Outcome Of Melanoma Patients Research Articles

The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Herein, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X, and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments. Significance: RORA forms a corepressor complex to inhibit PD-L1 expression and activate antitumor T-cell responses, indicating that RORA is a potential target and predictive biomarker to improve immunotherapy response in melanoma patients.

Effect of glucocorticoids for the management of immune-related adverse events on outcome in melanoma patients treated with immunotherapy—a retrospective and biomarker study

Immune-related adverse events (IRAEs) during therapy with immune checkpoint inhibitors (ICIs) are common, and their management sometimes requires glucocorticoids (GCs). Predictors for development of IRAEs and data about the impact of GCs on clinical outcome are missing. We evaluated the impact of GCs to treat IRAEs on clinical outcome, and plasmatic inflammatory proteins as predictors for IRAEs. Patients with melanoma (n= 98) treated with ICIs at Karolinska University Hospital were included. Clinical information and data regarding prescription of systemic GCs were collected. Baseline plasma samples (n= 57) were analyzed for expression of 92 inflammatory proteins. Forty-four patients developed at least one IRAE requiring systemic GCs and the most common was hypocortisolemia (n= 11). A median overall survival of 72.8 months for patients developing IRAEs requiring GCs, 17.7 months for those who did not, and 1.4 months for individuals receiving GCs at baseline was observed in Kaplan-Meier curves (P= 0.001). In immortal time bias adjusted analysis, patients receiving steroids to treat IRAE survived slightly longer, even though this time trend was not statistically significant. The median overall survival was 29 months for those treated with GCs within 60 days after ICIs start and was not reached for patients receiving GCs later. The number of ICI cycles was higher in subjects receiving GCs after 60 days (P= 0.0053). Hypocortisolemia occurred mainly in males (10/11) and correlated with favorable outcome. Male patients with hypocortisolemia had lower expression of interleukin 8, transforming growth factor-α, and fibroblast growth factor 5 and higher expression of Delta/Notch-like epidermal growth factor-related receptor. GCs may be used to treat IRAEs without major concern. GCs early during ICIs may, however, impact clinical outcome negatively. The prognostic value of hypocortisolemia and inflammation proteins as biomarkers should be further investigated.

Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis.

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.

Survival and treatment outcomes in patients with leptomeningeal disease from metastatic melanoma.

Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.

Abstract 3823: Clinical outcomes of uveal melanoma patients in the emergency department

Abstract Purpose: Uveal melanoma is a rare ocular malignancy that has not been well characterized at a large scale. Specifically, uveal melanoma diagnosis and outcomes in the emergency department (ED) has not been characterized. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a primary diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of inpatient admission. Results: From the last quarter of 2015 to 2019, there were 1,274 ED encounters with a primary diagnosis of uveal melanoma. Most patients were less than 11 years old (43.4%), male (51.1%), or a Medicaid beneficiary (37.8%), and most belonged to a family in the lowest income quartile (32.0%). The median age of these patients was 35 years (IQR: 2-64). Most patients presented to hospitals in the South (53.9%), with a Trauma Level I designation (51.4%), and most to a metropolitan teaching hospital (89.1%). The most common ED outcomes were same-day discharge (61.6%) and admission to the inpatient setting (31.2%). Patients presenting to Trauma Level I hospitals were most likely to be admitted (odds ratio [OR]=2.21; p=0.031). The factors that were most significantly associated with decreased odds of inpatient admission were: patients who were not charged for services (often due to charity) (OR=0.13; p=0.040), Medicaid beneficiaries (OR=0.27; p=0.031), and private insurance beneficiaries (OR=0.34; p=0.047). Among the admitted patients, patients can be discharged to home with self-care (76.2%) or with home-health care (14.9%) or can be transferred to an intermediate-care facility (8.1%). The mean hospital length of stay was 5.7±0.6 days. In-hospital mortality rate for admitted patients was very low (0.8%). Conclusion: Uveal melanoma patient outcomes are closely related to insurance status, indicating socioeconomic factors as a modulator of patient outcomes. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. Clinical outcomes of uveal melanoma patients in the emergency department [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3823.

