Therapy For Metastatic Melanoma Research Articles

Mesoporous silica coated spicules for photodynamic therapy of metastatic melanoma

We report on the fabrication of mesoporous silicon dioxide coated Haliclona sp. spicules (mSHS) to enhance the delivery of the insoluble photosensitizer protoporphyrin IX (PpIX) into deep skin layers and mediate photodynamic therapy for metastatic melanoma in mice. The mSHS are dispersed sharp edged and rod-like micro-particles with a length of approximate 143.6 ± 6.4 μm and a specific surface area of 14.9 ± 3.4 m2/g. The mSHS can be topically applied to the skin, adapting to any desired skin area and lesion site. The insoluble PpIX were incorporated into the mesoporous silica coating layers of mSHS (mSHS@PpIX) with the maximum PpIX loading capacity of 120.3 ± 3.8 μg/mg. The mSHS@PpIX significantly enhanced the deposition of PpIX in the viable epidermis (5.1 ± 0.4 μg/cm2) and in the dermis (0.5 ± 0.2 μg/cm2), which was 154 ± 11-fold and 22 ± tenfold higher than those achieved by SHS, respectively. Topical delivery of PpIX using mSHS (mSHS@PpIX) completely eradicated the primary melanoma in mice in 10 days without recurrence or metastasis over 60 days. These results demonstrate that mSHS can be a promising topical drug delivery platform for the treatment of diverse cutaneous diseases, such as metastatic melanoma.Graphic

TGF-β mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma.

Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-β (TGF-β) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-γ, and TGF-β were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-β expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8months; p = 0.006) and overall survival (17.9 vs. 2.63months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-β expression at baseline had smaller lesions (2.41 ± 3.27mL vs. 42.79 ± 101.08mL, p < 0.001) and higher dissimilarity (12.01 ± 28.23 vs. 5.65 ± 8.4; p = 0.018). Discussion: These results provide evidence that high TGF-β expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.

Abstract 2415: Resistance to immune checkpoint inhibitor (ICI) therapy in metastatic melanoma is revealed by deep circulating tumor DNA tracking in concert with tumor immune profiling

Abstract Monitoring clinically actionable and emerging mutations in circulating tumor DNA (ctDNA) may be crucial for guiding treatment, but adoption has been slow due to the narrow scope and reproducibility of current approaches. Here, we investigate melanoma patients receiving ICI over several years, beginning with extensive tumor mutational and immune profiling followed by deep, whole-exome ctDNA monitoring.Here, 66 plasma samples from 23 advanced stage melanoma patients that were collected throughout ICI treatment (up to 40 months) were profiled using the NeXT Liquid Biopsy® platform (NeXT LB). NeXT LB monitors exome-wide ctDNA by leveraging a patient’s tumor, PBMCs and plasma samples, detecting both tumor-derived and emerging mutations. In addition to ctDNA tracking, we also used the ImmunoID NeXT Platform® to immunologically profile tumor tissue; including gene expression quantification, HLA profiling (typing, mutation, and loss of heterozygosity), T-cell receptor and tumor microenvironment profiling, and neoantigen prediction. ctDNA dynamics and tumor immunity were correlated with clinical outcome. Patients who progressed had lower tumor mutational burden (TMB, Mann-Whitney (MW); p=0.03), and lower neoantigen burden (MW; p=0.04). Responding tumors were enriched for interferon gamma and inflammatory signaling (Wald; adjusted p&amp;lt;0.01) and myeloid dendritic cells (MW; p=0.01), as measured by baseline RNA expression profiling. With an average coverage of 2260X SD +/-157, plasma samples yielded from 4 to 4081 variants. The number of on-treatment tumor variants detected in plasma predicted increased OS hazard (HR=2.95, Wald p=0.03; Kaplan-Meier (KM) p=0.0003) and progression hazard (HR=1.74, Wald p=0.04; KM p=0.0003). Overall, 10% (4277) of all variants were novel mutations observed only in the plasma. Novel variants were less likely to emerge in genes conferring sensitivity to ICI therapy (mixed-model; p&amp;lt;0.001). Dynamic shifts in allelic fraction between baseline and the first available on-treatment timepoint predicted increased OS hazard (HR=3.02, Wald p=0.05) and progression hazard (HR=2.90, Wald p=0.02). In ctDNA clonal phylogenies, 100% of BRAF and NRAS mutations belonged to the dominant clone. By combining immune and ctDNA features, a multivariable model predicted resistance to ICI treatment (log-likelihood p=0.002; c-index=0.89). Using a single liquid biopsy platform, we profiled tumor immunity and tracked existing and emerging ctDNA variants over the course of ICI treatment. We demonstrate that, even though counts of on-treatment ctDNA variants were sufficient for significant survival models, deep profiling of both tumor immunity and ctDNA dynamics provided deeper understanding of ICI resistance. Subsequent studies will determine if ctDNA-guided intervention can improve clinical outcomes. Citation Format: Charles W. Abbott, Laura Keller, Isabel Heidrich, Julian Kött, Glenn Geidel, Daniel J. Smit, Ronald Simon, Stefan Schneider, Jason Pugh, Sean M. Boyle, Richard O. Chen, Klaus Pantel, Christoffer Gebhardt. Resistance to immune checkpoint inhibitor (ICI) therapy in metastatic melanoma is revealed by deep circulating tumor DNA tracking in concert with tumor immune profiling [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 2415.

