Systemic Therapy in Metastatic Melanoma.
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ABSTRACT:
SUBMITTER: Goyal G
PROVIDER: S-EPMC6375453 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Systemic Therapy in Metastatic Melanoma.
Goyal Gaurav G Silberstein Peter T PT
Federal practitioner : for the health care professionals of the VA, DoD, and PHS 20150501 Suppl 4
New targeted treatments and therapies for metastatic melanoma are improving patient prognosis and survival. ...[more]
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Project description:Simple Summary Malignant melanoma is more dangerous than most other skin cancers due to its ability to spread early and aggressively. Until the development of new therapeutic strategies, the median survival of patients with metastatic melanoma was just a few months. Immunotherapy, the first regimen, leading to significant improvement, blocks immune checkpoints, which normally dampen immune responses, enabling our defense cells to recognize and destroy cancer cells again. Immunotherapy achieves long-term survival in about 50% of metastatic melanoma patients. Besides, targeted therapy has also significantly improved the survival of melanoma patients, blocking cell-signaling proteins, which are altered in about 50% of melanomas and lead to uncontrolled tumor cell growth. In addition to the approved regimens, there are numerous new treatment strategies, ranging from modified viruses to personalized immune cells that attack and destroy tumor cells. This review shall give an insight into both already approved regimens and upcoming developments. Abstract This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.
| S-EPMC8003858 | biostudies-literature
Project description:PurposeLocal radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.Methods and materialsIn our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.ResultsCombination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.ConclusionThis is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.
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Project description:Management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the past 10 years due to better understanding of tumor biology. This development has changed mRCC to a chronic progressive disease with several lines of treatment options. The introduction of several new targeted therapies including immunotherapy has improved median overall survival of approximately 1 year to >2 years in mRCC.
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Project description:We report a case of rapidly enlarging metastatic melanoma in 45-year-old White male following primary resection of thin melanoma five years ago. Location and large size of the lesion possessed significant risk of complications from surgery, therefore provided a challenge in treatment options. Neoadjuvant targeted chemotherapy was commenced and resulted in a significant reduction in size of the lesion, which allowed subsequent safe surgical resection with no residual disease on histopathology results. This case provides a good example of successful utilization of neoadjuvant systemic therapy in advanced metastatic melanoma.
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Project description:The past decade has witnessed impressive new developments for the treatment of melanoma. The discovery of key oncogenic driver mutations, upon which tumor establishment and progression are dependent, changed the prognosis of patients with stage IV disease. Extensive preclinical and clinical studies have shown high response rates and survival benefits over conventional chemotherapies provided by target-specific inhibitors of BRAF- or NRAS-activating mutations. Recent genomic analyses of melanoma have also given new potentially targetable driver mutations. In addition, the quickened pace of development of immune checkpoint inhibitors for the treatment of melanoma offers the unique opportunity to provide a long-term clinical benefit. In this emerging era, predictive biomarkers for the selection of patients are required to help us develop an optimal therapeutic strategy.
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Project description:BackgroundLocoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing.MethodsThe relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents.ResultsIntralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary.ConclusionsDue to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.
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Project description:This review article is based on specifically targeted nanoparticles that have been used in the treatment of melanoma. According to the Skin Cancer Foundation, within 2017 an estimated 9730 people will die due to invasive melanoma. Conventional treatments for nonmalignant melanoma include surgery, chemotherapy, and radiation. For the treatment of metastatic melanoma, 3 therapeutic agents have been approved by the Food and Drug Administration: dacarbazine, recombinant interferon ?-2b, and high-dose interleukin 2. Photodynamic therapy is an alternative therapy that activates a photosensitizer at a specific wavelength forming reactive oxygen species which in turn induces cell death; it is noninvasive with far less side effects when compared to conventional treatments. Nanoparticles are generally conjugated to photosynthetic drugs, since they are biocompatible, stabile, and durable, as well as have a high loading capacity, which improve either passive or active photosensitizer drug delivery to targeted cells. Therefore, various photosynthetic drugs and nanoparticle drug delivery systems specifically targeted for melanoma were analyzed in this review article in relation to either their passive or their active cellular uptake mechanisms in order to deduce the efficacy of photodynamic therapy treatment for metastatic melanoma which currently remains ongoing. The overall findings from this review concluded that no current photodynamic therapy studies have been performed in relation to active nanoparticle platform photosensitizer drug carrier systems for the treatment of metastatic melanoma, and so this type of research requires further investigation into developing a more efficient active nano-photosensitizer carrier smart drug that can be conjugated to specific cell surface receptors and combinative monoclonal antibodies so that a further enhanced and more efficient form of targeted photodynamic therapy for the treatment of metastatic melanoma can be established.
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Project description: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.
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