Therapy For Metastatic Melanoma Research Articles

Cannabinoids Reduce Melanoma Cell Viability and Do Not Interfere with Commonly Used Targeted Therapy in Metastatic Melanoma In Vivo and In Vitro.

Background: Cannabinoids are mainly used for recreational purposes, but also made their way into oncology, since these substances can be taken to increase appetite in tumour cachexia. Since there are some hints in the literature that cannabinoids might have some anti-cancerous effects, the aim of this study was to study if and how cannabinoids mediate pro-apoptotic effects in metastatic melanoma in vivo and in vitro and its value besides conventional targeted therapy in vivo. Methods: Several melanoma cell lines were treated with different concentrations of cannabinoids, and anti-cancerous efficacy was assessed by proliferation and apoptosis assays. Subsequent pathway analysis was performed using apoptosis, proliferation, flow cytometry and confocal microscopy data. The efficacy of cannabinoids in combination with trametinib was studied in NSG mice in vivo. Results: Cannabinoids reduced cell viability in multiple melanoma cell lines in a dose-dependent way. The effect was mediated by CB1, TRPV1 and PPARα receptors, whereby pharmacological blockade of all three receptors protected from cannabinoid-induced apoptosis. Cannabinoids initiated apoptosis by mitochondrial cytochrome c release with consecutive activation of different caspases. Essentially, cannabinoids significantly decreased tumour growth in vivo and were as potent as the MEK inhibitor trametinib. Conclusions: We could demonstrate that cannabinoids reduce cell viability in several melanoma cell lines, initiate apoptosis via the intrinsic apoptotic pathway by cytochrome c release and caspase activation and do not interfere with commonly used targeted therapy.

BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge.

Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.

Abstract CT069: Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma

Abstract Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma

The design and synthesis of new promising compounds based on thienopyrimidine scaffold containing 2-aminothiophene fragments with good safety and favorable drug-like properties are highly relevant for chemotherapy. In this study, a series of 14 variants of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives (11aa-oa) and their precursors (31 compounds) containing 2-aminothiophenes fragments (9aa-mb, 10aa-oa) were synthesized and screened for their cytotoxicity against B16–F10 melanoma cells. The selectivity of the developed compounds was assessed by determining the cytotoxicity using normal mouse embryonic fibroblasts (MEF NF2 cells). The lead compounds 9cb, 10ic and 11jc with the most significant antitumor activity and minimum cytotoxicity on normal non-cancerous cells were chosen for further in vivo experiments. Additional in vitro experiments with compounds 9cb, 10ic and 11jc showed that apoptosis was the predominant mechanism of death in B16–F10 melanoma cells. With support from in vivo studies, compounds 9cb, 10ic and 11jc demonstrated the biosafety to healthy mice and significant inhibition of the metastatic nodules in pulmonary metastatic melanoma mouse model. Histological analysis detected no abnormal changes in the main organs (the liver, spleen, kidneys, and heart) after the therapy. Thus, the developed compounds 9cb, 10ic and 11jc demonstrate high efficiency in the treatment of pulmonary metastatic melanoma and can be recommended for further preclinical investigation of the melanoma treatment.

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis...

Systemic therapy of skin metastatic melanoma with BRAF gene mutation

Purpose of the study. To conduct a comparative analysis of the effectiveness of the use of mono‑mode immuno‑oncological and targeted drugs in the first line of therapy in patients with metastatic melanoma of the skin (SMM) in patients with BRAF mutation.Patients and methods. To achieve this goal, a retrospective analysis of the treatment results was carried out in 61 patients diagnosed with metastatic melanoma of the skin and the presence of a mutation in the BRAF gene who were treated at the Yaroslavl regional oncology hospital. The patients were divided into two groups: the first group (n = 18) included patients who received mono‑mode immunotherapy in the first line of treatment; the second group (n = 43) included patients who underwent targeted first-line therapy.Standard regimens of monotherapy with BRAF inhibitors (vemurafenib, dabrafenib) or combination therapy with BRAF and MEK inhibitors (dabrafenib + trametinib) were chosen as treatment. Immunotherapy was performed using the following drugs: pembrolizumab, nivolumab and prolgolimab. An intergroup comparative analysis of one‑year, three‑year and five‑year survival rates was carried out. Progression‑free survival rates and the frequency of objective responses were also studied.Results. The median follow–up period in the first group was 14.2 months, in the second – 15.7 months. The indicators of one‑year, three-year and five‑year overall survival in patients receiving immunotherapy in the first line were 88.8 %, 55.5 % and 33.3 %, respectively. The same indicators in patients in the first‑line targeted therapy group were 90.7 %, 46.5 % and 23.2 %, respectively. The median overall survival in the first group was 39.1 months, in the second group it was 30.4 months. Progression–free survival in the group of patients with targeted therapy was 8.7 months, in the immunotherapy group – 9.8 months. In the first group, stabilization of the disease was observed in 77.8 % of patients, while a complete response was noted in 5.6 %, a partial response was not registered. In the second group of patients, stabilization was noted in 39.6 % of patients, partial response in 25.6 % of patients, complete response was absent.Conclusion. The use of cancer immunotherapy drugs in the first line of treatment in patients with metastatic melanoma of the skin and the presence of BRAF mutation in the short term is not inferior in effectiveness to the use of targeted drugs, and in the medium and long term exceeds targeted drugs.

