Mek pd-1

Nalan Akgul Babacan, Zeynep Eroglu
PURPOSE OF REVIEW: While anti-PD-1 antibodies have been a breakthrough in the treatment of patients with advanced melanoma, a substantial proportion of patients are still refractory to or progress after treatment with anti-PD-1 immunotherapy. Here, we review the post anti-PD-1 therapy alternatives that may be possible for patients with unresectable or metastatic stage 3 or 4 melanoma. RECENT FINDINGS: Currently available treatment options include BRAF-targeted and MEK inhibitor-targeted therapies for those with BRAFV600 mutant melanoma, while for patients with BRAF-WT melanoma or those who have already received prior BRAF-targeted therapy, options include anti-CTLA-4 therapy, alone or in combination with anti-PD-1 therapy, or for selected patients, clinical trials that may incorporate other immune checkpoint inhibitors or co-stimulatory agonists, oncolytic virotherapies, adoptive cellular therapies, or other novel agents...
March 20, 2020: Current Oncology Reports
Mi-Heon Lee, Jane Yanagawa, Linh Tran, Tonya C Walser, Bharti Bisht, Eileen Fung, Stacy J Park, Gang Zeng, Kostyantyn Krysan, William D Wallace, Manash K Paul, Luc Girard, Boning Gao, John D Minna, Steven M Dubinett, Jay M Lee
Oncogenic KRAS mutations are frequently found in non-small cell lung carcinoma (NSCLC) and cause constitutive activation of the MEK-ERK pathway. Many cancer types have been shown to overexpress PD-L1 to escape immune surveillance. FRA1 is a MEK/ERK-dependent oncogenic transcription factor and a member of the AP-1 transcriptional factor superfamily. This study assesses the hypothesis that KRAS mutation directly regulates PD-L1 expression through the MEK-ERK pathway mediated by FRA1. Premalignant human bronchial epithelial cell (HBEC) lines harboring the KRAS mutationV12 , EGFR mutation, p53 knock-down, or both KRAS mutation and p53 knock-down were tested for levels of PD-L1, FRA1, and ERK activation (pERK)...
2020: American Journal of Translational Research
Selma Ugurel, Joachim Röhmel, Paolo A Ascierto, Jürgen C Becker, Keith T Flaherty, Jean J Grob, Axel Hauschild, James Larkin, Elisabeth Livingstone, Georgina V Long, Paul Lorigan, Grant A McArthur, Antoni Ribas, Caroline Robert, Lisa Zimmer, Dirk Schadendorf, Claus Garbe
BACKGROUND: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking...
March 13, 2020: European Journal of Cancer
Matilde Monti, Francesca Consoli, Raffaella Vescovi, Mattia Bugatti, William Vermi
The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells...
February 11, 2020: Cells
M D Hellmann, T-W Kim, C B Lee, B-C Goh, W H Miller, D-Y Oh, R Jamal, C-E Chee, L Q M Chow, J F Gainor, J Desai, B J Solomon, M Das Thakur, B Pitcher, P Foster, G Hernandez, M J Wongchenko, E Cha, Y-J Bang, L L Siu, J Bendell
BACKGROUND: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. PATIENTS AND METHODS: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts...
July 2019: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Claire Gorry, Laura McCullagh, Michael Barry
BACKGROUND: Many high cost treatments for advanced melanoma have become available in recent years. National health technology assessment agencies have raised concerns regarding uncertainty in their clinical and cost-effectiveness. OBJECTIVE: The aim of this systematic review is to identify economic evaluations of treatments for advanced melanoma and review model assumptions, outcomes, and quality as preparation for a health technology assessment. METHODS: A search of Embase, MEDLINE, EconLit, and the Cochrane Database was conducted...
January 2020: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Avner Friedman, Nourridine Siewe
One of the most frequently found mutations in human melanomas is in the B-raf gene, making its protein BRAF a key target for therapy. However, in patients treated with BRAF inhibitor (BRAFi), although the response is very good at first, relapse occurs within 6 months, on the average. In order to overcome this drug resistance to BRAFi, various combinations of BRAFi with other drugs have been explored, and some are being applied clinically, such as a combination of BRAF and MEK inhibitors. Experimental data for melanoma in mice show that under continuous treatment with BRAFi, the pro-cancer MDSCs and chemokine CCL2 initially decrease but eventually increase to above their original level, while the anticancer T cells continuously decrease...