Abstract 6411: The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors

Abstract The gut microbiome (GMB) plays a crucial role in immune checkpoint blockade (ICB) therapy outcomes for metastatic melanoma patients, yet there remains a lack of consensus regarding the specific microbiota associated with clinical outcomes, particularly across different geographic regions. Furthermore, investigations into the relationship between GMB and melanoma outcomes in the adjuvant setting are notably absent. This highlights the pressing need for a comprehensive, large-scale study spanning diverse geographic locations within a well-controlled clinical trial environment. In this study, we conducted shotgun sequencing on pre-treatment stool samples collected from 674 melanoma patients participating in an international, randomized, double-blind, phase III adjuvant trial evaluating clinical outcomes following adjuvant nivolumab plus ipilimumab versus nivolumab. Our recruitment encompassed three continents and five geographically distinct regions. Given the significant influence of geographic region on GMB composition, we employed three analytical approaches: (a) region-specific analyses, (b) combined meta-analyses across regions, and (c) sub-set paired analyses involving subjects closely matched for overall GMB. Additionally, we assessed GMB stability by examining samples collected serially prior to therapy and at weeks 7 and 29 of ICB treatment. Through region-specific and meta-analyses, we identified ten pre-treatment gut bacterial markers, including Eubacterium, Ruminococcus, Clostridium, and Firmicutes, which exhibited associations with melanoma recurrence in the adjuvant setting. The predictive capacity of these microbial markers was directly proportion to GMB similarity (Spearman correlation = 0.86, p<0.001 for AUC vs. beta-diversity). Notably, for closely matched patients in terms of their GMB composition, the prediction of recurrence using the recurrence-associated markers, in conjunction with clinical characteristics, yielded an AUC of 0.917 (95% CI: 0.825-1.00). Furthermore, GMB remained largely stable across serial samples collected before and after treatment (PERMANOVA R2 = 0.867, p-val<0.001, at baseline, week 7, and week 29). This study underscores the remarkable stability of GMB during adjuvant ICB therapy for melanoma and identifies specific bacterial biomarkers that hold promise for predicting melanoma recurrence within the adjuvant treatment setting. The gut microbiome emerges as a potential source of microbial biomarkers for individualized prediction of melanoma recurrence in clinical practice. Citation Format: Mykhaylo Usyk, Richard B. Hayes, Rob Knight, Antonio Gonzalez, Huilin Li, Iman Osman, Jeffrey S. Weber, Jiyoung Ahn. The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6411.

T-Cell Subtypes and Immune Signatures in Cutaneous Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome.

Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland.

Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Immunohistochemistry assessment of tissue neutrophil-to-lymphocyte ratio predicts outcomes in melanoma patients treated with anti-programmed cell death 1 therapy.

Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with diminished immunotherapy response in metastatic melanoma. Although NLR assessment in peripheral blood is established, tissue dynamics remain insufficiently explored. This study aimed to evaluate tissue NLR (tNLR)'s predictive potential through immunohistochemistry in immunotherapy-treated melanoma. Fifty melanoma patients who underwent anti-programmed cell death 1 (PD-1) therapy were assessed. Hematological, clinical and tumor features were collected from medical records. Responses were categorized using the Response Evaluation Criteria in Solid Tumors for immunotherapy (iRECIST) guidelines. Immunohistochemistry for tumor-infiltrating T cells (cluster differentiation 3) and neutrophils (myeloperoxidase) was performed on formalin-fixed paraffin-embedded tumor samples. NLR, derived NLR (dNLR) and tNLR were calculated. Overall survival (OS) and survival following immunotherapy (SFI) were calculated from diagnosis or immunotherapy start to loss of follow-up or death. Patients with high tNLR presented improved OS ( P = 0.038) and SFI with anti-PD-1 therapy ( P = 0.006). Both NLR and dNLR were associated with OS ( P = 0.038 and P = 0.046, respectively) and SFI ( P = 0.001 and P = 0.019, respectively). NLR was also associated with immunotherapy response ( P = 0.007). In conclusion, tNLR emerged as a novel potential biomarker of enhanced survival post anti-PD-1 therapy, in contrast to classical NLR and dNLR markers.

ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes

ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between ARID mutations, molecular features, and clinical outcomes in melanoma patients. Cutaneous melanoma samples (n = 1577) were analyzed by next-generation sequencing. Samples were stratified by pathogenic/likely pathogenic mutation in ARID genes (ARID1A/2/1B/5B). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor mutation burden (TMB)-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures predictive of response to immune checkpoint inhibitors—interferon gamma and T-cell inflamed score were calculated. Real-world overall survival (OS) information was obtained from insurance claims data, with Kaplan–Meier estimates calculated from time of tissue collection until last date of contact. Mann–Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p values adjusted for multiple comparisons. ARID2 mutations were more prevalent in cutaneous melanoma compared to ARID1A (11.0%: n = 451 vs 2.8%: n = 113), with concurrent ARID1A/ARID2 mutation in 1.1% (n = 46) of samples. ARID mutations were associated with a high prevalence of RAS pathway mutations—NF1 (ARID1A, 52.6%; ARID2, 48.5%; ARID1A/2, 63.6%; and ARID-WT, 13.3%; p < 0.0001) and KRAS (ARID1A, 3.5%; ARID2, 3.1%; ARID1A/2, 6.5%; and ARID-WT, 1.0%; p = 0.018)), although BRAF mutations were less common in ARID-mutated cohorts (ARID1A, 31.9%; ARID2, 35.6%; ARID1A/2, 26.1%; and ARID-WT, 50.4%; p < 0.0001). TMB-high was more common in ARID-mutated samples (ARID1A, 80.9%; ARID2, 89.9%; ARID1A/2, 100%; and ARID-WT, 49.4%; p < 0.0001), while PD-L1 positivity was similar across subgroups (ARID1A, 43.8%; ARID2, 51.1%; ARID1A/2, 52.5%; and ARID-WT, 44.9%; p = 0.109). Patients with ARID1A mutations had a higher prevalence of dMMR/MSI-H compared to those with ARID-WT (2.7% vs 0.2%, p = 0.030). Median IFN-γ and T-cell signatures were higher in ARID2-mutated samples compared to ARID-WT (IFN-γ: − 0.15 vs − 0.21, p = 0.0066; T-cell: 23.5 vs − 18.5, p = 0.041). ARID2-mutated patients had improved survival compared to ARID-WT; (HR: 1.22 (95% CI 1.0–1.5), p = 0.022). No additional OS benefit was observed with anti-PD-1 therapy for ARID2 mutation compared to ARID-WT. Melanoma patients with ARID mutations exhibited higher prevalence of markers associated with ICI response, including TMB-H, and immune-related signatures. Our data also suggests improved survival outcome in patients with ARID2 mutations, irrespective of anti-PD1 therapy.

Tumor-infiltrating γδ T cells as targets of immune checkpoint blockade in melanoma.

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell-related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay.

A-427 - Real-World Evaluation of ImmuCare Patient-Reported Outcomes in Melanoma Patients Treated with Immune-Checkpoint Inhibitors

A-427 - Real-World Evaluation of ImmuCare Patient-Reported Outcomes in Melanoma Patients Treated with Immune-Checkpoint Inhibitors

Detectable ctDNA at the time of treatment cessation of ipilimumab and nivolumab for toxicity predicts disease progression in advanced melanoma patients.

Immune checkpoint inhibition (ICI) has led to unprecedented outcomes for melanoma patients but is associated with toxicity. ICI resumption after high grade irAEs poses a significant challenge in the clinical management of melanoma patients and there are no biomarkers that can help identify patients that might benefit from resuming treatment. This study aims to determine if circulating tumor DNA (ctDNA) levels at the time of treatment-limiting irAE could guide treatment decisions in this clinical context. This is a retrospective exploratory biomarker study from 34 patients treated with combination ICI for stage IV melanoma. Patients had a treatment-limiting toxicity and a baseline plasma collection prior to commencing ICI and within 6 weeks of stopping therapy. Blood samples were tested for ctDNA at baseline and cessation therapy. Median progression free survival (PFS) and overall survival (OS) have not been reached (24-month PFS rate 54% and OS rate 72.3%). PD occurred in 47% (16/34) of patients. Median PFS with detectable ctDNA from plasma collected at the time of toxicity was 6.5 months while not reached (NR) with undetectable levels (HR: 4.0, 95% CI 0.95-17.5, p=0.0023). Median OS with detectable ctDNA at cessation for toxicity was 19.4 months and NR for undetectable ctDNA (HR: 3.9, 95%CI 20.8-18.6, p=0.024). Positive ctDNA at the time of cessation was highly specific (specificity 0.94, 95% CI 0.74-0.99, PPV 0.88, 95% CI 0.53-0.99). However, ctDNA negativity has low sensitivity as a predictor of ongoing disease control (sensitivity 0.437, 95% CI 0.23-0.67). Notably, 4/9 (44%) ctDNA negative patients who had disease progression had brain only disease progression. Undetectable ctDNA and CR on imaging after stopping immunotherapy for toxicity results in high rates of long-term durable control. For patients with immunotherapy related toxicity, who have persistent ctDNA at 8 - 12 weeks, the risk of disease progression is significant.

