior EFS, while time from neoadj start to surgery and receipt of adjuvant therapy were not associated with EFS. Conclusions: NST prolgolimab monotherapy achieved MPR rates above the historical benchmark with encouraging early EFS. MPR—especially pCR—was strongly associated with improved EFS, with no progressions observed among pCR pts. In exploratory analyses, neither time from neoadj start to surgery nor receipt of adjuvant therapy appeared to materially affect EFS. Clinical trial information: NCT06299878 .

9544 Background: BCD-217-2/OCTAVA is an international, multi-center, randomized, double-blind, placebo-controlled phase III study conducted to assess the efficacy and safety of nurulimab +prolgolimab (nuru + prolgo ) combination therapy with continued prolgolimab therapy compared to prolgolimab monotherapy at the 1st line treatment of 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) which was recently approved for this indication in Russia and Belarus. Here we present efficacy results based on 24 mos of therapy. Methods: Treatment-naïve pts with un/mM (stage IIIC–IV) were randomized 1:1 to two arms. The nuru+prolgo arm received a combo of nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) at 0.2 ml/kg Q3W for the first four infusions. The prolgo arm received prolgolimab monotherapy (3 mg/kg Q3W) for the first four infusions. Both arms then received prolgolimab maintenance therapy for up to two years. The primary endpoint of the study was PFS. Results: 271 pts were randomized to nuru+prolgo (n=135) or prolgo monotherapy (n=136) arms. After a median follow-up of 24.7 mos the mPFS was 15.4 (95% CI 8.4; NA) mos in the nuru+prolgo arm and 8.3 (95% CI 4.2; 14.8) mos in the prolgo monotherapy arm (HR 0.696, 95% CI 0.502; 0.965), iRECIST, ITT population). The PFS benefit was consistent per RECIST 1.1 (HR 0.717, 95% CI 0.533; 0.964). ORR, DCR and TTR were also higher in nuru+prolgo arm. mOS was not reached in both groups (HR 0.836, 95% CI 0.495; 1.41). 24-mos OS was 76.1% in nuru+prolgo arm and 71.7% in prolgo arm respectively. The mDOR was also not reached in any arm, meaning that more than half of the pts who responded to therapy maintained their response until the end of the FU period. Grade ≥3 treatment-related AEs occurred in 17.8% of pts (nuru+prolgo) vs 13.2% (prolgo). Gr ≥3 irAEs were 14.1% vs 5.1%, respectively (p=0.0126). Any-grade irAEs were reported in 51.9% vs 33.8% of cases (p=0.0027). Treatment discontinuation due to AEs was 11.1% vs 5.1%. Conclusions: The OCTAVA trial results demonstrated a statistically significant and clinically meaningful improvement in PFS for the 1st line low-dose nuru + prolgo combination followed by prolgo maintenance, compared to prolgo monotherapy, in patients with unresectable or metastatic melanoma. This efficacy benefit was accompanied by manageable rate of immune-related AE, consistent with the known profile of CTLA-4/PD-1 combinations. These results support the use of the nuru + prolgo regimen as a valuable 1st line treatment option for this population. Clinical trial information: NCT05732805 .

