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Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Shamit K Dutta, Debabrata Mukhopadhyay, Frank A Sinicrope
Oncogenic BRAFV600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAFV600E mutant CRCs, treatment failure may be related to BRAFV600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAFV600E -induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1...
October 7, 2016: Molecular Cancer Therapeutics
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
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...
October 3, 2016: Annals of Pharmacotherapy
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
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
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
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
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
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
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
Vemurafenib is an oral tyrosine kinase inhibitor which inhibits mutated serine/threonine protein kinase B-Raf (BRAF) and is approved as monotherapy or in combination with the MEK inhibitor cobimetinib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.(1-3) Currently vemurafenib is given in a fixed dose regimen of 960 mg bi-daily (BID). The pharmacokinetics of vemurafenib was previously investigated in a phase I trial and mean steady state plasma concentration of 40 ± 20 μg/mL was found at...
July 1, 2016: Journal of Clinical Pharmacology
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
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
Teresa Amaral, Noura Nouri, Claus Garbe
INTRODUCTION: In the recent years, melanoma patients' outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting. AREAS COVERED: This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib...
July 2016: Expert Review of Anticancer Therapy
Jill Stein, Janelle Mann
PURPOSE: Currently available oral oncology therapies are reviewed, and specialty pharmacy services for patients receiving these drugs are described. SUMMARY: Market introductions of new oral oncology drugs have increased substantially over the past decade, and 25-30% of all oncology agents in development are oral medications. Oral agents for treatment of breast cancer include capecitabine, lafatinib, and palbociclib. Several oral agents are used in treating patients with lung cancer driven by mutations of genes coding for anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR); currently available agents include the ALK inhibitors certinib and crizotinib and the EGFR inhibitors afatinib, erlotinib, and gefitinib...
June 1, 2016: American Journal of Health-system Pharmacy: AJHP
P Kouros, H Gerding
No abstract text is available yet for this article.
April 2016: Klinische Monatsblätter Für Augenheilkunde
M Galván-Banqueri, R Ubago-Pérez, T Molina-López
WHAT IS KNOWN AND OBJECTIVE: Melanoma causes the majority of skin cancer-related deaths. The outcome of melanoma depends on its stage at diagnosis. Currently, for patients with advanced melanoma, two MEK inhibitors (trametinib and cobimetinib) have been authorized by the European Medicines Agency. The main objective of this study was to compare the relative efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in patients with advanced melanoma through adjusted indirect treatment comparisons (ITCs)...
June 2016: Journal of Clinical Pharmacy and Therapeutics
Ryan H Takahashi, Shuguang Ma, Qin Yue, Heasook Kim-Kang, Yijun Yi, Justin Ly, Jason W Boggs, Alec Fettes, Andrew McClory, Yuzhong Deng, Cornelis E C A Hop, S Cyrus Khojasteh, Edna F Choo
1. The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled ((14)C) cobimetinib to Sprague-Dawley rats (30 mg/kg) and Beagle dogs (5 mg/kg). 2. The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2-3 h post-dose. Drug-derived radioactivity was fully recovered (∼90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs)...
April 8, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
(no author information available yet)
No abstract text is available yet for this article.
March 28, 2016: Medical Letter on Drugs and Therapeutics
Amélie Boespflug, Luc Thomas
INTRODUCTION: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway. AREAS COVERED: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib...
2016: Expert Opinion on Pharmacotherapy
Gillian M Keating
The MEK inhibitor cobimetinib (Cotellic(®)) is indicated for the treatment of patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf(®)). In the pivotal coBRIM trial, previously untreated patients with BRAF (V600) mutation-positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival...
April 2016: Drugs
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