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)

Vogt-Koyanagi-Harada-like Syndrome and Electronegative Electroretinogram after Nivolumab Therapy for Metastatic Cutaneous Melanoma: A Case Report

Background: Vogt-Koyanagi-Harada-like (VKH) syndrome or electronegative electroretinograms (ERG) have both been described before or after immunotherapy for metastatic cutaneous melanoma, but they have not been described occurring together. Objective: The objective of this study is to describe a case of VKH-like syndrome occurring simultaneously with an electronegative ERG after nivolumab therapy for metastatic cutaneous melanoma. Methods: Case report of a patient with ocular findings after nivolumab therapy for metastatic melanoma was reported. Multimodal imaging, including color fundus photography, optical coherence tomography (OCT), and both full-field and multifocal ERGs were used to describe the findings. Literature review was conducted with PubMed. Results: We reported a case of a patient with nivolumab-treated melanoma presenting with presumed VKH-like syndrome with panuveitis, choroidal depigmentation, and cutaneous vitiligo, as well as melanoma-associated retinopathy (MAR)-like electronegative ERG findings. Nivolumab was stopped and corticosteroid therapy was initiated. Although the patient’s visual acuity remained severely limited, her inflammation resolved, and the areas of choroidal depigmentation slowly decreased over years of subsequent follow-up. Conclusion: Vision loss accompanied by simultaneous VKH-like findings with choroidal vitiligo and a MAR-like electronegative ERG may develop after nivolumab therapy. The uveitic and vitiligo may improve with immunosuppressive therapy, but the vision loss and ERG findings may persist.

Acute Late-Onset Diffuse Encephalopathy Secondary to Target Therapies in Metastatic Melanoma

Acute Late-Onset Diffuse Encephalopathy Secondary to Target Therapies in Metastatic Melanoma

A Case of Autoimmune Hypophysitis Induced by Ipilimumab/Nivolumab Combination Therapy for Metastatic Melanoma

A Case of Autoimmune Hypophysitis Induced by Ipilimumab/Nivolumab Combination Therapy for Metastatic Melanoma

Momordica cochinchinensis (Gấc) Seed Extracts Induce Apoptosis and Necrosis in Melanoma Cells.

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration of proteins and peptides that was more cytotoxic to the melanoma cells than other extraction solvents. The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. This cytotoxicity was cancer-specific with lower cytotoxic effects on HaCaT epidermal keratinocytes. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma.

Selected Articles from This Issue

Shoushtari and colleagues report a pilot trial of ONCOS-102, a novel oncolytic adenovirus encoding GM-CSF, administered intratumorally either sequentially or in combination with pembrolizumab in patients with melanoma resistant to prior PD-1 blockade. Treatment was well tolerated. Objective responses were seen in 7 of 20 patients, and size reductions in noninjected lesions suggested local delivery of ONCOS-102 can drive a systemic anti-tumor effect. Serial biopsies of injected tumors at baseline, Week 3 (following ONCOS-102 and prior to pembrolizumab), and Week 9 (following ONCOS-102 and pembrolizumab) indicated that while most tumors experience CD8+ and CD4+ infiltration after ONCOS-102 injection, sustained infiltration at Week 9 was associated with clinical benefit. Future trials of ONCOS-102 and checkpoint inhibition are warranted in anti-PD-1-resistant melanoma. These findings suggest trials using viral agents in anti-PD-1-resistant disease should not solely rely on early onset of cytotoxicity to predict clinical response.Wainberg and colleagues report on the combination of very low doses of chemotherapy (10% of the usual dose) with a full dose of talazoparib (TAL). The study design reports preferentially increasing the dose of TAL before increasing the chemotherapy to improve the hematologic profile as well as exploring efficacy signals among non-BRCA patients. This phase I study demonstrates that TAL with low-dose temozolomide or irinotecan shows an improved hematologic toxicity profile than most prior chemo/PARP inhibitor combinations and has signals of clinical activity in small cell lung cancer and ovarian cancer. The results of this phase I study are supportive of ongoing trials with this combination.Obesity has been unexpectedly associated with improved outcomes with immune checkpoint inhibitors and BRAF-targeted therapies in metastatic melanoma; however, the biology underlying this observation is unknown. Hahn and colleagues examined associations between body mass index (BMI) and molecular, immune, and metabolic features of melanoma tumors as well as host microbiome in 782 patient specimens. Host BMI was associated with altered tumor metabolism, with downregulation of oxidative phosphorylation (OXPHOS) and other metabolic pathways in tumors from high BMI patients. OXPHOS has been associated with resistance to targeted and immune therapies, suggesting a potential mechanism underlying the “obesity paradox” in metastatic melanoma.Circulating tumor DNA (ctDNA) levels are associated with tumor volume and minimal residual disease in lymphoid malignancies. Fernández-Miranda and colleagues suggest that pre-treatment ctDNA levels in follicular lymphoma patients could be useful to predict response to treatment and early progression as an independent predictive biomarker or in combination with clinical variables. Circulating tumor DNA levels and cell-free DNA genotyping at mid-treatment and end-of-treatment are associated with treatment response and early progression follicular lymphoma. Circulating tumor DNA measurement at diagnosis and follow-up is a valuable tool that might feasibly be used in clinical trials and, eventually, in daily clinical practice.

