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Importance: Acral melanoma, known for low tumor mutation burden, responds poorly to immunotherapy. A standard therapy is still lacking., Objective: To investigate the activity and safety of camrelizumab (an anti-programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) and temozolomide as first-line treatment in patients with advanced acral melanoma., Design, Setting, and Participants: In this single-arm, single-center, phase 2 nonrandomized clinical trial, patients with treatment-naive unresectable stage III or IV acral melanoma were enrolled at Peking University Cancer Hospital and Institute between June 4, 2020, and August 24, 2021. The data cutoff date was April 10, 2022., Interventions: Patients received 4-week cycles of intravenous camrelizumab, 200 mg, every 2 weeks; oral apatinib 250 mg, once daily; and intravenous temozolomide, 200 mg/m2, once daily on days 1 to 5 until disease progression or unacceptable toxic effects., Main Outcomes and Measures: The primary end point was objective response rate as assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (version 1.1). Secondary end points included progression-free survival, time to response, duration of response, disease control rate, overall survival, and safety., Results: A total of 50 patients (32 men [64%]; median age, 57 years [IQR, 52-62 years]) were enrolled and received treatment. The median follow-up duration was 13.4 months (IQR, 9.6-16.2 months). The objective response rate was 64.0% (32 of 50; 95% CI, 49.2%-77.1%). The median time to response and duration of response were 2.7 months (IQR, 0.9-2.9 months) and 17.5 months (95% CI, 12.0 to not reached), respectively. The disease control rate was 88.0% (44 of 50; 95% CI, 75.7%-95.5%). The estimated median progression-free survival was 18.4 months (95% CI, 10.6 to not reached). The median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse events were increased gamma-glutamyltransferase levels (15 [30%]), decreased neutrophil count (11 [22%]), increased conjugated bilirubin levels (10 [20%]), and increased aspartate aminotransferase levels (10 [20%]). No treatment-related deaths occurred., Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that camrelizumab plus apatinib and temozolomide may be a potential first-line treatment option for patients with advanced acral melanoma, which warrants further validation in a randomized clinical trial., Trial Registration: ClinicalTrials.gov Identifier: NCT04397770.

Background: At present, immune monotherapy and combination therapy has not shown satisfactory effects on acral melanoma, and still no standard treatment is available for advanced acral melanoma. Here, a phase II trial was performed to explore the safety and efficacy of apatinib combined with camrelizumab in advanced acral melanoma patients as first-line therapy (NCT03955354)., Methods: Patients with pathologically confirmed, locally unresectable or metastatic treatment native acral melanoma received 250 mg apatinib once daily and camrelizumab 200 mg once every two weeks intravenously every 28-day cycle. The primary end-point was objective response rate and the secondary end-points were disease control rate, overall survival, progression-free survival and safety., Results: Thirty patients were recruited between January 2015 and January 2022. Among them, 21 (70.0%) had stage IV, and a median tumour burden was 50 mm (range: 11-187). Objective response rate was 24.1%, and 7 of 29 patients had an anti-tumour response, including partial response (n = 5) and complete response (n = 2). Disease control rate was 82.8%, median progression-free survival was 7.39 months (confidence interval: 3.65-9.92), and median overall survival was 13.4 months (confidence interval: 1.9-25.0). Grade 3-4 treatment-related toxicity (grade 3 50.5%; grade 4 3.3%) included transaminase elevations, proteinuria, leukocytopenia, vomiting, diarrhea and drug-induced liver injury. No treatment-related mortality occurred. The mutations of TTN, MUC16, VPS13D, ALPK2 and SCUBE1 showed significant alterations with survival outcome., Conclusions: Apatinib combined with camrelizumab showed manageable safety profile and reasonable anti-tumour activity in advanced acral melanoma patients as first-line therapy., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jun Guo serves consulting/advisory roles in Merck Sharp & Dohme, Roche, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences and Oriengene. Lu Si has received speakers’ honoraria from MSD, Roche, Novartis, Shanghai Jun- shi Biosciences and Oriengene. For the remaining authors, there are no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The current evaluation methods for tumor infiltrating lymphocytes (TILs), particularly CD8 + TILs, mainly rely on semiquantitative immunohistochemistry with high variability. We aimed to construct an individualized DNA methylation-based signature for CD8 + TILs (CD8 + MeTIL) that may characterize melanoma immune microenvironment and guide therapeutic selection., Methods: The transcriptome profiles and DNA methylation data of 