January 14, 2020: Bulletin of Mathematical Biology
Claus Garbe, Teresa Amaral, Ketty Peris, Axel Hauschild, Petr Arenberger, Lars Bastholt, Veronique Bataille, Veronique Del Marmol, Brigitte Dréno, Maria Concetta Fargnoli, Jean-Jacques Grob, Christoph Höller, Roland Kaufmann, Aimilios Lallas, Celeste Lebbé, Josep Malvehy, Mark Middleton, David Moreno-Ramirez, Giovanni Pellacani, Philippe Saiag, Alexander J Stratigos, Ricardo Vieira, Iris Zalaudek, Alexander M M Eggermont
A unique collaboration of multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with 1- to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumour thickness ≥1...
December 19, 2019: European Journal of Cancer
Jacopo Scala, Aleksandra Vojvodic, Petar Vojvodic, Tatjana Vlaskovic-Jovicevic, Zorica Peric-Hajzler, Dusica Matovic, Sanja Dimitrijevic, Jovana Vojvodic, Goran Sijan, Nenad Stepic, Uwe Wollina, Michael Tirant, Nguyen Van Thuong, Massimo Fioranelli, Torello Lotti
The main surgical treatment for melanoma consists in wide surgical excision of the primary lesion and the sentinel node but in recent times management of melanoma is rapidly evolving with the introduction of new systemic therapies, like BRAF inhibitors, MEK inhibitors and antibodies anti-PD-1 that show good results in controlling even advanced stages of the disease. This review aims to present data for the optimal surgical management of patients with malignant melanoma.
September 30, 2019: Open Access Macedonian Journal of Medical Sciences
Filipe Martins, Luis Schiappacasse, Marc Levivier, Constantin Tuleasca, Michel A Cuendet, Veronica Aedo-Lopez, Bianca Gautron Moura, Krisztian Homicsko, Adrienne Bettini, Gregoire Berthod, Camille L Gérard, Alexandre Wicky, Jean Bourhis, Olivier Michielin
BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS...
December 14, 2019: Journal of Neuro-oncology
Jinhua Dai, Jianbo Ma, Yufeng Liao, Xianhai Luo, Guofang Chen
Polydatin (PD), a monocrystalline polyphenolic drug mainly found in the roots of Polygonum cuspidatum, has various pharmacological activities. Long non-coding RNAs (lncRNA) DiGeorge syndrome critical region gene 5 (DGCR5) was found to participate in the suppression of multiple cancers. Here, we proposed to study the effect of PD on myocardial infarction (MI) by inducing DGCR5. CCK-8 assay was performed to detect the viability of H9c2 cells. Flow cytometry was utilized to test apoptosis of H9c2 cells. These results determined the optimal concentration and effect time of hypoxia as well as PD...
2019: Brazilian Journal of Medical and Biological Research
Delong Liu
Tumor-associated antigens (TAA) or cancer biomarkers are major targets for cancer therapies. Antibody- based agents targeting the cancer biomarkers include monoclonal antibodies (MoAbs), radiolabeled MoAbs, bispecific T cell engagers, and antibody-drug conjugates. Antibodies targeting CD19, CD20, CD22, CD30, CD33, CD38, CD79B and SLAMF7 are in clinical applications for hematological malignancies. CD123, CLL-1, B cell maturation antigen, and CD138 are targets for cancer immunotherapeutic agents, including the chimeric antigen receptor - engineered T cells...
2019: Biomarker Research
Martina Strudel, Lucia Festino, Vito Vanella, Massimiliano Beretta, Francesco M Marincola, Paolo A Ascierto
BACKGROUND: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Prognostic factors: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, and elevated serum levels of lactate dehydrogenase and S100B...
