Systematic review of medical treatment in melanoma: current status and future prospects.
ABSTRACT: The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite advances in the field. Standard treatment for patients with thick (?2.0 mm) primary melanoma with or without regional metastases to lymph nodes is surgery followed by adjuvant therapy or clinical trial enrollment. Adjuvant therapy with interferon-? and cancer vaccines is discussed in detail. Patients who progress to stage IV metastatic melanoma have a median survival of ?1 year. Standard treatment with chemotherapy yields low response rates, of which few are durable. Cytokine therapy with IL-2 achieves durable benefits in a greater fraction, but it is accompanied by severe toxicities that require the patient to be hospitalized for support during treatment. A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the promise of those still in clinical development that may yield incremental improvements in the treatment of advanced, metastatic melanoma.
Project description:Melanoma is the most aggressive and deadly type of skin cancer. Surgical resection with or without lymph node sampling is the standard of care for primary cutaneous melanoma. Adjuvant therapy decisions may be informed by careful consideration of prognostic factors. High-dose adjuvant interferon alpha-2b increases disease-free survival and may modestly improve overall survival. Less toxic alternatives for adjuvant therapy are currently under study. External beam radiation therapy is an option for nodal beds where the risk of local recurrence is very high. In-transit melanoma metastases may be treated locally with surgery, immunotherapy, radiation, or heated limb perfusion. For metastatic melanoma, the options include chemotherapy or immunotherapy; targeted anti-BRAF and anti-KIT therapy is under active investigation. Standard chemotherapy yields objective tumor responses in approximately 10%-20% of patients, and sustained remissions are uncommon. Immunotherapy with high-dose interleukin-2 yields objective tumor responses in a minority of patients; however, some of these responses may be durable. Identification of activating mutations of BRAF, NRAS, c-KIT, and GNAQ in distinct clinical subtypes of melanoma suggest that these are molecularly distinct. Emerging data from clinical trials suggest that substantial improvements in the standard of care for melanoma may be possible.
Project description:Introduction:Breakthroughs in targeted therapy have significantly improved outcomes for many patients with advanced melanoma, including those with BRAFV600 mutant disease. Targeted therapy for BRAFV600-mutant metastatic melanoma includes combinations of BRAF inhibitors and MEK inhibitors, which improve response rates and prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, while durable responses have been observed, many patients develop acquired resistance to these drugs. Areas covered:Recent clinical trial updates and ongoing studies with targeted therapy for BRAF-V600 mutant melanoma are reviewed. Expert opinion:Although BRAF targeted therapy remains an effective treatment for BRAF-mutant for melanoma, ongoing trials are exploring combinations with other targeted therapeutics and immunotherapeutics to determine whether tumor responses can be prolonged, and these drugs are increasingly utilized in the neoadjuvant and adjuvant settings.
Project description:Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment.
Project description:The accelerated development in the treatment of metastatic melanoma, both in molecular targeted therapy and immunotherapy, is already starting to impact on adjuvant therapy in stage III melanoma. Following the approval of ipilimumab for adjuvant therapy in melanoma, clinical trials assessing other checkpoint modulators and MAPK pathway inhibitors as adjuvant treatments for melanoma are currently ongoing. As results from these trials mature in the next few years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.
Project description:Until recently there was no effective systemic therapy for metastatic melanoma. Increased understanding of tumor biology and immune regulation has led to the development of drugs targeting the mitogen-activated protein kinase (MAPK) pathway (BRAF inhibitors and MEK inhibitors) and T-cell regulation (CTLA4 antibodies). These drugs are the new standard of care, however barriers to better patient outcomes include limited responses and significant toxicities (CTLA4 antibodies) and lack of durability in the majority of cases (BRAF and MEK inhibitors). This review discusses the next stages of development of treatments in melanoma, including immune checkpoint blocking drugs targeting the PD-1/PD-L1 axis, and the use of BRAF and MEK inhibitors in combination. Both approaches lead to a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes even further, clinical trials of combinations of MAPK inhibitors, immunotherapies and other signal pathway inhibitors are underway. Adjuvant studies of many of these drugs have commenced, with the hope of also improving outcomes in patients with early-stage melanoma.
Project description:Melanoma is the most aggressive form of skin cancer whose worldwide incidence is rising faster than any other cancer. Few treatment options are available to patients with metastatic disease, and standard chemotherapeutic agents are generally ineffective. Cytokines such as IFN-? or IL-2 can promote immune recognition of melanoma, occasionally inducing dramatic and durable clinical responses. Here, we discuss several immunomodulatory agents, the safety of which are being evaluated in clinical trials. Challenges include an incomplete understanding of signaling pathways, appropriate clinical dose and route, and systemic immunosuppression in advanced melanoma patients. We consider how targeted cytokine therapy will integrate into the clinical arena, as well as the low likelihood of success of single cytokine therapies. Evidence supports a synergy between cytokine immunotherapy and other therapeutic approaches in melanoma, and strengthening this area of research will improve our understanding of how to use cytokine therapy better.
Project description:Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.
Project description:Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.
Project description:Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastatic melanoma and widely used as adjuvant therapy for stage III disease. With the observation that higher tumor mutational burden correlates with a better response, checkpoint inhibitors are tested in other skin cancer types of known high tumor mutational burden with promising results and recently became the first-ever FDA-approved treatment for metastatic Merkel cell carcinoma. The emerging new standards-of-care will necessitate more precise biomarkers and predictors for treatment response and immune-related adverse events. Measurable immune-related mediators are currently under investigation as factors that promote or block the response to cancer immunotherapy and may provide insights into the underlying immune response to the tumor. Cytokines and chemokines are such mediators and are crucial for facilitating the recruitment and activation of specific subsets of leukocytes within the microenvironment of skin cancers. The exact mechanisms of how these meditators, both immunological and non-immunological, operate in the tumor microenvironment is an area of active research, so to reliable biomarkers of responses to cancer immunotherapy. Here, we will review and summarize the expanding body of literature for immune-related biomarkers pertaining to Melanoma, Basal cell carcinoma, Squamous cell carcinoma, and Merkel cell carcinoma, highlighting clinically relevant checkpoint inhibitor therapy biomarker advancements.
Project description:Locally/regionally advanced melanoma confers a major challenge in terms of surgical and medical management. Surgical treatment carries the risks of surgical morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of relapse and death despite the use of standard adjuvant therapy. Neoadjuvant therapy has the potential to significantly improve the clinical outcome of these patients, particularly in this era of newer and effective targeted and immunotherapeutic agents. Previous neoadjuvant studies tested chemotherapy with temozolomide where the clinical activity was limited. Biochemotherapy (BCT) was tested in two studies in the neoadjuvant setting and showed high tumor response rates; however, BCT was ultimately abandoned following its failure to demonstrate survival benefits in randomized trials of metastatic disease. Success of immunotherapy and targeted therapy in prolonging the lives of patients with metastatic melanoma generated considerable interest to investigate these novel strategies in the adjuvant and neoadjuvant settings. A number of neoadjuvant targeted and immunotherapy studies have been completed in melanoma to date and have yielded promising clinical activity. Given these encouraging results, a number of studies with other molecularly targeted and immunotherapeutic agents and their combinations are ongoing in the neoadjuvant setting; long-term outcome data are eagerly awaited. Such studies also provide access to biospecimens before and during therapy, allowing for the conduct of biomarker and mechanistic studies that may have a significant impact in guiding adjuvant therapy choices and drug development.