Looking into a Better Future: Novel Therapies for Metastatic Melanoma

Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-021-00525-9 REVIEW Looking into a Better Future: Novel Therapies for Metastatic Melanoma Alessia Villani . Massimiliano Scalvenzi . Gabriella Fabbrocini . Jorge Ocampo-Candiani . Sonia Sofı́a Ocampo-Garza Received: March 2, 2021 Ó The Author(s) 2021 ABSTRACT Even though melanoma represents a small percentage of all cutaneous cancers, it is responsible for most deaths from skin neoplasms. In early stages it can be successfully treated with surgery, but as the disease expands the survival rate drops significantly. For many years the mainstay of treatment for metastatic melanoma was chemotherapeutic agents, even though they failed to prove survival prolongation. After the advent of ipilimumab, a survival benefit and better overall response rate could be offered to the patients. Other new therapies, such as immunotherapies, targeted therapies, vaccines, and small molecules, are currently being studied. Also, combination regimens have demonstrated superiority to some monotherapies. Nowadays, ipilimumab should no longer be considered the first-line therapy given its severe Alessia Villani and Massimiliano Scalvenzi are contributed equally to the manuscript. A. Villani (&)
M. Scalvenzi
G. Fabbrocini
S. S. Ocampo-Garza Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy e-mail: J. Ocampo-Candiani
S. S. Ocampo-Garza Dermatology Department, Universidad Autónoma de Nuevo León, University Hospital ‘‘Dr. José Eleuterio González’’, Monterrey, NL, Mexico toxicity and lower efficacy, while nivolumab remains efficacious and has a good safety profile. T-VEC as monotherapy has been shown to be an elegant alternative even for the elderly or cases of head and neck melanomas. If the BRAF mutation status is positive, the combination of dabrafenib and trametinib could be an option to consider. Despite the success of the novel treatments, their effectiveness is still limited. New studies have opened up new avenues for future research in melanoma treatment, which is expected to lead to better therapeutic outcomes for our patients. The objective of this review is to discuss the novel therapies for metastatic melanoma that have been tested in humans during the last 3 years to obtain a sharper perspective of the available treatment options for specific patient characteristics. Keywords: Melanoma; Metastatic melanoma; Targeted therapy; Immune checkpoint inhibitors; Vaccines; Small molecules Dermatol Ther (Heidelb) Key Summary Points Even though melanoma represents a small percentage of all cutaneous cancers, it is responsible for most deaths from skin cancers The survival rate at 5 years for localized melanoma is 98.3% while for metastatic melanoma (MM) is 16% In the last decade melanoma clinical research has completely changed the scenario of therapeutic approaches for patients with unresectable advanced melanoma Multiple targets for drug development have been identified to treat advanced melanoma and are currently undergoing development DIGITAL FEATURES This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/ m9.figshare.14317787. INTRODUCTION Cutaneous melanoma is responsible for most deaths from cutaneous neoplasms with an increasing incidence worldwide [1, 2]. Survival rates vary depending on tumor stage at the time of diagnosis, which depends on the depth of the tumor (Breslow) as well as lymph node involvement or distant metastasis [3]. Stage I and II involve localized disease, stage III is characterized by metastasis to the local lymph nodes, and stage IV represents distant metastasis [4]. The survival rate at 5 years for localized melanoma is 98.3% while for metastatic melanoma (MM) is 16% [3]. Surgery remains the first treatment option for resectable melanoma [2]. For many years the mainstay of treatment for MM was chemotherapeutic agents, even though they failed to prove survival prolongation [3, 5]. Finally, in 2010 the advent of ipilimumab changed the overall response rate (ORR) and offered a survival benefit [5]. After ipilimumab, other new therapies, such as immunotherapies, targeted therapies, vaccines, small molecules, and combination therapies, have changed the prognosis for patients with MM. Although nowadays patients can be offered a wider variety of therapies, many characteristics have to be taken into account, such as the presence of melanoma genome mutations, specific features of the tumor, comorbidities and tolerability of the patient, as well as risks associated with treatment [2]. In this study we discuss the novel therapies for metastatic melanoma that have been tested in humans during the last 3 years to obtain a sharper perspective related to the available treatment options for specific patient characteristics. METHODS A literature search on PubMed, Medline, EBSCO, Google Scholar, and the Cochrane Library databases regarding treatment of metastatic melanoma from January 2018 to February 2021 was made. Reviews, metanalyses, clinical trials (CT), real-life studies (RLS), case reports, and series were reviewed. The most relevant articles were included. A revision of the references was also made to include articles that could have been missed. Assessment of treatment efficacy was made through overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), disease-free survival (DFS), durable response rate (DRR), and overall response rate (ORR). A summary of available therapies for MM is shown in Fig. 1. All included studies are shown in Table 1. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. Dermatol Ther (Heidelb) Five-year OS was 40.9%, and the median OS was 39 months. In 25.8% of the included patients, the oncologist considered a complete response (CR). At 3 years the probability of being alive and of not requiring other therapy was 72.1%. Patients with M1b disease were more likely to have CR compared to other stage IV and stage III combined [7]. Fig. 1 Summary of some of the available therapies for metastatic melanoma Immune Checkpoint Inhibitors Programmed Cell Death protein-1 (PD-1) and cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) are immune checkpoint molecules that downregulate T cell activation pathways, important in the immune tolerance. PD-1 is expressed on activated T cells, B and NK cells, and monocytes. It binds to its ligand PDL-1 and inhibits the signaling of T cell receptor, preventing T cell activation and the release of proinflammatory cytokines. CTLA-4 is a homolog of CD28 and is expressed on regulatory T cells, inhibiting signals to T cells [6]. Anti-PD1 In 2020, a retrospective, single-center analysis with stage III/IV melanoma patients (...truncated)