457 melanoma patients from The Cancer Genome Atlas (TCGA) database were analyzed. Differential methylation analysis between groups with high and low CD8 + TILs was performed to select differentially methylated positions (DMPs) and define CD8 + MeTIL. The prognostic value of CD8 + MeTIL and its predictive value for immunotherapy response were investigated using multiple melanoma cohorts., Results: We successfully constructed the CD8 + MeTIL signature based on four DMPs. The survival analyses showed that higher CD8 + MeTIL score was associated with worse survival outcomes in TCGA-SKCM and GSE144487 cohorts. The ROC curve for the predictive analysis revealed that the survival prediction of CD8 + MeTIL score was superior compared with CD8 + TILs (CIBERSORT) and CD8B mRNA expression. Furthermore, we founded that tumors with higher CD8 + MeTIL score were marked with immunosuppressive characteristics, including low immune score and downregulated immune-related pathways. More importantly, the CD8 + MeTIL score showed a potential predictive value for the benefit from immunotherapy in two published cohorts. When combined CD8 + MeTIL with PD-L1 expression, the patient classification showed significantly different immunotherapy response rates and long-term survival outcomes., Conclusions: The CD8 + MeTIL signature might be as a novel method to evaluate CD8 + TILs and guide immunotherapy approaches., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Anti-programmed cell death receptor-1 (PD-1) monotherapy is the standard treatment for metastatic melanoma in current. Camrelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody whose safety and efficacy have not been reported in advanced Asian melanoma patients., Methods: This phase I study investigated the safety, activity, and pharmacokinetics of camrelizumab in Chinese patients with advanced melanoma. The study included two phases, the dose-escalation phase ("3 + 3" design at 60 mg, 200 mg, and 400 mg) and the dose-expansion phase., Results: No dose-limiting toxicities were recorded over the dose-escalation phase, and the maximum tolerated dose was not reached. The most common treatment-related adverse events (TRAEs) in 36 patients were reactive cutaneous capillary endothelial proliferation, followed by rash, fever, hypothyroidism, hyperthyroidism, vitiligo, and fatigue. Five grade 3 or above TRAEs were reported (13.9%), including two cases of elevated γ-glutamyltransferase and blood triglycerides without clinical symptoms, and one liver injury recovered after symptomatic treatment. The confirmed overall response rate was 13.9% (95%CI: 4.7, 29.5%) and disease control rate was 38.9% (95%CI: 23.1, 56.5%). The median progression-free survival was 1.8 months (95%CI: 1.1, 2.4) and the median overall survival was 11.1 months (95%CI: 6.8, 15.4)., Conclusions: Camrelizumab had acceptable tolerability and similar anti-tumor activity compared with other anti-PD-1 antibodies in advanced Asian melanoma patients., Trial Registration: ClinicalTrials.gov identification: NCT02738489. Registered on 14/04/2016, prospectively registered., (© 2022. The Author(s).)

Background: Melanoma is a type of malignant tumor with high aggressiveness and poor prognosis. At present, metastasis of melanoma is still an important cause of death in melanoma patients. However, the potential functions and molecular mechanisms of most circular RNAs (circRNAs) in melanoma metastasis remain unknown., Methods: circRNAs dysregulated in melanoma cell subgroups with different metastatic abilities according to a screening model based on repeated Transwell assays were identified with a circRNA array. The expression and prognostic significance of circZNF609 in skin cutaneous melanoma and acral melanoma cells and tissues were determined by qRT-PCR, nucleoplasmic separation assays and fluorescence in situ hybridization. In vitro wound healing, Transwell and 3D invasion assays were used to analyse melanoma cell metastasis ability. Tail vein injection and intrasplenic injection were used to study in vivo lung metastasis and liver metastasis, respectively. The mechanism of circZNF609 was further evaluated via RNA immunoprecipitation, RNA pull-down, silver staining, and immunofluorescence colocalization assays., Results: circZNF609 was stably expressed at low levels in melanoma tissues and cells and was negatively correlated with Breslow depth, clinical stage and prognosis of melanoma patients. circZNF609 inhibited metastasis of acral and cutaneous melanoma in vivo and in vitro. Mechanistically, circZNF609 promoted the binding of FMRP protein and RAC1 mRNA, thereby enhancing the inhibitory effect of FMRP protein on the stability of RAC1 mRNA and ultimately inhibiting melanoma metastasis., Conclusions: Our findings revealed that circZNF609 plays a vital role in the metastasis of acral and cutaneous melanoma through the circRNF609-FMRP-RAC1 axis and indicated that circZNF609 regulates the stability of RAC1 mRNA by combining with FMRP, which might provide insight into melanoma pathogenesis and a new potential target for treatment of melanoma., (© 2022. The Author(s).)

