Treatment Of Advanced Metastatic Melanoma Research Articles

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Treatment of Advanced Metastatic Melanoma.

The introduction in clinical practice of new drug compounds both targeted therapies anti-BRAF and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. This has led to a significant improvement in terms of response rates and particularly in the overall survival (OS). The long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median OS rates around 24 months, with 5-year survival rates around 35-40%. As to the drugs currently available and reimbursed by the Italian National Health System, 3 combinations of anti-BRAF/anti-MEK inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). As for checkpoint inhibitors, first line immunotherapy is represented by anti-PD1 blockers (nivolumab and pembrolizumab), whilst the anti-CTLA-4 ipilimumab can be used as second line immunotherapy. The decision-making factors that define the best treatment approach in stage IV patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. This review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. It will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice.

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance.

In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such et al. (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. De novo HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.

Anti-PD-1 immunotherapy in advanced metastatic melanoma: State of the art and future challenges

Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 drugs, is an area in increasing development for its efficacy and advantages in the treatment of advanced metastatic melanoma. In fact, immunotherapy has been the target of several and recent studies in different types of cancer, namely in melanoma, a globally growing threat. Contributing to the increasing incidence of this cancer is climate change, particularly global warming of the past century, which has increased the tendency to spend more time outdoors and, consequently, exposure to sunlight and ultraviolet radiation. Among the most relevant risk factors for melanoma is the increase in ultraviolet radiation due to ozone layer depletion, one of the main factors responsible for the incidence of new cases. Anti-PD-1 agents like Nivolumab and Pembrolizumab allow a more effective treatment, enhancing the duration of the responses to therapy and prolonging the survival of the patient. However, recent studies about safety and tolerability have stated that, although these drugs present less adverse effects and toxicity, they may lead to specific autoimmune-mediated adverse events. Overall, immunotherapy with anti-PD-1 agents represents a highly promising area in the treatment of some types of cancer such as melanoma.

Electrochemotherapy: an effective local treatment of cutaneous and subcutaneous melanoma metastases

Treatment of multiple cutaneous and subcutaneous melanoma metastases is still represents a therapeutic challenge for both dermatologists and oncologists. Electrochemotherapy (ECT) is a promising therapeutic procedure, owing to its ability to improve the penetration of cytotoxic drugs into cancer cells by application of current electric pulses. The aim of our study is to evaluate efficacy, tolerability and long-term efficacy of ECT in the treatment of advanced metastatic melanoma. Thirty patients affected by a total of 654 cutaneous and subcutaneous melanoma metastatic nodules were recruited. All patients were treated after they had undergone to a mild general anesthesia. Intravenous Bleomicina solution was administered 8 minutes before the application of electric pulses, generated by a Cliniporator (TM) (the device validated for ECT). The objective response rate of 100% (67.28% complete response and 32.72% partial response) was observed. A total of 214 metastatic lesions from 24 patients received a second ECT session, among them 141 showed a further complete response. Twenty-four months later, the local tumor control rate was 72%. The results of this study seem to demonstrate that ECT is an effective and valid therapeutic tool for the treatment of cutaneous metastases from melanoma. ECT can be considered a first-line palliative treatment since it is able to alleviate pain and reduce the tumor's spontaneous bleeding with a significant improve of patients' quality of life.

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dosedense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon- alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dosedense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach

Targeted inhibition of BRAF kinase: opportunities and challenges for therapeutics in melanoma

Malignant melanoma is the most aggressive form of skin cancer and its incidence has increased dramatically in the last two decades. Even with a high rate of success in the treatment of early stages of this malignancy, currently there are no effective strategies for the treatment of advanced metastatic melanoma. Much effort has been put into the use of different target-specific drugs, among which BRAF kinase-specific small-molecule inhibitors have rendered promising results as therapeutic agents in metastatic melanoma. Nonetheless, some side effects, such as development of SCC (squamous cell carcinoma), as well as tumour resistance and recurrence, are common limitations of this therapeutic strategy. The use of combination treatments in which different regulatory pathways or the immunological response are targeted seems to be a promising tool for the future success of melanoma therapeutics.

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKbeta (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-kappaB. BMS-345541 inhibits IKKbeta-mediated phosphorylation of IkappaBalpha and thus blocks the nuclear localization of NF-kappaB, whereas BAY 54-9085 inhibits activation of NF-kappaB through a mechanism that does not involve stabilization of IkappaBalpha. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-kappaB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-kappaB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-kappaB is not also targeted.

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dose-dense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon-alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dose-dense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach for the treatment of advanced metastatic melanoma.

Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma.

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.

Treatment of advanced metastatic melanoma -some new approaches with chemotherapy and interleukin 2 (IL-2)

Treatment of advanced metastatic melanoma -some new approaches with chemotherapy and interleukin 2 (IL-2)

Positive phase II study in the treatment of advanced malignant melanoma with fotemustine

To date, dacarbazine (DTIC) has been the most effective drug in the treatment of advanced metastatic melanoma, achieving response rates of up to 28% (mean, 21%). Multidrug responses were generally no better than those obtained using monotherapy. A quite promising clinical trial was conducted using the new nitrosourea fotemustine. A total of 19 patients presenting with advanced malignant melanoma (clinical stage IV according to the 1987 UICC classification system) underwent treatment involving a more rapid infusion of the drug and a reduction in the rest period from 5 to 3 weeks. This monotherapy with fotemustine yielded two complete responses and seven partial responses; in addition, four patients showed no change and six cases progressed after the induction cycle (median duration of response to date, 7.6 months, including four cases that have not relapsed). Fotemustine was well tolerated by the patients, with the only mild side effects being thrombocytopenia, leukocytopenia and easily controlled nausea/vomiting. Preclinical studies performed previously indicated that fotemustine inhibits enzymes involved in the ribonucleotide reduction pathway (i.e. DNA synthesis), whereby responding patients (n = 3) appeared to favor the thioredoxin reductase/thioredoxin electron transfer to ribonucleotide reductase, whereas non-responders (n = 4) expressed the alternate glutathione reductase/glutaredoxin mechanism. The 47% response rate obtained in these studies vs the 24% reported previously for fotemustine may reflect variations in enzymes in the ribonucleotide reduction pathway in different patients. However, the efficacy of fotemustine against advanced melanoma warrants more extensive trials of this drug, especially since the quality of life of the patients during and after chemotherapy was not severely affected.