e21520 Background: Post–anti–PD-1 advanced melanoma has few effective salvage options and CHEMO outcomes are modest. We evaluated real-world comparative effectiveness (incl. OS) of LENVA+Pembro versus non-Lenva-based therapy after anti–PD-1 progression, given encouraging activity in LEAP-004 despite negative 1L data in LEAP-003. Methods: Single-center retrospective RWD study at N.N. Blokhin NMRCO using the full EMR (01/2022–09/2025; 37,942 records; 7,061 pts). Advanced cutaneous melanoma pts progressing after anti–PD-1 were identified (ICD-10 C43 + free-text; non-cutaneous primaries manually excluded). Results: Treatment assignment was available for 235 patients (chemo without lenva, n = 117; lenva-based regimen, n = 118). Baseline characteristics were broadly similar: median age 59 (32–95) vs 61 (25–86) years, men 46.2% vs 37.3%, BRAF-mutant 30.8% vs 28.0%, and metastatic stage at treatment start (M1d 26.5% vs 22.9%; M1c 32.5% vs 32.2%). Prior ipilimumab was more frequent in the lenva group (66.1% vs 56.4%). The main imbalance was the therapy line: among patients with documented lines (70/117 and 80/118), the median line was 2 (1–6) vs 2.5 (1–6) and ≥3rd line used 42.9% vs 50.0%. Median FU was 16.2 mo (95% CI 11.2–22.2) with chemo and 14.4 mo (95% CI 10.8–22.6) with lenva. In OS Kaplan–Meier analysis (N = 235; 82 deaths), median OS was 77.2 mo (95% CI 24.5–NR) with chemo (37 deaths) and 24.6 mo (95% CI 13.4–NR) with lenva-based therapy (45 deaths) (log-rank p = 0.183). A multivariable Cox model with time-varying lenva effect was fitted in pts with known BRAF (WT/mutant) and complete covariates (n = 129; 46 deaths), adjusting for age, BRAF, metastatic stage at treatment start, prior ipilimumab, and line of therapy. Line of therapy was independently associated with OS (HR 1.36 per one-line increase; 95% CI 1.03–1.79). To account for non-proportional effects, lenva exposure was modeled piecewise (0–6, 6–12, ≥12 months), yielding interval-specific hazard ratios vs chemotherapy-only: 0–6 mo HR 0.82 (95% CI 0.35–1.92), 6–12 mo HR 3.13 (0.65–14.99), and ≥12 mo HR 3.11 (0.80–12.09). The proportional hazards test for the interval-specific lenva effect was borderline (p = 0.063), while the global test was not significant (p = 0.27). Exploratory effect-modification analyses did not identify heterogeneity of the time-varying lenva association by therapy line across pre-specified cutoffs (likelihood ratio tests for interaction p = 0.20 for 1 vs ≥2, p = 0.81 for 1–2 vs ≥3, and p = 0.13 for 1–3 vs ≥4), noting limited power and sparse events in early-line strata. Conclusions: LENVA-based salvage was not associated with improved OS vs CHEMO in aPD-1–refractory melanoma and effect estimates were time-dependent/uncertain amid strong confounding by therapy line. These data do not justify prioritizing a LENVA-vs-CHEMO prospective trial and highlight the need for new strategies in PD-1–resistant disease.

e21576 Background: Cutaneous melanoma is the most aggressive form of skin cancer, necessitating reliable prognostic markers for risk stratification. Despite the availability of clinical parameters such as Breslow thickness and ulceration, accurate molecular prognostic markers remain a major unmet need. Molecular tools like DecisionDx-Melanoma (31 genes) and MelaGenix (11 genes) provide advanced risk classification for recurrence and survival. Previously, we identified novel RNA markers distinguishing melanomas from nevi (NCT04353050), distinct from those commonly investigated for prognostication. These markers include melanoma-specific CXCL8, DUXAP8/9/10, MAGEA3/6/12, and nevus-specific circCDR1-AS (LINC00632) and CMIP. This study evaluates whether these markers serve as reliable prognostic indicators in melanoma patients. Methods: Formalin-fixed, paraffin-embedded (FFPE) melanoma samples from 120 patients (59 with good prognosis, 61 with poor prognosis) were analyzed. Good prognosis was defined as event-free survival of ≥10 years, while poor prognosis was defined as recurrence, metastasis, or death within ≤5 years. A previously validated RT-PCR panel was employed to assess correlations between marker expression and prognosis. Results: Of 120 melanoma samples, informative results were obtained for 119 using standard procedures. Among the 120 samples, 80 showed definitive melanoma-specific markers, 27 fell into a "grey zone," and 13 exhibited no conclusive melanoma markers. Expression levels of melanoma-specific markers correlated with Breslow thickness but not prognosis. We performed a subgroup analysis stratified into thick (≥4 mm) and thin (≤1 mm) melanomas (Table). The strong prognostic value of CXCL8 and DUXAP8_9_10 in thick melanomas suggests their involvement in aggressive tumor behavior, potentially linked to inflammatory and proliferative pathways. CMIP expression inversely correlated with poor prognosis, indicating its possible role in less aggressive melanoma subtypes. In contrast, no markers demonstrated significant prognostic utility in thin melanomas, highlighting the need for alternative molecular signatures. Conclusions: These findings suggest that RNA marker panels could enhance current prognostic models for thick melanomas. However, their utility in thin melanomas remains limited, warranting further investigation into alternative molecular signatures. Future studies should focus on identifying additional biomarkers to improve risk stratification in early-stage melanoma patients. Marker AUROC P value RNA-markers prognostic significance in thick (≥4 mm) melanomas CXCL8 0.65 0.004 CMIP 0.37 0.011 DUXAP8_9_10 0.61 0.032 cirCDR1.AS 0.41 0.083 MAGEA3_6 0.54 0.470 RNA-markers prognostic significance in thin (≤1 mm) melanomas DUXAP8_9_10 0.32 0.021 MAGEA3_6 0.35 0.056 cirCDR1.AS 0.59 0.285 CXCL8 0.59 0.318 CMIP 0.48 0.838

