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Pembrolizumab in the management of metastatic melanoma.

ABSTRACT: Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role in the treatment of advanced melanoma. Through blockade of PD-1, it leads to an increase in effector T-cell activity in the tumor microenvironment. Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, pharmacodynamics and safety of the compound are discussed in this article. Phase I trials have demonstrated safety and efficacy of pembrolizumab in advanced, pretreated melanoma patients. When compared with chemotherapy in a Phase II trial of ipilimumab-refractory patients, those treated with pembrolizumab showed superior progression-free survival. In addition, in the pivotal Phase III trial pembrolizumab improved overall survival compared with ipilimumab in patients naive to immune checkpoint inhibition. Pembrolizumab is well tolerated and has a favorable safety profile. Common adverse events are fatigue, rash, itching and diarrhea. Less frequent immune-related adverse events include hypothyroidism, colitis, hepatitis and pneumonitis.

SUBMITTER: Spain L

PROVIDER: S-EPMC6094659 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Pembrolizumab in the management of metastatic melanoma.

Spain Lavinia L Younger Eugenie E Hatipoglu Emine E Larkin James J

Melanoma management 20151112 4

Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role in the treatment of advanced melanoma. Through blockade of PD-1, it leads to an increase in effector T-cell activity in the tumor microenvironment. Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, pharmacodynamics and safety of the compound are discussed in this article. Phase I trials have demonstrated safety and efficacy of pembrolizumab in advanced, pretreated melanoma patients. When compare ...[more]

PMID: 30190860

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Pembrolizumab and tavokinogene telseplasmid electroporation in metastatic melanoma.

Project description:IntroductionTavokinogene Telseplasmid Electroporation Therapy (TAVO) and Pembrolizumab therapy is being studied in subjects with immune checkpoint inhibitor (ICI) resistant melanoma. TAVO is a novel office-based local therapy shown to be effective in patients with advanced melanoma. The technique involves the direct injection of a plasmid encoding IL-12 into an accessible tumor driven by electroporation. The tumor cells have then been shown to express high levels of IL-12 resulting in a local inflammatory response within the tumor microenvironment.Presentation of caseThe patient with stage IIB, pT3b melanoma was treated with primary tumor resection and found to have a negative sentinel node biopsy. She subsequently developed regional recurrence and was treated with inguinal lymphadenectomy and adjuvant Nivolumab. Despite therapy, she had progression of disease with skin and subcutaneous metastases (in-transit lesions), brain and liver lesions, hilar and iliac nodal disease. She was transitioned to nivolumab + ipilimumab, and Talimogene Laherparepvec (T-VEC) therapy for the in-transit lesions, without success. Stereotactic radiosurgery was used for the brain metastasis. Groin subcutaneous and in-transit lesions were treated with TAVO and intravenous pembrolizumab. Serial physical exams and CT scans were used to assess response.DiscussionAll lesions treated with TAVO resolved. An abscopal response was also noted: hilar and mediastinal lymphadenopathy resolved. The liver mass and pelvic lymphadenopathy decreased in size, and her brain metastasis remained stable after radiation.ConclusionThis case suggests that combination TAVO and Pembrolizumab is a safe and effective local treatment for ICI resistant metastatic melanoma in the setting of rheumatoid arthritis. An abscopal effect was also noted through control of systemic disease.

| S-EPMC7708754 | biostudies-literature

New developments in the management of advanced melanoma - role of pembrolizumab.

Project description:Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma.

| S-EPMC4576895 | biostudies-literature

CD103 and periplakin are potential biomarkers for response of metastatic melanoma to pembrolizumab.

Project description:This study was designed to screen for preliminary evidence of predictive markers of melanoma response to PD-1 blockade. We hypothesized that the following immune markers would be positive predictors of response: increased densities of CD103 + CD8 + T cells or Th1 lineage T-bet + T cells, high expression of CXCL9-11 and presence of tertiary lymphoid structures. Conversely, we hypothesized that the high expression of barrier molecules would be a negative predictor of response. Patients with advanced melanoma treated with pembrolizumab were identified, and clinical response as well as overall survival data were collected. Tumor samples were evaluated by multiplex immunofluorescence histology. All statistical analyses were performed in R Studio and Microsoft Excel using the Mann-Whitney U test, chi-square test, Spearman's rank correlation and Kaplan-Meier survival curves. Sixty-five advanced melanoma patients were identified, of whom 46 met inclusion criteria and were included in this study. Increased densities ( P = 0.04) and proportions ( P = 0.02) of CD8 + T cells expressing CD103 + were associated with complete response (CR) to pembrolizumab. Improved survival was associated with increased proportions of CD8 + cells expressing CD103 ( P = 0.0085) as well as decreased density of periplakin + cells ( P = 0.012) and periplakin + SOX10 + cells ( P = 0.0012). The density and proportion of CD8 + T cells expressing CD103 + positively correlated with PD-L1 expression, though PD-L1 expression was not significantly correlated with outcomes. This screening study found that increased density and proportion of CD8 + T cells expressing CD103 and decreased density of periplakin were associated with positive outcomes in patients with melanoma metastases treated with pembrolizumab and may warrant further study.

| S-EPMC9633418 | biostudies-literature

The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma.