Abstract 5879: Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma

Abstract Introduction: Metastatic melanoma is one of the most aggressive cancers, despite recent improvements in therapy. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to find more effective therapeutic targets. The efficacy of targeted MAPK signaling pathway inhibitors (MAPKi) in metastatic melanoma therapy is limited by the development of resistance mechanisms that result in disease relapse. This situation necessitates alternative treatments for melanoma patients who develop resistance to targeted therapy. We have recently found out that there exists a group of human tumors that express lower levels of Mic60, a mitochondrial structural protein also known as mitofilin or inner membrane mitochondrial protein (IMMT). In a model of prostate cancer, we showed that Mic60-low tumors have lower mitochondrial fitness, but increased cell motility, invasion, and propensity to metastasize. However, a potential differential expression of Mic60 in melanoma has not been investigated and whether reduced mitochondrial fitness in Mic60-low tumors can expose new therapeutic vulnerabilities in combination with targeted therapies has not been determined. Experimental Procedures: We analyzed melanoma-specific TMA for differential expression of Mic60 in tumor vs. adjacent normal tissue by IHC. Differential mRNA expression levels were examined by single-cell RNA-Seq and quantified by bioinformatics analysis. Differential therapeutic vulnerabilities of Mic60-low melanoma cell lines to mitochondrial-targeted small molecule Hsp90 inhibitor, Gamitrinib, were assessed for cell death induction and mitochondrial dysfunction. Results: We identified subsets of melanoma patients with constitutively reduced or outright undetectable expression of Mic60, in vivo. By single-cell RNA-Seq, Mic60-low melanomas were characterized by reduced oxidative phosphorylation and decreased ATP production, slower cell cycle progression but paradoxically increased cell motility and invasion. Loss of Mic60 exposed new, actionable therapeutic vulnerabilities, and the combination of Gamitrinib plus MAPKi potently induced mitochondrial cell death in MAPKi-resistant melanoma cell lines. Conclusion: Mic60 is heterogeneously expressed and often reduced in melanoma. Although this is associated with increased cell invasion and metastatic propensity, the combination of Gamitrinib plus MAPKi restored mitochondrial cell death in therapy-resistant, Mic60-low melanoma cells. Citation Format: Jagadish C. Ghosh, Segundo Del Aguila, Haiyin Li, Jessie Villanueva, Dario C. Altieri. Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma [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 5879.

Neo-Adjuvant Therapy for Metastatic Melanoma.

Melanoma treatment is leading the neo-adjuvant systemic (NAS) therapy field. It is hypothesized that having the entire tumor in situ, with all of the heterogeneous tumor antigens, allows the patient's immune system to have a broader response to the tumor in all its shapes and forms. This translates into a higher clinical efficacy. Another benefit of NAS therapy potentially includes identifying patients who have a favorable response, which could offer an opportunity for the de-escalation of the extent of surgery and the need for adjuvant radiotherapy and/or adjuvant systemic therapy, as well as tailoring the follow-up in terms of the frequency of visits and cross-sectional imaging. In this paper, we will review the rationale for NAS therapy in resectable metastatic melanoma and the results obtained so far, both for immunotherapy and for BRAF/MEKi therapy, and discuss the response assessment and interpretation, toxicity and surgical considerations. All the trials that have been reported up to now have been investigator-initiated phase I/II trials with either single-agent anti-PD-1, combination anti-CTLA-4 and anti-PD-1 or BRAF/MEK inhibition. The results have been good but are especially encouraging for immunotherapies, showing high durable recurrence-free survival rates. Combination immunotherapy seems superior, with a higher rate of pathologic responses, particularly in patients with a major pathologic response (MPR = pathologic complete response [pCR] + near-pCR [max 10% viable tumor cells]) of 60% vs. 25-30%. The SWOG S1801 trial has recently shown a 23% improvement in event-free survival (EFS) after 2 years for pembrolizumab when giving 3 doses as NAS therapy and 15 as adjuvant versus 18 as adjuvant only. The community is keen to see the first results (expected in 2024) of the phase 3 NADINA trial (NCT04949113), which randomized patients between surgery + adjuvant anti-PD-1 and two NAS therapy courses of a combination of ipilimumab + nivolumab, followed by surgery and a response-driven adjuvant regimen or follow-up. We are on the eve of neo-adjuvant systemic (NAS) therapy, particularly immunotherapy, becoming the novel standard of care for macroscopic stage III melanoma.