December 5, 2019: Current Medicinal Chemistry
Minliang Wu, Yuchong Wang, Yalong Xu, Ji Zhu, Chuan Lv, Mengyan Sun, Rui Guo, Yu Xia, Wei Zhang, Chunyu Xue
Background: This systematic review and meta-analysis aims to provide comparative and quantitative data about immune checkpoint inhibitor (IMM) and targeted therapy (TAR) in this work. Methods: A literature search was performed with PubMed, Embase, PMC database, and Web of Science databases to identify relevant studies. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) for overall response rate (ORR) were estimated. Results: Eighteen manuscripts were ultimately utilized for indirect comparisons...
2019: Journal of Cancer
Anna M Czarnecka, Paweł Teterycz, Anna Mariuk-Jarema, Iwona Lugowska, Pawel Rogala, Monika Dudzisz-Sledz, Tomasz Switaj, Piotr Rutkowski
BACKGROUND: Although BRAF/MEK inhibitors are generally considered to be equally effective whether given before or after immunotherapy, no prospective trial has confirmed this hypothesis and contradictory data have been published in the melanoma field. OBJECTIVE: We aimed to investigate the outcomes of patients with metastatic melanoma depending on the first-line treatment. PATIENTS AND METHODS: In this ambidirectional cohort, single-center study, we included 253 consecutive melanoma patients treated in our institution with an anti-PD1 antibody or BRAF/MEK inhibitors, who started first-line treatment between December 2015 and March 2018...
November 21, 2019: Targeted Oncology
Alexandra M Haugh, Douglas B Johnson
The optimal management of advanced stage BRAF-mutated melanoma is widely debated and complicated by the availability of several different regimens that significantly improve outcomes but have not been directly compared. While there are many unanswered questions relevant to this patient population, the major uncertainty in current practice is the choice between BRAF/MEK inhibitors or immunotherapy for those with previously untreated metastatic or high-risk disease. Decisions regarding first line therapy should include consideration of patient preference as well as the presence of symptomatic metastatic disease and degree of comorbidity, particularly secondary to any history of severe auto-immune disorder...
November 18, 2019: Current Treatment Options in Oncology
Antoni Ribas, Adil Daud, Anna C Pavlick, Rene Gonzalez, Karl D Lewis, Omid Hamid, Thomas F Gajewski, Igor Puzanov, Matthew Wongchenko, Isabelle Rooney, Jessie J Hsu, Yibing Yan, Erica Park, Grant A McArthur
PURPOSE: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. PATIENTS AND METHODS: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF V600 -mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve ( n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); n = 66]...
November 15, 2019: Clinical Cancer Research
Daniela Massi, Eliana Rulli, Mara Cossa, Barbara Valeri, Monica Rodolfo, Barbara Merelli, Francesco De Logu, Romina Nassini, Michele Del Vecchio, Lorenza Di Guardo, Roberta De Penni, Michele Guida, Vanna Chiarion Sileni, Anna Maria Di Giacomo, Marco Tucci, Marcella Occelli, Francesca Portelli, Viviana Vallacchi, Francesca Consoli, Pietro Quaglino, Paola Queirolo, Gianna Baroni, Fabrizio Carnevale-Schianca, Laura Cattaneo, Alessandro Minisini, Giuseppe Palmieri, Licia Rivoltini, Mario Mandalà
BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors...
November 15, 2019: Journal for Immunotherapy of Cancer
Justin C Moser, Danli Chen, Siwen Hu-Lieskovan, Kenneth F Grossmann, Shiven Patel, Sarah V Colonna, Jian Ying, John R Hyngstrom
BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi...
November 2, 2019: Cancer Medicine
Kaycee B Moshofsky, Hyun J Cho, Guanming Wu, Kyle A Romine, Matthew T Newman, Yoko Kosaka, Shannon K McWeeney, Evan F Lind
Acute myeloid leukemia (AML) remains difficult to treat due to mutational heterogeneity and the development of resistance to therapy. Targeted agents, such as MEK inhibitors, may be incorporated into treatment; however, the impact of MEK inhibitors on the immune microenvironment in AML is not well understood. A greater understanding of the implications of MEK inhibition on immune responses may lead to a greater understanding of immune evasion and more rational combinations with immunotherapies. This study describes the impact of trametinib on both T cells and AML blast cells by using an immunosuppressive mouse model of AML and primary patient samples...
October 22, 2019: Blood Advances
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