AbstractPurpose: This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma. Patients and Methods: This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced. Patients received 10 mg FAP-IL2v either continuously once every 3 weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg. Results: Eighty-three patients were treated: 16 patients in two safety run-in cohorts and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The pharmacokinetics of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v–related grade 3/4 adverse events were lymphopenia (23%), elevated γ-glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and 2 of 8 CPI-naïve patients (one complete response and one partial response). The median progression-free survival was 3.1 months. Conclusions: The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in patients with melanoma with prior CPI due to the lack of clinical activity. Significance: In this phase Ib study, the combination of FAP-IL2v, an immune-cytokine developed to overcome the limitations of wild-type IL2, with the CPI pembrolizumab did not show meaningful antitumor activity in patients who had progressed on prior CPI therapy, suggesting that FAP-IL2v alone cannot overcome CPI resistance or unresponsiveness.

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.

Background. Basal cell skin carcinoma (BCSC) is the most common skin cancer. Most cases are diagnosed early and successfully treated using local methods. However, a small proportion of patients develop locally advanced or metastatic BCRCs, which is a challenging clinical issue. The number of locally advanced and/or metastatic forms of BCSCs is based on the experience of individual centers or the analysis of individual databases because the skin cancer cases generally are coded and accounted under the C44 category without counting separately the nosological forms and data on the disease prevalence. Aim. To estimate the number of patients with locally advanced and metastatic BCRCs among all patients treated in the N.N. Blokhin National Medical Research Center of Oncology from 2019 to July 2024 with the diagnosis code C44 according to the International Classification of Diseases, 10th Edition. Results. Between 2019 and July 2024, 3,801 individual cases of non-melanoma skin cancer (C44) were reported. Most of the 3,801 patients had BCSCs (n=2,796, 73.6%), followed by squamous cell carcinoma (n=857, 22.5%), Merkel cell carcinoma (n=100, 2.6%), and other skin tumors and neoplasms originating from the skin appendages (n=48, 1.3%). Among all cases of BCSCs, 94 (3.4%) cases of locally advanced and metastatic forms of the disease were reported. These patients were divided into two groups: with locally advanced BCSC (78 patients, 2.8%) and metastatic BCSC (16 patients, 0.6%). Conclusion. Most patients with early stages of BCSCs can be completely cured with radical surgery and/or radiation therapy, and a small number of patients develop disease progression that is not amenable to surgery or radiation therapy. We obtained the following results: 2.8% of locally advanced BCSCs and 0.6% of metastatic BCSCs, which is consistent with the literature data, where locally advanced BCSCs are reported in 1-2% of patients, and BCSC metastasis is reported in 0.0028-0.55%.