Project description:Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016-002114-50.

| S-EPMC8397717 | biostudies-literature

Management of metastatic cutaneous melanoma: updates in clinical practice.

Project description:In recent years, several drugs have been approved for the treatment of patients with metastatic cutaneous melanoma, completely reshaping the landscape of this aggressive disease. Immune therapy with cytotoxic T-lymphocyte antigen 4 and programmed cell death-1 inhibitors yielded significant and durable responses, achieving long-term disease control in up to 40% of the patients. BRAF inhibitors (BRAFi), in combination with MEK inhibitors, also resulted in improved overall survival compared with single-agent BRAFi in patients with BRAFV600-mutated metastatic melanoma. The optimized sequencing and duration of treatment, however, is yet to be found. In this article, we thoroughly review current data and discuss how to best sequence the various treatment modalities available at present, based on four distinct clinical presentations commonly seen in clinic. In addition, we review treatment options beyond checkpoint inhibitors and targeted therapy, which may be required by patients failing such effective treatments.

| S-EPMC6535734 | biostudies-literature

Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma.

Project description:BACKGROUND:To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab. METHODS:The study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect efti antibody formation and determine long-lived CD8 T cell responses and associated pharmacodynamic parameters. RESULTS:Twenty-four patients with melanoma received pembrolizumab and bi-weekly subcutaneous (s.c.) injections of efti at doses 1 mg, 6 mg or 30 mg/injection for up to 6 months (part A) or 30 mg/injection for up 12 months (part B). No dose-limiting toxicities were reported and the main adverse event for efti was injection site reactions. Sustained systemic exposure to the product was obtained in all patients following s.c. injections of 30 mg dose. Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-?, a Th1 signature cytokine. An overall response rate (ORR) of 33% was observed in patients partly with pembrolizumab-refractory of part A and ORR of 50% was observed in patients with PD-1 naïve of part B. CONCLUSIONS:Efti was well tolerated in combination with pembrolizumab with encouraging antitumor activity. This warrants further clinical studies of this new combination therapy combining an antigen-presenting cell activator with an immune checkpoint inhibitor.

| S-EPMC7682474 | biostudies-literature

Drug targets and predictive biomarkers in the management of metastatic melanoma.

Project description:Melanoma is the leading cause of fatal skin cancer, and in the past few decades, there has been an increase in the incidence of and mortality from metastatic melanoma. Until recently, the therapeutic options for treatment of metastatic melanoma were limited. The approval of ipilimumab (an anti-CTLA-4 antibody) and vemurafenib (mutant B-RAF(V600E) kinase inhibitor) by the Federal Drug Administration has led to a new era in melanoma treatment, and additional promising drugs and drug combinations are currently being investigated. As the choices of treatment for melanoma have expanded, the need to identify predictive biomarkers to tailor treatment strategies to individual tumor or immune system characteristics has become necessary. Such strategies have the potential of maximizing antitumor effect while minimizing toxicity and improving clinical benefit. In this article, we review the currently approved targeted therapies in melanoma and discuss the future of personalized therapy for this disease.

| S-EPMC3513235 | biostudies-literature

Pembrolizumab in metastatic gastric cancer

Project description:Pembrolizumab in metastatic gastric cancer: comprehensive molecular characterization of clinical response

| PRJEB25780 | ENA

Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment.

Project description:The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential.

| S-EPMC4881844 | biostudies-literature

Pembrolizumab for the treatment of advanced melanoma.

Project description:IntroductionSince 2010 multiple targeted therapies and immunotherapies have been approved for the treatment of advanced melanoma. Pembrolizumab, a humanized monoclonal antibody directed against programed death receptor 1 has shown significant activity in advanced melanoma resulting in its approval first as post-ipilimumab and subsequently as frontline treatment.Areas coveredThis article reviews the approved agents for the treatment of advanced melanoma with a focus on the preclinical and clinical evidence for the use of pembrolizumab in this setting. Primary emphasis is given to the clinical development of pembrolizumab, including phase I-III trials. Finally, we explore the role of pembrolizumab in combination with other therapies and ongoing investigations into its effectiveness in expanded patient populations.Expert opinionPembrolizumab provides durable responses and represents a major advancement in the treatment options for patients with advanced melanoma. Early studies of pembrolizumab in combination with other therapeutic agents have generated significant interest and further investigations including advanced clinical trials are warranted to evaluate safety and potential improved outcomes. Pembrolizumab and other immune checkpoint inhibitors are likely to play an expanded role in the treatment of advanced melanoma and other solid tumors over the next decade.

| S-EPMC5010088 | biostudies-literature

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