What Is the Timing and Role of Targeted Therapy in Metastatic Melanoma?

Melanoma is the most lethal cutaneous malignancy worldwide. The last 15 years have ushered in several regulatory approvals that have dramatically altered the landscape of treatment options for patients with melanoma. Many patients with melanoma harbor activating mutations in the BRAF proto-oncogene, a key component of the mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therapies targeting BRAF have led to remarkable improvements in both response rates and survival in patients with metastatic disease. In parallel with these developments in MAPK-targeted therapy has been the clinical development of immune checkpoint inhibitors, which also have improved response rates and survival in patients with metastatic disease including randomized trials compared with MAPK-targeted therapy in patients with advanced, BRAF-mutant melanoma. Immune checkpoint inhibitors have become the preferred first-line standard-of-care treatment for patients with newly diagnosed metastatic disease in patients irrespective of BRAF mutational status. Given these developments, it is now less clear how to optimize the use of MAPK-targeted therapy regarding treatment setting and in sequence with immune checkpoint inhibitor.

Current Role and Status for Intratumoral Injection Therapies in Metastatic Melanoma.

Intratumoral therapies represent a unique avenue for drug development in melanoma as patients often have accessible lesions that are particularly amenable to these approaches. In addition, a majority of intratumoral therapies have focused on stimulating antitumor immune responses, making them a particularly attractive option for use in melanoma. In this review, we describe applications for talimogene laherparepvec, a US Food and Drug Administration-approved intratumoral therapy in melanoma, as well as several classes of intratumoral therapies in development including novel oncolytic viruses, mRNA-based intratumoral injections, and cytokines and other signaling molecules.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma.

Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.

Targeted therapy or immunotherapy in BRAF-mutated metastatic melanoma: a Spanish center's decade of experience.

Targeted therapies and immunotherapy are currently considered the mainstay first-line treatment for advanced BRAF-mutated melanoma. However, the impact of treatment (targeted therapy and immunotherapy) and the prognostic factors are still not clear. Medical records of 140 patients diagnosed with advanced melanoma between 2011 and 2021 were retrospectively reviewed to extract demographic, BRAF status, treatment, performance status, and survival data. ORR, PFS, and OS were compared between patients diagnosed with advanced melanoma and treated with first-line IT or BRAF/MEKi. The prognostic factors were assessed using Cox regression models. In all patients and those treated with immunotherapy, we did not find any effect of BRAF status on ORR, PFS, or OS. In patients with BRAF-mutated melanoma, ORR was 43.8% vs. 70% (P=0.04), PFS was 19.2 vs. 11.5 months (p=0.22), and OS was 33.4 vs. 16.4 months for the immunotherapy and targeted therapy groups, respectively (P=0.04). ECOG, presence of brain metastases, and high LDH level from initiation of first-line treatment were all associated with differences in PFS and OS. Patients with advanced BRAF-mutated melanoma treated with first-line immunotherapy had a significantly longer PFS and OS than those treated with first-line BRAF/MEKi; however, first-line BRAF/MEKi treatment had a significantly higher ORR than first-line immunotherapy.

Nivolumab and Relatlimab (Opdualag)

&#x0D; CADTH recommends that Opdualag be reimbursed for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma if certain conditions are met.&#x0D; Opdualag should only be covered to treat patients aged 12 years or older who have a histologically confirmed diagnosis of unresectable stage III or stage IV (metastatic) melanoma and have not received prior systemic therapy for advanced melanoma. Patients should be in relatively good health (i.e., have a good performance status, as determined by a specialist).&#x0D; Patients who had prior adjuvant or neoadjuvant anti–programmed death-1 (PD-1) or anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) therapy if the therapy was completed at least 6 months before the date of recurrence are eligible for reimbursement. Opdualag should not be reimbursed in patients with active brain metastases, uveal melanoma, and active autoimmune disease. Opdualag should only be reimbursed if the price of Opdualag is reduced. The feasibility of adoption of Opdualag must also be addressed.&#x0D;

Immune checkpoint inhibitors in metastatic melanoma therapy (Review).