Background. Adjuvant targeted therapy (ATT) with a combination of dabrafenib and trametinib after radical surgical treatment in patients with stage III skin melanoma (SM) with a BRAF V600 mutation reduces the risk of disease recurrence. The effectiveness of this approach has been demonstrated in randomized clinical trials, and also confirmed in several large non-Russian real-world (RW) studies. Aim. To evaluate, in RW settings, the effectiveness of ATT with a combination of dabrafenib and trametinib after definitive surgical treatment in patients with BRAF V600-positive SM in Russia. Materials and methods. The RATIONALE study is a prospective, non-interventional, multicenter RW study. The follow-up duration for the study was 1 year. Patients with SM older than 18 years who had previously started dabrafenib and trametinib therapy no more than 8 weeks prior to Visit 1 were included in the study. The paper presents results from the analysis of Cohort 1 only (patients who received dabrafenib and trametinib in the adjuvant setting). Results. The cohort included 214 patients with BRAF V600-mutated SM of stages IIIA–D and IV resectable. At the time of therapy initiation, the majority of patients were stage IIIc (54.7%) or IIIb (22.0%). The most common mutation – BRAF V600E – occurred in 66.3% of cases, while the second most common variant – BRAF V600 not otherwise specified – was detected in 31.3%. One-year overall survival for all included patients was 94%, one-year relapse-free survival was 84%, and one-year distant metastasis-free survival was 86%. No previously listed adverse events were reported. Adverse events led to therapy discontinuation in only 11.7% of cases. ATT did not reduce patients' quality of life. In the subgroup analysis, the effectiveness of the combination of dabrafenib and trametinib after removal of distant metastases (equivalent to stage IV resectable) was found, in particular, the one-year relapse-free survival rate was 83%, and the one-year overall survival rate was 100%, which is comparable to these indicators for stage IIIB-D (72–86 and 78–100%, respectively). Conclusion. The effectiveness and favorable safety profile of the combination of dabrafenib and trametinib in ATT after radical surgical treatment was confirmed in a population of Russian patients with SM in the RW settings.

Aim:Uveal melanoma (UM) is a rare primary intraocular malignant tumor with an extremely poor prognosis. Our study evaluated the feasibility to improve metastatic UM treatment outcomes with a combined approach of immunotherapy and radiation therapy. Methods:The retrospective study enrolled 24 patients with metastatic uveal melanoma who had combined treatment with stereotactic radiation therapy (RT) and immune checkpoint inhibitor therapy. 35% of patients received combination immunotherapy, and the others received mono-immunotherapy with anti-PD-1 drugs. All patients underwent stereotactic RT for metastases in the liver (75% patients), bones (8%), soft tissues (8%), brain (4%), and lungs (4%). Results:Overall response rate (ORR) was 39.1%. Complete response (CR) was achieved in 8.7% patients and partial response (PR) - in 30.4% patients, median progression free survival (PFS) was 11.6 months [95% confidence interval (CI), 5.4-14.4], and median overall survival (OS) was 27.6 months [95% CI, 16.9 - 49.1]. Conclusions:The study has demonstrated a safe combination of stereotactic radiation therapy and immune checkpoint inhibitor immunotherapy in patients with metastatic uveal melanoma. The combination shows a potential treatment option for this patient cohort since no other effective therapies are available at present.

9580 Background: The differential diagnosis of nevi and melanomas remains a significant clinical challenge, as misclassification can result in overtreatment or delayed care. Despite advances in clinical, dermatoscopic, and histopathological methods, benign lesions are frequently misclassified as nevi, SAMPUS, or MELTUMP, while atypical melanomas are often mistaken for nevi. This study aimed to identify novel RNA markers for the differential diagnosis of nevi and melanomas. Methods: Ninety histological samples of melanocytic neoplasms were analyzed, including 45 morphologically confirmed nevi and 45 melanomas. Massive parallel sequencing was performed using the NextSeq 550 system (Illumina, USA) with the “NextSeq High Output 150 Cycles Kit” reagent set, following the manufacturer’s protocol. Data normalization employed FPKM and TPM metrics, and differential gene expression analysis utilized 26 algorithms on the RNA-Seq 2G web server. Selected RNA markers were further validated on an independent cohort of 120 samples (60 verified nevi and 60 melanomas) using RT-PCR. Results: The study analyzed the expression of over 18,000 coding and 42,000 non-coding RNAs (primarily long non-coding) in histologically confirmed melanomas and nevi, balanced between "classical" and dysplastic nevi. Initial RNA-Seq quality control confirmed high data integrity and sufficient sequencing depth in 87 of 90 samples. Melanoma-specific markers identified included CSAG1, CXCL1, CXCL8, CXCL9, DUXAP8 + DUXAP9 + DUXAP10, FCRL3, IGHA1, IGHG1, LRP2, MAGEA3 + MAGEA6 + MAGEA12, MMP1, OR2I1P, SPP1, and VGF, while nevus-specific markers included CD44-AS1, CDR1-AS (LINC00632), DSCAS, and ENSG00000287270. For RNA marker testing at the next stage, all 120 samples were deemed suitable for analysis. Modeling of multimarker tests achieved an AUROC of 0.94, with a model incorporating only 5 preselected markers outperforming those with a larger number of markers. The most informative logistic regression model included the following marker combinations: MAGEA3 + MAGEA6, CXCL8 + LINC00632, DUXAP8 + DUXAP9 + DUXAP10, CSAG1, and CXCL1. Conclusions: The model, incorporating only 5 markers, achieved an AUROC of 0.94 in an independent validation cohort. It is now positioned for further validation in cohorts enriched with samples of uncertain malignant potential based on histological evaluation. Clinical trial information: NCT04353050 .

