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https://www.readbyqxmd.com/read/29449192/association-of-body-mass-index-and-outcomes-in-patients-with-metastatic-melanoma-treated-with-targeted-therapy-immunotherapy-or-chemotherapy-a-retrospective-multicohort-analysis
#1
Jennifer L McQuade, Carrie R Daniel, Kenneth R Hess, Carmen Mak, Daniel Y Wang, Rajat R Rai, John J Park, Lauren E Haydu, Christine Spencer, Matthew Wongchenko, Stephen Lane, Dung-Yang Lee, Mathilde Kaper, Meredith McKean, Kathryn E Beckermann, Samuel M Rubinstein, Isabelle Rooney, Luna Musib, Nageshwar Budha, Jessie Hsu, Theodore S Nowicki, Alexandre Avila, Tomas Haas, Maneka Puligandla, Sandra Lee, Shenying Fang, Jennifer A Wargo, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Paul B Chapman, Jeffrey A Sosman, Dirk Schadendorf, Jean-Jacques Grob, Keith T Flaherty, Dana Walker, Yibing Yan, Edward McKenna, Jeffrey J Legos, Matteo S Carlino, Antoni Ribas, John M Kirkwood, Georgina V Long, Douglas B Johnson, Alexander M Menzies, Michael A Davies
BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy...
February 12, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29437873/brain-distribution-of-a-novel-mek-inhibitor-e6201-implications-in-the-treatment-of-melanoma-brain-metastases
#2
Gautham Gampa, Minjee Kim, Nicholas Cook-Rostie, Janice Laramy, Jann N Sarkaria, Linda Paradiso, Louis DePalatis, William F Elmquist
Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and MEK has been identified to be an important target. E6201 is a potent synthetic small molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the BBB on the CNS exposure of E6201...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29363351/mitogen-activated-protein-kinase-mek-inhibitors-to-treat-melanoma-alone-or-in-combination-with-other-kinase-inhibitors
#3
Elnaz Faghfuri, Shekoufeh Nikfar, Kamal Niaz, Mohammad Ali Faramarzi, Mohammad Abdollahi
Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway...
January 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29356791/success-of-rechallenging-dabrafenib-and-trametinib-combination-therapy-after-trametinib-induced-rhabdomyolysis-a-case-report
#4
Yusuke Muto, William Ng, Kenjiro Namikawa, Akira Takahashi, Arata Tsutsumida, Makiko Nishida, Naoya Yamazaki
The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting...
January 29, 2018: Melanoma Research
https://www.readbyqxmd.com/read/29346301/braf-and-mek-inhibitors-influence-the-function-of-reprogrammed-t-cells-consequences-for-adoptive-t-cell-therapy
#5
Jan Dörrie, Lek Babalija, Stefanie Hoyer, Kerstin F Gerer, Gerold Schuler, Lucie Heinzerling, Niels Schaft
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs...
January 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29239458/treatment-of-advanced-melanoma-a-changing-landscape
#6
Adriana Hepner, Alessandra Salgues, Carlos A Dos Anjos, Marina Sahade, Veridiana P Camargo, Bernardo Garicochea, Alexander N Shoushtari, Michael A Postow, Gustavo S Fernandes, Rodrigo R Munhoz
Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival...
September 2017: Revista da Associação Médica Brasileira
https://www.readbyqxmd.com/read/29233910/targeting-cdk1-and-mek-erk-overcomes-apoptotic-resistance-in-braf-mutated-human-colorectal-cancer
#7
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAFV600E mutation occurs in ~8% of human colorectal cancers (CRCs) and is associated with therapeutic resistance that is due, in part, to re-activation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells. BRAFV600E CRC cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1,2,5,9 inhibitor)...
December 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#8
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
December 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29156488/association-of-pd-l1-expression-with-treatment-outcomes-in-patients-with-braf-mutation-positive-melanoma-treated-with-vemurafenib-or-cobimetinib-combined-with-vemurafenib
#9
Matthew J Wongchenko, Antoni Ribas, Brigitte Dréno, Paolo A Ascierto, Grant A McArthur, Jorge D Gallo, Isabelle A Rooney, Jessie Hsu, Hartmut Koeppen, Yibing Yan, James Larkin
The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1(+) melanoma, with hazard ratios (HRs) (PD-L1(+) versus PD-L1(-) ) of 0...
November 20, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29149136/mapk-pathway-targeted-therapies-care-and-management-of-unique-toxicities-in-patients-with-advanced-melanoma%C3%A2
#10
Krista M Rubin
BACKGROUND: Agents targeting the MAPK pathway, including inhibitors of BRAF and MEK, have dramatically transformed the treatment landscape for patients with BRAF-mutant metastatic melanoma. Although generally well tolerated, targeted agents were associated with unique toxicities.
. OBJECTIVES: This article aims to provide nurses with an overview of the key toxicities and associated management strategies of the characteristic adverse event (AE) profile associated with agents targeting the MAPK pathway...
December 1, 2017: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/29064427/the-mek-inhibitors-trametinib-and-cobimetinib-induce-a-type-i-interferon-response-in-human-keratinocytes
#11
Daniela Lulli, Maria Luigia Carbone, Saveria Pastore
Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash...
October 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28915798/vemurafenib-plus-cobimetinib-in-unresectable-stage-iiic-or-stage-iv-melanoma-response-monitoring-and-resistance-prediction-with-positron-emission-tomography-and-tumor-characteristics-reposit-study-protocol-of-a-phase-ii-open-label-multicenter-study
#12
Bernies van der Hiel, John B A G Haanen, Marcel P M Stokkel, Daniel S Peeper, Connie R Jimenez, Jos H Beijnen, Bart A van de Wiel, Ronald Boellaard, Alfons J M van den Eertwegh
BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with (18)F-Fluorodeoxyglucose ((18)F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of (18)F-FDG uptake within 2 weeks following treatment...
