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https://www.readbyqxmd.com/read/28112278/cobimetinib-inhibiting-mek1-2-in-braf-v600-mutant-melanoma
#1
A Jimeno, J R Eagles
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
#2
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. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, 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. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression...
January 20, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28058658/combination-treatment-of-patients-with-braf-mutant-melanoma-a-new-standard-of-care
#3
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
#4
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
https://www.readbyqxmd.com/read/27956260/allosteric-mek1-2-inhibitors-including-cobimetanib-and-trametinib-in-the-treatment-of-cutaneous-melanomas
#5
REVIEW
Robert Roskoski
The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer...
December 9, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#6
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGFβ receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
February 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27861317/development-and-validation-of-a-simultaneous-quantification-method-of-fourteen-tyrosine-kinase-inhibitors-in-human-plasma-using-lc-ms-ms
#7
Huu-Hien Huynh, Claire Pressiat, Hélène Sauvageon, Isabelle Madelaine, Patricia Maslanka, Céleste Lebbé, Catherine Thieblemont, Lauriane Goldwirt, Samia Mourah
BACKGROUND: A sensitive LC-MS/MS method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors (TKIs) currently used (imatinib, dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multi-analyte LC-MS/MS assay is of interest for anticancer drug combination therapy. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using a UPLC system coupled with MS/MS in a positive ionization mode...
November 16, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-us-fda-in-2015
#8
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter...
January 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27765849/mutant-braf-upregulates-mcl-1-to-confer-apoptosis-resistance-that-is-reversed-by-mcl-1-antagonism-and-cobimetinib-in-colorectal-cancer
#9
Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Shamit K Dutta, Debabrata Mukhopadhyay, Frank A Sinicrope
Oncogenic BRAF(V600E) mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer. In BRAF(V600E)-mutant colorectal cancers, treatment failure may be related to BRAF(V600E)-mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAF(V600E) can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using colorectal cancer cell lines isogenic for BRAF BRAF(V600E)-induced MCL-1 upregulation was confirmed by ectopic BRAF(V600E) expression that activated MEK/ERK signaling to phosphorylate (MCL-1(Thr163)) and stabilize MCL-1...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27729681/cangrelor
#10
EDITORIAL
Danial E Baker, Kyle T Ingram
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line...
November 2015: Hospital Pharmacy
https://www.readbyqxmd.com/read/27701080/cobimetinib
#11
Jessie Signorelli, Arpita Shah Gandhi
OBJECTIVE: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. DATA SOURCES: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English...
February 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/27690220/vemurafenib-resistant-braf-v600e-mutated-melanoma-is-regressed-by-mek-targeting-drug-trametinib-but-not-cobimetinib-in-a-patient-derived-orthotopic-xenograft-pdox-mouse-model
#12
Kei Kawaguchi, Takashi Murakami, Bartosz Chmielowski, Kentaro Igarashi, Tasuku Kiyuna, Michiaki Unno, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Fritz C Eilber, Robert M Hoffman
Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. 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 PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0...
September 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27641727/vemurafenib-in-combination-with-cobimetinib-in-relapsed-and-refractory-extramedullary-multiple-myeloma-harboring-the-braf-v600e-mutation
#13
Ulrich J M Mey, Christoph Renner, Roger von Moos
BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches...
September 19, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27613168/optimal-use-of-braf-targeting-therapy-in-the-immunotherapy-era
#14
REVIEW
Kevin Wood, Jason J Luke
PURPOSE OF REVIEW: The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma. RECENT FINDINGS: Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted...
November 2016: Current Oncology Reports
https://www.readbyqxmd.com/read/27424159/a-first-in-human-phase-i-study-to-evaluate-the-mek1-2-inhibitor-cobimetinib-administered-daily-in-patients-with-advanced-solid-tumors
#15
Lee S Rosen, Patricia LoRusso, Wen Wee Ma, Jonathan W Goldman, Amy Weise, A Dimitrios Colevas, Alex Adjei, Salim Yazji, Angela Shen, Stuart Johnston, Hsin-Ju Hsieh, Iris T Chan, Branimir I Sikic
Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule...
October 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27382311/the-evolution-of-combined-molecular-targeted-therapies-to-advance-the-therapeutic-efficacy-in-melanoma-a-highlight-of-vemurafenib-and-cobimetinib
#16
REVIEW
Theresa M Medina, Karl D Lewis
Metastatic melanoma is an aggressive, rapidly progressive disease which historically had very few effective treatment options. However, since 2011, the therapeutic landscape of melanoma has undergone a dramatic transformation with two distinct approaches and has catalyzed the successful advancement in the clinical field of immuno-oncology. In addition, the recognition of a key oncogenic driver mutation in melanoma, BRAF, stimulated the development of multiple potent kinase inhibitors which has also influenced the expansion and use of targeted agents in the practice of oncology...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27367293/diagnosis-and-treatment-of-melanoma-european-consensus-based-interdisciplinary-guideline-update-2016
#17
Claus Garbe, Ketty Peris, Axel Hauschild, Philippe Saiag, Mark Middleton, Lars Bastholt, Jean-Jacques Grob, Josep Malvehy, Julia Newton-Bishop, Alexander J Stratigos, Hubert Pehamberger, Alexander M Eggermont
Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organisation of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically using dermoscopy and staging is based upon the AJCC system...
August 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27365214/clinical-pharmacokinetics-of-vemurafenib-in-braf-mutated-melanoma-patients
#18
C M Nijenhuis, A D R Huitema, C Blank, J B A G Haanen, J V van Thienen, H Rosing, J H M Schellens, J H Beijnen
No abstract text is available yet for this article.
January 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27226502/major-changes-in-systemic-therapy-for-advanced-melanoma
#19
John A Thompson
Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib...
May 2016: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/27225997/evaluation-of-cytochrome-p450-3a4-mediated-drug-drug-interaction-potential-for-cobimetinib-using-physiologically-based-pharmacokinetic-modeling-and-simulation
#20
Nageshwar R Budha, Tao Ji, Luna Musib, Steve Eppler, Mark Dresser, Yuan Chen, Jin Y Jin
BACKGROUND AND OBJECTIVES: Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions. METHODS: A physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data...
May 25, 2016: Clinical Pharmacokinetics
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