Prognostic value of body composition on survival outcomes in melanoma patients receiving immunotherapy.

The influence of body composition on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with melanoma is still uncertain in clinical practice. Therefore, the objective of this study was to examine the potential association between body composition and clinical outcomes in patients with melanoma undergoing ICIs treatment. A systematic literature search was performed across several databases, including PubMed, Embase, Cochrane Library and Google Scholar, to gather relevant studies. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), assessed by hazard ratios (HR). Secondary outcomes, such as adverse events (AE), were evaluated using odds ratios (OR). This meta-analysis comprised ten articles involving a total of 1,283 patients. Systemic analysis of all collected evidence revealed that body composition, including low skeletal muscle index (SMI) (OS: HR = 1.66, 95% CI = 1.13-2.43, p = 0.010; PFS: HR = 1.28, 95% CI = 1.06-1.55, p = 0.009), high subcutaneous adipose tissue density (SMD) (OS: HR = 1.93, 95% CI = 1.09-3.44, p = 0.025; PFS: HR = 1.31, 95% CI = 1.06-1.63, p = 0.012), and sarcopenia (OS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022; PFS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022), were significantly associated with OS and PFS in melanoma patients treated with ICIs. However, these markers did not show a significant association with treatment-related adverse events. Interestingly, no significant correlation was found between visceral fat index (VFI) (OS: HR = 0.71, 95% CI = 0.29-1.76, p = 0.462; PFS: HR = 0.98, 95% CI = 0.93-1.02, p = 0.274) and OS or PFS in melanoma patients under ICIs treatment. Body composition was found to be associated with decreased treatment response and lower long-term efficacy in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy. However, it is important to note that body composition did not appear to contribute to increased incidence of adverse events in these patients.

Tumour regression predicts better response to interferon therapy in melanoma patients: a retrospective single centre study.

We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan-Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1-T4) of the primary tumour. Regression was significantly positively related to PFS ( P = 0.0018, HR = 0.352) and OS ( P = 0.0112, HR = 0.380), while ulceration showed a negative effect (PFS: P = 0.0001, HR = 2.629; OS: P = 0.0003, HR = 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.

Weighted Trajectory Analysis and Application to Clinical Outcome Assessment

The Kaplan–Meier (KM) estimator is widely used in medical research to estimate the survival function from lifetime data. KM estimation is a powerful tool to evaluate clinical trials due to simple computational requirements, its use of a logrank hypothesis test, and the ability to censor patients. However, KM estimation has several constraints and fails to generalize to ordinal variables of clinical interest, such as toxicity and ECOG performance. We devised weighted trajectory analysis (WTA) to combine the advantages of KM estimation with the ability to visualize and compare treatment groups for ordinal variables and fluctuating outcomes. To assess statistical significance, we developed a new hypothesis test analogous to the logrank test. We demonstrated the functionality of WTA through 1000-fold clinical trial simulations of unique stochastic models of chemotherapy toxicity and schizophrenia disease course. With increments in sample size and hazard ratio, we compared the performance of WTA to KM estimation and the generalized estimating equation (GEE). WTA generally required half the sample size to achieve comparable power to KM estimation; advantages over the GEE included its robust nonparametric approach and summary plot. We also applied WTA to real clinical data: the toxicity outcomes of melanoma patients receiving immunotherapy and the disease progression of patients with metastatic breast cancer receiving ramucirumab. The application of WTA demonstrated that using traditional methods such as KM estimation can lead to both type I and II errors by failing to model illness trajectory. This article outlines a novel method for clinical outcome assessment that extends the advantages of Kaplan–Meier estimates to ordinal outcome variables.

Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies

ABSTRACT Lymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 53 patients treated with combination anti-LAG-3 + anti-PD-1-based therapies. Eleven patients had received prior anti-PD-1-based treatment. Patients were categorized as responders (complete/partial response; n = 36) or non-responders (stable/progressive disease; n = 17) based on the Response Evaluation Criteria in Solid Tumours (RECIST). Tumor-infiltrating lymphocytes (TILs) were scored on hematoxylin and eosin-stained sections. LAG-3 expression was observed in 81% of patients, with staining in TILs and dendritic cells. Responders displayed significantly higher proportions of LAG-3+ cells compared to non-responders (P = .0210). LAG-3 expression positively correlated with TIL score (P < .01). There were no significant differences in LAG-3 expression between different sites of metastases (P > .05). Patients with ≥ 1% LAG-3+ cells in their tumors had significantly longer PFS compared to patients with < 1% LAG-3 expression (P = .0037). No significant difference was observed in overall survival between the two groups (P = .1417). Therefore, the assessment of LAG-3 expression via IHC warrants further evaluation to determine its role as a predictive marker of response and survival in metastatic melanoma.