September 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28827234/multiple-treatment-comparison-of-seven-new-drugs-for-patients-with-advanced-malignant-melanoma-a-systematic-review-and-health-economic-decision-model-in-a-norwegian-setting
#13
Eva Pike, Vida Hamidi, Ingvil Saeterdal, Jan Odgaard-Jensen, Marianne Klemp
OBJECTIVE: To assess the relative effectiveness and cost-effectiveness of seven new drugs (cobimetinib, dabrafenib, ipilimumab, nivolumab, pembrolizumab, trametinib and vemurafenib) used for treatment of patients with advanced malignant melanoma in the Norwegian setting. DESIGN: A multiple technology assessment. PATIENTS: Patients with advanced malignant melanoma aged 18 or older. DATA SOURCES: A systematic search for randomised controlled trials in relevant bibliographic databases...
August 21, 2017: BMJ Open
https://www.readbyqxmd.com/read/28711086/the-new-paradigm-of-systemic-therapies-for-metastatic-melanoma
#14
REVIEW
Virginia O Volpe, Daniel M Klufas, Upendra Hegde, Jane M Grant-Kels
New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.
August 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28692456/focal-necrotizing-myopathy-with-dropped-head-syndrome-induced-by-cobimetinib-in-metastatic-melanoma
#15
Marie-Léa Gauci, Pauline Laly, Sarah Leonard-Louis, Anthony Behin, Jérémy Gottlieb, Isabelle Madelaine-Chambrin, Barouyr Baroudjian, Laetitia Da-Meda, Samia Mourah, Maxime Battistella, Nicole Basset-Seguin, Martine Bagot, Cécile Pages, Laetitia Vercellino, Thierry Maisonobe, Céleste Lebbé
Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction...
October 2017: Melanoma Research
https://www.readbyqxmd.com/read/28665153/risk-of-peripheral-edema-in-cancer-patients-treated-with-mek-inhibitors-a-systematic-review-and-meta-analysis-of-clinical-trials
#16
Yong Yang, Yi-Hua Liu, Xu Sun, Ming-Wei Yu, Lin Yang, Pei-Yu Cheng, Guo-Wang Yang, Xiao-Min Wang
BACKGROUND: MEK inhibitors are a group of drugs that have shown reliable effects in the treatment of metastatic melanoma and non-small-cell lung cancer. Peripheral edema is an adverse event associated with MEK inhibitors; however, there has been no systematic attempt to evaluate peripheral edema data observed with these agents. This meta-analysis aimed to determine the risk of peripheral edema in cancer patients treated with MEK inhibitors. MATERIALS AND METHODS: The authors searched PubMed, the Cochrane Library, EMBASE, and Clinical Trials...
September 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28655764/role-of-the-e3-ubiquitin-ligase-rnf157-as-a-novel-downstream-effector-linking-pi3k-and-mapk-signaling-pathways-to-the-cell-cycle
#17
Taner Dogan, Florian Gnad, Jocelyn Chan, Lilian Phu, Amy Young, Mark J Chen, Sophia Doll, Matthew P Stokes, Marcia Belvin, Lori S Friedman, Donald S Kirkpatrick, Klaus P Hoeflich, Georgia Hatzivassiliou
The interconnected PI3K and MAPK signaling pathways are commonly perturbed in cancer. Dual inhibition of these pathways by the small-molecule PI3K inhibitor pictilisib (GDC-0941) and the MEK inhibitor cobimetinib (GDC-0973) suppresses cell proliferation and induces cell death better than either single agent in several preclinical models. Using mass spectrometry-based phosphoproteomics, we have identified the RING finger E3 ubiquitin ligase RNF157 as a target at the intersection of PI3K and MAPK signaling. We demonstrate that RNF157 phosphorylation downstream of the PI3K and MAPK pathways influences the ubiquitination and stability of RNF157 during the cell cycle in an anaphase-promoting complex/cyclosome-CDH1-dependent manner...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28649441/clinical-responses-to-erk-inhibition-in-braf-v600e-mutant-colorectal-cancer-predicted-using-a-computational-model
#18
Daniel C Kirouac, Gabriele Schaefer, Jocelyn Chan, Mark Merchant, Christine Orr, Shih-Min A Huang, John Moffat, Lichuan Liu, Kapil Gadkar, Saroja Ramanujan
Approximately 10% of colorectal cancers harbor BRAF(V600E) mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth...
2017: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/28646893/clinical-features-of-serous-retinopathy-observed-with-cobimetinib-in-patients-with-braf-mutated-melanoma-treated-in-the-randomized-cobrim-study
#19
Luis de la Cruz-Merino, Lorenza Di Guardo, Jean-Jacques Grob, Alfredo Venosa, James Larkin, Grant A McArthur, Antoni Ribas, Paolo A Ascierto, Jeffrey T R Evans, Antonio Gomez-Escobar, Giulio Barteselli, Susan Eng, Jessie J Hsu, Anne Uyei, Brigitte Dréno
BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF (V600)-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed...
June 24, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28628251/a-network-meta-analysis-of-short-and-long-term-efficacy-of-targeted-therapy-with-single-or-double-drug-regimens-in-the-treatment-of-stage-iii-iv-malignant-melanoma-based-on-16-randomized-controlled-trials
#20
Ting Xie, Chun-Yu Huang, Xu Kang, Jia-Sheng Luo, Xiao-Min Qin, Feng Han
For the treatment of stage III/IV malignant melanoma (MM), a network meta-analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed...
June 19, 2017: Journal of Cellular Biochemistry
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