The durable responses and favorable long-term outcomes are limited to a proportion of advanced melanoma patients treated with immune checkpoint inhibitors (ICI). Considering the critical role of antitumor immunity status in the regulation of ICI therapy responsiveness, we focused on the immune-related gene profiles and aimed to develop an individualized immune signature for predicting the benefit of ICI therapy. During the discovery phase, we integrated three published datasets of metastatic melanoma treated with anti-PD-1 (n = 120) and established an immune-related gene pair index (IRGPI) for patient classification. The IRGPI was constructed based on 31 immune-related gene pairs (IRGPs) consisting of 51 immune-related genes (IRGs). The ROC curve analysis was performed to evaluate the predictive accuracy of IRGPI with AUC = 0.854. Then, we retrospectively collected one anti-PD-1 therapy dataset of metastatic melanoma (n = 55) from Peking University Cancer Hospital (PUCH) and performed the whole-transcriptome RNA sequencing. Combined with another published dataset of metastatic melanoma received anti-CTLA-4 (VanAllen15; n = 42), we further validated the prediction accuracy of IRGPI for ICI therapy in two datasets (PUCH and VanAllen15) with AUCs of 0.737 and 0.767, respectively. Notably, the survival analyses revealed that higher IRGPI conferred poor survival outcomes in both the discovery and validation datasets. Moreover, correlation analyses of IRGPI with the immune cell infiltration and biological functions indicated that IRGPI may be an indicator of the immune status of the tumor microenvironment (TME). These findings demonstrated that IRGPI might serve as a novel marker for treating of melanoma with ICI, which needs to be validated in prospective clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yan, Wu, Yu, Kong and Cang.)

Background: Mucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising response rate in patients with metastatic mucosal melanoma (MM) in a phase Ib study. Here, we report the updated overall survival (OS), duration of response (DoR), and biomarker analysis results., Methods: Patients with advanced MM received toripalimab 1 or 3 mg/kg intravenously every 2 weeks combined with axitinib 5 mg orally two times per day until disease progression or unacceptable toxicity. Tumor programmed cell death ligand-1 (PD-L1) expression, tumor mutational burden (TMB), and gene expression profile (GEP) by messenger RNA sequencing were evaluated for correlation with survival., Results: As of April 2, 2021, the median follow-up was 42.5 months. Among 29 chemotherapy-naïve patients with metastatic MM, the median OS was 20.7 months (95% CI 9.7 to 32.7 months); the median progression-free survival (PFS) was 7.5 months (95% CI 3.8 to 14.8 months); and the median DoR was 13.4 months (95% CI 5.5 to 20.6 months). The OS rates of 1, 2, and 3 years were 62.1%, 44.8%, and 31.0%, respectively. Biomarker analysis found that PD-L1 expression and TMB level were not associated with survival benefits. In contrast, a 12-GEP signature correlated with improved PFS (17.7 vs 5.7 months, p=0.0083) and OS (35.6 vs 17.6 months, p=0.039)., Conclusions: The 3-year survival update confirmed the antitumor activity and long-term survival benefit of the toripalimab plus axitinib combination in patients with advanced MM. The 12-gene GEP is of value in predicting the outcomes of vascular endothelial growth factor receptor-tyrosine kinase inhibitor and PD-1 blockade combination therapy, but requires further validation., Trial Registration Numbers: NCT03086174., Competing Interests: Competing interests: JG is a member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, and Oriengene. KF serves on the board of directors of Loxo Oncology, Clovis Oncology, Strata Oncology, and Vivid Biosciences; on the corporate advisory boards of X4 Pharmaceuticals and PIC Therapeutics; on the scientific advisory boards of Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Array BioPharma, Shattuck Labs, Arch Oncology, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon Therapeutics, and Tvardi; and as a consultant to Novartis, Genentech, BMS, Merck, Takeda, Verastem, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm. XT, HF, and SY are employed by Shanghai Junshi Bioscience. The rest of the authors have no disclosures of potential conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Copy number variations are frequently observed in cell cycle-related genes in acral melanoma. However, the clinical significance of copy number gain of CCNE1 in acral melanoma has not been fully elucidated. In this study, 490 acral melanoma samples were examined for CCNE1 copy number using the QuantiGenePlex DNA Assay. Correlation between CCNE1 copy number and acral melanoma patients' clinicopathologic features were analyzed using Chi-squared test. The impact of CCNE1 copy number on patients' progression-free survival (PFS) and overall survival (OS) probability were analyzed using Kaplan-Meier analysis. The impact of CCNE1 copy number on patients' median PFS after receiving chemotherapy was also evaluated. The results showed that CCNE1 copy number gain was observed in 28.30% of patients, with 3.16% of patients carrying both CCNE1 copy number gain and BRAF mutation and 4.34% of patients carrying both CCNE1 copy number gain and NRAS mutation. The median PFS time for patients with CCNE1 copy number gain was shorter than that of patients without CCNE1 copy number gain (17.0 vs. 27.0 months, P = 0.002).In the cohort that received chemotherapy (n = 82), the median PFS time for patients with CCNE1 copy number gain was shorter than that of patients without CCNE1 copy number gain (4.8 vs. 7.4 months, P = 00.006). CCNE1 copy number gain was an independent prognostic marker for acral melanoma patients' PFS. Our study indicates that CCNE1 copy number gain is frequent in acral melanoma and may be a biomarker to predict acral melanoma patients' outcomes after receiving chemotherapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)