Characterization the prognosis role and effects of snoRNAs in melanoma patients.

Melanoma is a melanocyte-derived malignant cancer and is known for its early metastasis and high mortality rates. It is a highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, and the identification of reliable diagnostic and prognostic markers is crucial for improving patient outcomes. In the search for biomarkers, various types of RNAs have been discovered and recognized as reliable prognostic markers. Among these, small nucleolar RNAs (snoRNAs) have emerged as a promising avenue for studying early diagnosis and prognostic markers in tumours due to their widespread presence in tissues, tumour specificity and stability. In our study, we analysed snoRNAs data from melanoma samples in the TCGA-SKCM cohort and developed a prognostic model comprising 12 snoRNAs (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 and AC004839). This model exhibited unique prognostic accuracy and demonstrated a significant correlation with the immune infiltration tumour microenvironment. Additionally, analysis of the GSE213145 dataset, which explored the sensitivity and resistance of immune checkpoint inhibitors, further supported the potential of snoRNAs as prognostic markers for immunotherapy. Overall, our study contributes reliable prognostic and immune-related biomarkers for melanoma patients. These findings can offer valuable insights for the future discovery of novel melanoma treatment strategies and hold promise for improving clinical outcomes in melanoma patients.

Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy

ABSTRACT Although immune checkpoint inhibitor (ICI) therapy has dramatically improved outcome for metastatic melanoma patients, many patients do not benefit. Since adverse events may be severe, biomarkers for resistance would be valuable, especially in the adjuvant setting. We performed high-plex digital spatial profiling (DSP) using the NanoString GeoMx® on 53 pre-treatment specimens from ICI-treated metastatic melanoma cases. We interrogated 77 targets simultaneously in four molecular compartments defined by S100B for tumor, CD68 for macrophages, CD45 for leukocytes, and nonimmune stromal cells defined as regions negative for all three compartment markers but positive for SYTO 13. For DSP validation, we confirmed the results obtained for some immune markers, such as CD8, CD4, CD20, CD68, CD45, and PD-L1, by quantitative immunofluorescence (QIF). In the univariable analysis, 38 variables were associated with outcome, 14 of which remained significant after multivariable adjustment. Among them, CD95 was further validated using multiplex immunofluorescence in the Discovery immunotherapy (ITX) Cohort and an independent validation cohort with similar characteristics, showing an association between high levels of CD95 and shorter progression-free survival. We found that CD95 in stroma was associated with resistance to ICI. With further validation, this biomarker could have value to select patients that will not benefit from immunotherapy.

Demographics, Clinical Characteristics and Survival Outcomes of Primary Urinary Tract Malignant Melanoma Patients: A Population-Based Analysis.

All primary urinary tract malignant melanoma (ureter vs. bladder vs. urethra) patients were identified from within the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020. Kaplan-Maier plots depicted the overall survival (OS) rates. Univariable and multivariable Cox regression (MCR) models were fitted to test the differences in overall mortality (OM). In the overall cohort (n = 74), the median OS was 22 months. No statistically significant or clinically meaningful differences were recorded according to sex (female vs. male; p = 0.9) and treatment of the primary (endoscopic vs. surgical; p = 0.6). Conversely, clinically meaningful but not statistically significant (p ≥ 0.05) differences were recorded according to the patient's age at diagnosis (≤80 vs. ≥80 years old; p = 0.2), marital status (married 26 vs. unmarried 16 months; p = 0.2), and SEER stage (localized 31 vs. regional 14 months; p = 0.4), and the type of systemic therapy (exposed 31 vs. not exposed 20 months; p = 0.06). Finally, in univariable and MCR analyses, after adjustment for the SEER stage and type of systemic therapy, tumor origin within the bladder was associated with a three-fold higher OM (Hazard ratio: 3.00; p = 0.004), compared to tumor origin within the urethra. In conclusion, primary urinary tract malignant melanoma patients have poor survival. Specifically, tumor origin within the bladder independently predicted a higher OM, even after adjustment for the SEER stage and systemic therapy status.