New approaches to targeted therapy for metastatic melanoma in the presence of rare genetic changes in the tumor

<h3></h3> За последние 10 лет произошел существенный прорыв в лечении меланомы кожи, связанный с разработкой и применением таргетных препаратов. Долгое время единственными таргетными препаратами в лечении меланомы кожи являлись BRAF/МЕК и c-KIT-ингибиторы, а также препараты иммунотерапии. Трижды негативные опухоли с отсутствием стандартных мутаций <i>BRAF, NRAS и с-KIT</i> составляют, по разным данным, до 40%. Для этой группы отсутствуют какие-либо эффективные способы лечения после отрицательной динамики на фоне имммунотерапии. Поэтому последние годы ведется активный поиск новых точек приложения лекарственных препаратов в ДНК опухоли, ее белках и микроокружении. Ведутся исследования как драйверных мутаций, так и соматических, обладающих онкогенными свойствами. Однако на данный момент для лечения меланомы с редкими генетическими изменениями FDA (Food and Drug Administration) одобрила только ингибиторы NTRK. В данном обзоре рассмотрены некоторые редкие молекулярно-генетические особенности опухолевых клеток, которые в перспективе могут быть использованы в клинической практике.

New clinical developments in combination therapy for metastatic melanoma: ASCO annual congress, June 2022

New clinical developments in combination therapy for metastatic melanoma: ASCO annual congress, June 2022

Impact of Covid-19 on the management of patients with metastatic melanoma

The Covid-19 pandemic created new uncertainties in the management of metastatic melanoma patients. In particular, the impact of immunotherapy, targeted therapy, or chemotherapy on the risk of Sars-CoV-2 infection and severity was debated. In this study, we analyzed all patients with metastatic melanoma receiving therapy who developed Covid-19 between February 2020 and February 2022. We retrospectively collected demographic data, cancer-specific parameters, melanoma treatment regimen, comorbidities and Covid-19-specific parameters in these patients. Of the 350 patients with metastatic melanoma, 25 had Covid-19. The median age at the time of Covid-19 diagnosis was 66 years (range 36-86), 10 patients were female, and 15 patients were male. The treatment regimen during infection was immunotherapy in 12 cases, followed by targeted therapy (n = 8), chemotherapy (n = 2), and TVEC injections, follow-up and palliative therapy in 1 case each. The severity was mild in 17 patients and 8 had a moderate to critical course. Patients with a severe Covid-19 course were often older and had more comorbidities than patients with a mild infection. Many of the patients had a mild Covid-19 course despite having metastatic melanoma and systemic therapy. We therefore recommend continuing systemic therapy whenever possible, even in such exceptional situations as the Covid-19 pandemic.

Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.

This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort

Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. No record of standard diagnostic criteria of MUP used in the participating centers. Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway

BET inhibition or BRD4 depletion is a promising and attractive therapy for metastatic melanoma; however, the mechanism is still unclear. Here, we indicated that BET inhibition suppressed melanoma metastasis both in vitro and in vivo and identified a new mechanism by which BET inhibitors suppress melanoma metastasis by blocking the direct interaction of BRD4 and the SPINK6 enhancer. Moreover, we demonstrated that SPINK6 activated the EGFR/EphA2 complex in melanoma and the downstream ERK1/2 and AKT pathways. Thus, these results identified the SPINK6/EGFR-EphA2 axis as a new oncogenic pathway in melanoma metastasis and support the further development of BRD4 inhibitors for the treatment of metastatic melanoma in the clinic.

239P Survival outcomes predicted by irAEs on 18F-FDG-PET in response to PD-1 antibody therapy in metastatic melanoma

PD-1 antibody therapy has revolutionised the landscape of metastatic cutaneous melanoma treatments and outcomes. The aim of our study is to investigate whether immune related adverse events (irAEs) or granulomatous/reactive nodal changes visible on 18F-FDG-PET during treatment with PD-1 antibody therapy for metastatic cutaneous melanoma predicts improved overall survival.