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https://www.readbyqxmd.com/read/28649441/clinical-responses-to-erk-inhibition-in-braf-v600e-mutant-colorectal-cancer-predicted-using-a-computational-model
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28611627/panniculitis-associated-with-mek-inhibitor-therapy-an-uncommon-adverse-effect
#4
Miruna Negulescu, Florian Deilhes, Vincent Sibaud, Emilie Tournier, Laurence Lamant, Serge Boulinguez, Nicolas Meyer
The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors...
January 2017: Case Reports in Dermatology
https://www.readbyqxmd.com/read/28592615/a-phase-ib-dose-escalation-study-of-the-safety-tolerability-and-pharmacokinetics-of-cobimetinib-and-duligotuzumab-in-patients-with-previously-treated-locally-advanced-or-metastatic-cancers-with-mutant-kras
#5
Christopher H Lieu, Manuel Hidalgo, Jordan D Berlin, Andrew H Ko, Andres Cervantes, Patricia LoRusso, David E Gerber, J Paul Eder, S Gail Eckhardt, Amy V Kapp, Amy Tsuhako, Bruce McCall, Andrea Pirzkall, Anne Uyei, Josep Tabernero
LESSONS LEARNED: Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. BACKGROUND: KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling...
June 7, 2017: Oncologist
https://www.readbyqxmd.com/read/28537897/mek-inhibitors-cobimetinib-and-trametinib-regressed-a-gemcitabine-resistant-pancreatic-cancer-patient-derived-orthotopic-xenograft-pdox
#6
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Thinzar M Lwin, Ho Kyoung Hwang, Jonathan C Delong, Bryan M Clary, Michael Bouvet, Michiaki Unno, Robert M Hoffman
A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#7
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
May 23, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28536307/gene-expression-profiling-in-braf-mutated-melanoma-reveals-patient-subgroups-with-poor-outcomes-to-vemurafenib-that-may-be-overcome-by-cobimetinib-plus-vemurafenib
#8
Matthew J Wongchenko, Grant A McArthur, Brigitte Dréno, James Larkin, Paolo A Ascierto, Jeffrey Sosman, Luc Andries, Mark Kockx, Stephen D Hurst, Ivor Caro, Isabelle Rooney, Priti S Hegde, Luciana Molinero, Huibin Yue, Ilsung Chang, Lukas C Amler, Yibing Yan, Antoni Ribas
The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF(V600)-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. <br /><br />Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P<0 .05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures...
May 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28526719/management-of-treatment-related-adverse-events-with-agents-targeting-the-mapk-pathway-in-patients-with-metastatic-melanoma
#9
Adil Daud, Katy Tsai
Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients...
May 18, 2017: Oncologist
https://www.readbyqxmd.com/read/28506716/mek-retinopathy-clinical-case-reports
#10
P Rocha Cabrera, E Quijada Fumero, M J Losada Castillo, J A Abreu Reyes, J Lorenzo Morales
CASE REPORTS: Three clinical cases are presented of MEK retinopathy associated with the combination of cobimetinib and vemurafenib characterised by alteration of the retinal pigment epithelium and neurosensory detachment. Two of the cases conserved the vision of the unit, and the third developed a large bilateral neurosensory detachment with final visual acuity of 0.6 for the right eye and 0.1 for the left one. DISCUSSION: The new therapeutic strategies against metastatic cutaneous melanoma condition the appearance of alterations of the pigmentary epithelium of the retina with serous detachments, leading to close monitoring with macular optical coherence tomography...
May 12, 2017: Archivos de la Sociedad Española de Oftalmología
https://www.readbyqxmd.com/read/28474232/ets-targeted-therapy-can-it-substitute-for-mek-inhibitors
#11
REVIEW
Osamu Tetsu, Frank McCormick
BACKGROUND: The RAS/MAPK pathway has been intensively studied in cancer. Constitutive activation of ERK1 and ERK2 is frequently found in cancer cells from a variety of tissues. In clinical practice and clinical trials, small molecules targeting receptor tyrosine kinases or components in the MAPK cascade are used for treatment. MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and distinctive structural characteristics...
December 2017: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/28444112/incidence-course-and-management-of-toxicities-associated-with-cobimetinib-in-combination-with-vemurafenib-in-the-cobrim-study
#12
B Dréno, A Ribas, J Larkin, P A Ascierto, A Hauschild, L Thomas, J-J Grob, D O Koralek, I Rooney, J J Hsu, E F McKenna, G A McArthur
Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28412197/an-uplc-ms-ms-method-for-the-quantification-of-braf-inhibitors-vemurafenib-dabrafenib-and-mek-inhibitors-cobimetinib-trametinib-binimetinib-in-human-plasma-application-to-treated-melanoma-patients
#13
Marine Rousset, Karine Titier, Stephane Bouchet, Caroline Dutriaux, Anne Pham-Ledard, Sorilla Prey, Mireille Canal-Raffin, Mathieu Molimard
Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile...
July 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28396940/adjunction-of-a-mek-inhibitor-to-vemurafenib-in-the-treatment-of-metastatic-melanoma-results-in-a-60-reduction-of-acute-kidney-injury
#14
Cécile Teuma, Solenne Pelletier, Mona Amini-Adl, Marie Perier-Muzet, Delphine Maucort-Boulch, Luc Thomas, Maurice Laville, Denis Fouque, Stéphane Dalle
INTRODUCTION: A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF. PATIENTS AND METHODS: To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France...
May 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28303522/nanotechnology-for-the-treatment-of-melanoma-skin-cancer
#15
REVIEW
Lucas B Naves, Chetna Dhand, Jayarama Reddy Venugopal, Lakshminarayanan Rajamani, Seeram Ramakrishna, Luis Almeida
Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. This literature review intends to elucidate the possibilities to treat melanoma skin cancer using hybrid nanofibers developed by advanced electrospinning process. In this review we have shown that the enhanced permeability and retention is the basis for using nanotechnology, aiming topical drug delivery. The importance of the detection of skin cancer in the early stages is directly related to non-metastatic effects and survival rates of melanoma cells...
May 2017: Progress in biomaterials
https://www.readbyqxmd.com/read/28246434/cobimetinib-for-metastatic-melanoma
#16
REVIEW
(no author information available yet)
No abstract text is available yet for this article.
February 2017: Australian Prescriber
https://www.readbyqxmd.com/read/28112278/cobimetinib-inhibiting-mek1-2-in-braf-v600-mutant-melanoma
#17
REVIEW
J R Eagles, A Jimeno
Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib...
November 2016: Drugs of Today
https://www.readbyqxmd.com/read/28106277/tumor-targeting-salmonella-typhimurium-a1-r-sensitizes-melanoma-with-a-braf-v600e-mutation-to-vemurafenib-in-a-patient-derived-orthotopic-xenograft-pdox-nude-mouse-model
#18
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Ming Zhao, Yong Zhang, Bartosz Chmielowski, Tasuku Kiyuna, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation...
August 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28058658/combination-treatment-of-patients-with-braf-mutant-melanoma-a-new-standard-of-care
#19
REVIEW
Ester Simeone, Antonio M Grimaldi, Lucia Festino, Vito Vanella, Marco Palla, Paolo A Ascierto
Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance...
February 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28052762/indirect-treatment-comparison-of-dabrafenib-plus-trametinib-versus-vemurafenib-plus-cobimetinib-in-previously-untreated-metastatic-melanoma-patients
#20
Adil Daud, Japinder Gill, Sheily Kamra, Lei Chen, Amit Ahuja
BACKGROUND: Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies...
January 4, 2017: Journal of Hematology & Oncology
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