An increase in the incidence of melanoma has been observed in recent decades, which poses a significant challenge due to its poor prognosis in the advanced and metastatic stages. Previously, chemotherapy and high doses of interleukin-2 were available treatments for melanoma; however, they offered limited survival benefits and were associated with severe toxicities. The treatment of metastatic melanoma has been transformed by new developments in immunotherapy. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PDL-1, have emerged as promising therapeutic options. Commonly used ICIs, such as ipilimumab, nivolumab and pembrolizumab, have been found to be associated with an improved median overall survival, recurrence-free survival and response rates compared to traditional chemotherapies. Combination therapies involving different types of ICIs, such as anti-PD1 with anti-CTLA-4, have further enhanced the overall survival and response rates by targeting various phases of T-cell activation. Additionally, the development of novel biomarkers has facilitated the assessment of responses to ICI therapy, with tissue and serum-based prognostic and predictive biomarkers now available. The increased response observed with ICIs also provides potential for immune-related adverse effects on various organ systems. Further research is required to evaluate the efficacy and safety of various combinations of ICIs, while ongoing clinical trials explore the potential of newer ICIs. Concerns regarding the development of resistance to ICIs also warrant attention. The present review summarizes and discusses the advent of ICIs with a marked significant breakthrough in the treatment of metastatic melanoma, providing improved outcomes compared to traditional therapies.

The Effect of Non-Overlapping Somatic Mutations in BRAF, NRAS, NF1, or CKIT on the Incidence and Outcome of Brain Metastases during Immune Checkpoint Inhibitor Therapy of Metastatic Melanoma

The Effect of Non-Overlapping Somatic Mutations in BRAF, NRAS, NF1, or CKIT on the Incidence and Outcome of Brain Metastases during Immune Checkpoint Inhibitor Therapy of Metastatic Melanoma

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology.

Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma.

Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.

Isolated Limb Infusion as First, Second, or Third or Later-Line Therapy for Metastatic In-Transit Melanoma.

Ten percent of patients with melanoma develop in-transit metastases (ITM). Isolated limb infusion (ILI) is a well-established therapy for unresectable ITM on the extremities, but the ideal sequencing/line of therapy of ILI has not been defined. This study evaluates ILI as first-line, second-line, or third or later-line therapy. A retrospective review included all patients with unresectable ITM who underwent ILI from 2006-2023. A total of 130 patients were identified, 61% female, median age of 71 (31-89) years. Median follow-up was 37.5 months. ILI was first-line therapy in 80% (n = 104), second-line in 15% (n = 19), and third or later-line in 5.4% (n = 7). Overall response rate (ORR) and complete response (CR) rates for ILI as any line of therapy were 74% and 41%, respectively. ORR for ILI as first, second, or third or later-line therapy were 78%, 63%, and 57%, respectively. CR rates for ILI as first, second, or third or later-line therapy were 42%, 37%, and 43%, respectively. There were no significant differences in ORR, progression-free survival (PFS), overall survival, or disease-free survival between therapy lines. Median PFS for ILI as first, second, or third or later-line therapy were 6.9, 5.4, and 18months, respectively. Patients responded well to ILI, whether or not they received previous therapies for unresectable ITM. First-line ILI appears to have a better ORR than later lines of ILI. Although sample size limited statistical significance, there was a 21% improvement in ORR when ILI was used as first-line vs third-line therapy, which is clinically meaningful. ILI is effective for unresectable melanoma ITM and can be used as salvage therapy.

Diagnostic challenges of posterior scleritis in pembrolizumab treated patient for cutaneous melanoma: A case report

PurposeTo describe various clinical pictures of posterior scleritis following pembrolizumab therapy for metastatic cutaneous melanoma. MethodsDescription of the clinical case with data from patient presentation and recurrences, diagnostic examinations, treatment, and six-months follow up. Clinical presentation of previous reports of pembrolizumab related of eye inflammation are discussed. ResultsA 49-year-old patient underwent resection of metastatic melanoma of the skin with sentinel lymph nodes removal and pembrolizumab adjuvant therapy every three weeks. Nine months after pembrolizumab initiation the patient accessed ophthalmology emergency service complaining one week vision loss on her right eye associated with pain on eye movement. Ocular examination revealed right eye papillitis and posterior scleritis. Intravenous corticosteroid treatment was started associated with topical prednisolone drops, after which complete resolution of the subretinal fluid was seen. During the six months follow up one episode of posterior scleritis was observed in the contralateral eye and resolved after peribulbar corticosteroid injection and oral therapy and one recurrence of intermediate scleritis in the right eye which resolved after oral therapy. ConclusionPosterior and intermediate scleritis may be added to the spectrum of pembrolizumab related eye inflammation; in the case presented posterior scleritis occurred asymmetrically in both eyes suggesting chronic features, importance of steroid tapering and follow up.