e21594 Background: There is no standard treatment for mUM and the efficacy and safety of IT and comparison with chemotherapy in real-world practice has not been well defined. Methods: We conducted a single-center retrospective observational study approved by the Institutional Review Board (IRB) at the N.N. Blokhin National Medical Research Center of Oncology, focusing on the treatment of patients with metastatic uveal melanoma (mUM) from 2000 to 2023. Our primary objectives were to evaluate clinical outcomes in real-world settings between patients who received chemotherapy (ChT) prior to 2017 and those who received immunotherapy (IT) after 2017. No formal balancing methods were applied, the group analyzed based on the treatment periods and available clinical data. Results: A total of 347 pts with mUM were included. The mean age was 54 years (range: 20-76). 56 pts were lost to follow-up, and 23 declined the proposed treatment. 124 pts were included in the ChT group, and 144 in the IT group. In the ChT, the most commonly prescribed regimens were cyclophosphamide+vincristine+dacarbazine (n = 39, 41.5%) and paclitaxel+carboplatin (n = 18, 19.1%). In the IT - anti-PD-1 (n = 78, 54.2%), ipilimumab+nivolumab (n = 48, 33.3%), ipilimumab (n = 10, 6.9%), and tebentafusp (n = 8, 5.6%)*. Only 4 pts (3.2%) in the ChT received 3 lines of therapy, while in the IT, 63.9% (92) received 3 or more lines of therapy, with 2 of them receiving 6 lines. The results are reported in Table 1. Furthermore, we observed that in the IT group, 26 patients received additional local treatment methods (STRT/Isolated hepatic perfusion/TACE) alongside immunotherapy, resulting in a median PFS of 3.4 months (95% CI: 3.1–4.1) compared to 9.1 months (95% CI: 6.8–14.2) with IT alone (HR: 0.46, 95% CI: 0.30–0.71, p < 0.001), a 36-month OS of 20% versus 59%, and a median OS of 47 months (95% CI: 21.7–51.8) compared to 18.6 months (95% CI: 16.5–26.0) (HR: 0.46, 95% CI: 0.24–0.88, p = 0.02). Gr 3-4 treatment-related AEs in the ChT were observed in 28.2% vs 30.6% in the IT. Conclusions: Despite the low frequency of objective response, the administration of IT significantly increases the survival of patients with mUM. The addition of local treatment methods to IT in cases of isolated liver involvement could be considered as a viable approach. Results. ChT IT all HR The median time to metastasis from the primary tumor 3.02 yrs 2.10 yrs Median PFS 1.8 mon. (95% CI 1.4-2.1) 4.07 mon. (95% CI 3.4-5.3) 0.36, 95% CI 0.28-0.47, p<0.0001) ORR 0% 11.8% (4-CR, 13-PR) Disease control rate (DCR) 25% 36.8% Median OS since initiation of first-line therapy 5.6 mon (95% CI 4.2-6.83) with a median follow-up of 5.69 mon 21.7 mon (95% CI 17.63-27.17) with a median follow-up of 17.27 mon 0.21, 95% CI 0.16-0.29, p<0.005). 24 mon-OS 7% 48% 36 mon-OS 0% 29%

The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.

e21581 Background: Improving the accuracy of non-invasive diagnosis of skin tumors is becoming an urgent problem, given the clear increase in the incidence of melanoma in many countries. Dermoscopy and examination by an experienced dermatologist can reduce the NNE to 5–10 per melanoma (M) detected, however, achieving even this, clearly suboptimal, rate requires a long specialist training. Methods: We report results of prospective nonrandomized trial evaluating sensitivity and specificity of RNA profiling of cytological samples from adhesive transparent patches (ATP) applied to skin lesions. Routine pathology reports were obtained for all surgery samples. RNA extracted from ATP specimens (N = 126) was tested for mRNA expression of PRAME and LINC00518 genes. GAPDH was used as a reference gene. Sample was considered marker-positive if either PRAME or LINC00518 expression was detected. Results: Between June 2021 and November 2021, 126 pts undegoing excisional biopsy of skin lesions were included in the study at 5 centers. On pathology, invasive M was detected in 49 (38.9%) patients (mean Breslow thickness was 2.41 mm [95%CI 1,44 to 3.37]), M in situ in 6 (4.8%), non-melanoma skin cancer in 4 (3.2%) and dysplastic nevus in 56 (44.4%). In the day of preplanned excision ATP was applied to the target lesion for 5–6 min and sent to the central lab. Amplifiable mRNA was found in all 126 ATP samples. 82 samples of 126 (65,1%) tested marker-positive. Sensitivity of RNA profiling for detection of skin cancers reached 88.14% (95% CI 77.07% – 95.09%), while specificity was only 53.85% (41.03% – 66.30%), with PPV of 63.41% (56.74% – 69.61%), NPV of 83.33% (70.65% – 91.22%) and accuracy of 70.16% (61.29% – 78.04%). Among the seven false negative results there were 3 M in situ and 4 invasive M. Conclusions: RNA profiling of skin ATP specimens is feasible and has high sensitivity but rather low specificity. Randomized studies are needed to evaluate if this technique can add anything to dermoscopy or other noninvasive diagnostic modalities. Clinical trial information: NCT04353050. [Table: see text]

The number of cases of melanoma of the skin is steadily increasing every year, which leads to an increase in cases of melanoma associated with pregnancy. To date, there is no convincing evidence of an increased risk of skin melanoma or death from melanoma during pregnancy, however, the treatment of such patients is not an easy task for oncologists. And if surgical treatment of patients with primary melanoma of the skin during pregnancy should be carried out according to modern standards, then the use of targeted drugs and checkpoint inhibitors has been little studied during pregnancy, therefore each individual case requires an individual approach. The article describes the clinical experience of the treatment of melanoma associated with pregnancy at the N.N. Blokhin National Research Medical Center of Oncology.

Uveal melanoma (UM) is the most common primary intraocular tumor. Despite successful treatment of the primary tumor, 50% of patients develop distant metastases. To date, there are no clear standards for choosing the first line of therapy for metastatic UM. The article presents a retrospective analysis of the effectiveness and safety of first-line therapy in 125 patients with metastatic UM who applied to the N.N. Blokhin National Medical Research Center of Oncology in the period from 2020 to 2023.

Background. According to current clinical guidelines, patients with inoperable and/or metastatic melanoma (IMM) should undergo a molecular genetic study for the presence of mutations in the BRAF V600 gene in order to select drug therapy. Its accessibility and timing may vary in the regions of Russia. Aim. To assess the possibility, accessibility, and timing of a molecular genetic study for melanoma in Russia. Results. From November 15, 2023, to December 11, 2023, a survey was conducted, which included 32 respondents (oncologists and heads of depart- ments/laboratories) from various federal districts, where 1 to 1000 IMM patients are being diagnosed and treated annually. A mutation in the BRAF gene was detected in 79,1% of patients. The duration of the study was about 15 (3-35) days. The mutations were detected in a local institution in 60% of cases, within the Russian Society of Clinical Oncology diagnostic program in 21,1%, and in other programs in 18,9%. Conclusion. The wide accessibility of the detection of BRAF gene mutations in the Russian Federation was reported due to the following factors: the introduction of molecular genetic diagnostics programs, in particular the Russian Society of Clinical Oncology program, as well as other programs sponsored by pharmaceutical companies and the possibility of testing under a compulsory health insurance policy. However, approximately 21% (20,9%) of patients with IMM do not test for mutations in the BRAF gene, even if they have their own laboratory in the institution. It is crucial to test all patients with melanoma from stage III onwards for BRAF mutations, especially when treatment is started with immunotherapy and there is enough time for the BRAF mutation result to be routinely obtained.