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https://www.readbyqxmd.com/read/29620078/acute-polyneuropathy-in-a-metastatic-melanoma-patient-treated-with-vemurafenib-and-cobimetinib
#1
Annette Compter, Willem Boogerd, Johannes V van Thienen, Dieta Brandsma
No abstract text is available yet for this article.
October 2017: Neurology. Clinical Practice
https://www.readbyqxmd.com/read/29572333/risk-of-clinically-relevant-pharmacokinetic-based-drug-drug-interactions-with-drugs-approved-by-the-u-s-food-and-drug-administration-between-2013-and-2016
#2
Jingjing Yu, Zhu Zhou, Jessica Tay-Sontheimer, Rene H Levy, Isabelle Ragueneau-Majlessi
A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions...
March 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29544202/quantification-of-the-next-generation-oral-anti-tumor-drugs-dabrafenib-trametinib-vemurafenib-cobimetinib-pazopanib-regorafenib-and-two-metabolites-in-human-plasma-by-liquid-chromatography-tandem-mass-spectrometry
#3
Evelina Cardoso, Thomas Mercier, Anna Dorothea Wagner, Krisztian Homicsko, Olivier Michielin, Kim Ellefsen-Lavoie, Laurène Cagnon, Manuel Diezi, Thierry Buclin, Nicolas Widmer, Chantal Csajka, Laurent Decosterd
A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards...
February 8, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29471699/atezolizumab-for-the-treatment-of-colorectal-cancer-the-latest-evidence-and-clinical-potential
#4
Gonzalo Tapia Rico, Timothy J Price
Atezolizumab is a fully humanized, engineered monoclonal antibody that specifically targets PD-L1, key molecule in the cancer-immunity pathway. Atezolizumab is currently approved for the treatment of metastatic non-small-cell lung cancer and advanced urothelial carcinomas. Areas covered: In this review, we will present the available data supporting the efficacy of atezolizumab for the treatment of metastatic colorectal cancer (mCRC). We will also provide an update on the ongoing/future clinical trials evaluating the role of atezolizumab for the treatment of CRC in different settings (alone or in combination with other checkpoint inhibitors and/or targeted therapies)...
April 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29469793/lesiones-subcut%C3%A3-neas-dolorosas-en-paciente-con-melanoma-metast%C3%A3-sico-un-caso-de-paniculitis-linfoc%C3%A3-tica-asociado-a-vemurafenib
#5
Felipe Benavente-Villegas, Francisco Ferrando-Roca, Raquel Dolz-Gaitón, María Royo-Peiró
Vemurafenib ha probado ser una herramienta útil en el tratamiento de melanoma metastásico con mutación BRAF-V600E. Los efectos adversos incluyen artralgias, fatiga y toxicidad cutánea, siendo infrecuente la paniculitis. Presentamos el caso de una paciente de 43 años con melanoma metastásico que desarrolla lesiones subcutáneas dolorosas en miembros inferiores y superiores, asociadas a clínica sistémica después de 2 semanas de inicio de tratamiento con Vemurafenib + Cobimetinib. La histología demostró paniculitis linfocitaria septal y lobulillar...
October 15, 2017: Dermatology Online Journal
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
#6
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
#7
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
#8
REVIEW
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...
March 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
#9
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...
April 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
#10
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
#11
REVIEW
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-mutant-human-colorectal-cancer
#12
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAF V600E mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAF V600E colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAF V600E colorectal cancer cells. BRAF V600E colorectal cancer 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 inhibitors)...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#13
REVIEW
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...
January 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29156488/association-of-programmed-death-ligand-1-pd-l1-expression-with-treatment-outcomes-in-patients-with-braf-mutation-positive-melanoma-treated-with-vemurafenib-or-cobimetinib-combined-with-vemurafenib
#14
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+ vs...
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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