Prognostic and predictive biomarkers in melanoma

Biomarkers help to inform the clinical management of patients with melanoma. For patients with clinically localised primary melanoma, biomarkers can help to predict post-surgical outcome (including via the use of risk prediction tools), better select patients for sentinel lymph node biopsy, and tailor catch-all follow-up protocols to the individual. Systemic drug treatments, including immune checkpoint inhibitor (ICI) therapies and BRAF-targeted therapies, have radically improved the prognosis of metastatic (stage III and IV) cutaneous melanoma patients, and also shown benefit in the earlier setting of stage IIB/C primary melanoma. Unfortunately, a response is far from guaranteed. Here, we review clinically relevant, established, and emerging, prognostic, and predictive pathological biomarkers that refine clinical decision-making in primary and metastatic melanoma patients. Gene expression profile assays and nomograms are emerging tools for prognostication and sentinel lymph node risk prediction in primary melanoma patients. Biomarkers incorporated into clinical practice guidelines include BRAF V600 mutations for the use of targeted therapies in metastatic cutaneous melanoma, and the HLA-A∗02:01 allele for the use of a bispecific fusion protein in metastatic uveal melanoma. Several predictive biomarkers have been proposed for ICI therapies but have not been incorporated into Australian clinical practice guidelines. Further research, validation, and assessment of clinical utility is required before more prognostic and predictive biomarkers are fluidly integrated into routine care.

The features and management of acquired resistance to PD1-based therapy in metastatic melanoma

BackgroundAnti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. MethodsPts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. Results299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). ConclusionsAcquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

Cost-effectiveness analysis of encorafenib and binimetinib combination as first-line treatment for metastatic or unresectable &lt;i&gt;BRAF&lt;/i&gt; V600-mutated metastatic melanoma in Russia

Objective: to perform a cost-effectiveness analysis of using encorafenib and binimetinib combination in the first-line therapy for metastatic or unresectable BRAF V600-mutated melanoma in the Russian Federation. Material and methods. The comparators included “dabrafenib + trametinib” combination and vemurafenib monotherapy, which are listed in the Russian clinical guidelines and the Vital and Essential Drugs List. Since “encorafenib and binimetinib” combination demonstrated superior overall response rate compared to “dabrafenib + trametinib” and vemurafenib monotherapy, the method of cost-effectiveness analysis was used. We developed a disease progression model based on data from the COLUMBUS randomized control trial and published network meta-analysis. The model was used to calculate the direct medical costs associated with the considered alternatives over a 3-year modeling horizon. We compared the incremental cost-effectiveness ratio for “encorafenib + binimetinib” vs. “dabrafenib + trametinib” to the same ratio calculated for “dabrafenib + trametinib” vs. vemurafenib monotherapy.Results. Mean costs of using “encorafenib + binimetinib” combination over a 3-year period, considering the discontinuation of treatment as the disease progresses, was 6,547,693.07 rubles. Meanwhile, it was 5,962,742.52 rubles for “dabrafenib + trametinib” and 2,581,781.45 rubles for vemurafenib monotherapy. The incremental cost-effectiveness ratio of “encorafenib + binimetinib” vs. “dabrafenib + trametinib” was 3,846,818.71 rubles per 1 patient with a response to therapy. This was 85.14% lower than the same ratio estimated for “dabrafenib + trametinib” vs. vemurafenib monotherapy (25,890,022.64 rubles per 1 patient with a response to therapy).Conclusion. The “encorafenib + binimetinib” combination is a cost-effective treatment method for patients with unresectable or metastatic BRAF V600-mutated melanoma in the Russian Federation.

Kinome profiling identifies MARK3 and STK10 as potential therapeutic targets in uveal melanoma

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the “dark kinome”. Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. A custom siRNA screen targeting these kinases demonstrated that knockdown of microtubule affinity regulating kinase 3 (MARK3) and serine/threonine kinase 10 (STK10) significantly reduced uveal melanoma cell growth and decreased expression of cell cycle proteins. Additionally, knockdown of MARK3 but not STK10 decreased ERK1/2 phosphorylation. Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma.