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https://www.readbyqxmd.com/read/29765547/signature-program-a-platform-of-basket-trials
#1
Eric D Slosberg, Barinder P Kang, Julio Peguero, Matthew Taylor, Todd M Bauer, Donald A Berry, Fadi Braiteh, Alexander Spira, Funda Meric-Bernstam, Steven Stein, Sarina A Piha-Paul, August Salvado
Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29651128/encorafenib-a-new-agent-for-advanced-stage-disease
#2
Peter Sidaway
No abstract text is available yet for this article.
April 12, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29573941/encorafenib-plus-binimetinib-versus-vemurafenib-or-encorafenib-in-patients-with-braf-mutant-melanoma-columbus-a-multicentre-open-label-randomised-phase-3-trial
#3
Reinhard Dummer, Paolo A Ascierto, Helen J Gogas, Ana Arance, Mario Mandala, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion-Sileni, Caroline Dutriaux, Jan Willem B de Groot, Naoya Yamazaki, Carmen Loquai, Laure A Moutouh-de Parseval, Michael D Pickard, Victor Sandor, Caroline Robert, Keith T Flaherty
BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600 -mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600 -mutant melanoma. METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy...
March 21, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29568360/methotrexate-sensitizes-drug-resistant-metastatic-melanoma-cells-to-braf-v600e-inhibitors-dabrafenib-and-encorafenib
#4
Kayleigh C Ross, Kevin F Chin, Daehwan Kim, Christopher D Marion, Timothy J Yen, Vikram Bhattacharjee
Acquired resistance of metastatic melanoma (MM) tumors to BRAF V600E inhibitors (BRAFi's) is commonplace in the clinic. Habitual relapse of patients contributes to <20% 5-year survival rates in MM. We previously identified serine synthesis as a critical detrminant of late-stage cancer cell resistance to BRAFi's. Pre-treatment with DNA damaging agent gemcitabine (a nucleoside analog) re-sensitized drug-resistant cancer cells to BRAFi's dabrafenib and vemurafenib. Importantly, the combination treatments were effective against BRAF wild type cancer cells potentially expanding the clinical reach of BRAFi's...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29485551/aged-looking-skin-and-encorafenib-an-adverse-event-of-braf-inhibitors
#5
Clara Fernández-Sartorio, Aram Boada, Marion M Chavez-Bourgeois, Gustavo J Ruiz Ares, Ana M Arance, José L Manzano, Adriana García-Herrera, Cristina Carrera
No abstract text is available yet for this article.
April 2018: Melanoma Research
https://www.readbyqxmd.com/read/29356698/development-of-encorafenib-for-braf-mutated-advanced-melanoma
#6
Peter Koelblinger, Olaf Thuerigen, Reinhard Dummer
PURPOSE OF REVIEW: To describe the pharmacological properties, preclinical and clinical data of the novel V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor encorafenib (LGX818) and to compare these with established BRAF-inhibitors in the treatment of locally advanced or metastatic melanoma. RECENT FINDINGS: Encorafenib has shown improved efficacy in the treatment of metastatic melanoma in comparison with vemurafenib. Combination with the MEK inhibitor (MEKi) binimetinib allows for higher dose intensities of encorafenib further improving response rates (RRs)...
March 2018: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#7
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
March 2018: Oncogene
https://www.readbyqxmd.com/read/29210065/hdac-inhibitors-restore-braf-inhibitor-sensitivity-by-altering-pi3k-and-survival-signalling-in-a-subset-of-melanoma
#8
Stuart J Gallagher, Dilini Gunatilake, Kimberley A Beaumont, Danae M Sharp, Jessamy C Tiffen, Anja Heinemann, Wolfgang Weninger, Nikolas K Haass, James S Wilmott, Jason Madore, Peter M Ferguson, Helen Rizos, Peter Hersey
Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment...
May 1, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29155017/p-glycoprotein-mdr1-abcb1-and-breast-cancer-resistance-protein-bcrp-abcg2-affect-brain-accumulation-and-intestinal-disposition-of-encorafenib-in-mice
#9
Jing Wang, Changpei Gan, Rolf W Sparidans, Els Wagenaar, Stéphanie van Hoppe, Jos H Beijnen, Alfred H Schinkel
Encorafenib (LGX818) is a promising BRAFV600E inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b-/- , Abcg2-/- , and Abcb1a/1b;Abcg2-/- mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains...
March 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29040252/in-the-pipeline-encorafenib-and-binimetinib-in-braf-mutated-melanoma
#10
Keith Flaherty
No abstract text is available yet for this article.
October 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28724666/braf-inhibitors-amplify-the-proapoptotic-activity-of-mek-inhibitors-by-inducing-er-stress-in-nras-mutant-melanoma
#11
Heike Niessner, Tobias Sinnberg, Corinna Kosnopfel, Keiran S M Smalley, Daniela Beck, Christian Praetorius, Marion Mai, Stefan Beissert, Dagmar Kulms, Martin Schaller, Claus Garbe, Keith T Flaherty, Dana Westphal, Ines Wanke, Friedegund Meier
Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma...
October 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28640105/glomerulonephritis-and-granulomatous-vasculitis-in-kidney-as-a-complication-of-the-use-of-braf-and-mek-inhibitors-in-the-treatment-of-metastatic-melanoma-a-case-report
#12
Mehdi Maanaoui, Camille Saint-Jacques, Viviane Gnemmi, Marie Frimat, Arnaud Lionet, Marc Hazzan, Christian Noël, François Provot
RATIONALE: BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP-kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis. PATIENT CONCERNS: We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28611198/phase-i-dose-escalation-and-expansion-study-of-the-braf-inhibitor-encorafenib-lgx818-in-metastatic-braf-mutant-melanoma
#13
Jean-Pierre Delord, Caroline Robert, Marta Nyakas, Grant A McArthur, Ragini Kudchakar, Amit Mahipal, Yasuhide Yamada, Ryan Sullivan, Ana Arance, Richard F Kefford, Matteo S Carlino, Manuel Hidalgo, Carlos Gomez-Roca, Daniela Michel, Abdelkader Seroutou, Vassilios Aslanis, Giordano Caponigro, Darrin D Stuart, Laure Moutouh-de Parseval, Tim Demuth, Reinhard Dummer
Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma...
September 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#14
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...
December 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28363909/a-phase-ib-dose-escalation-study-of-encorafenib-and-cetuximab-with-or-without-alpelisib-in-metastatic-braf-mutant-colorectal-cancer
#15
MULTICENTER STUDY
Robin M J M van Geel, Josep Tabernero, Elena Elez, Johanna C Bendell, Anna Spreafico, Martin Schuler, Takayuki Yoshino, Jean-Pierre Delord, Yasuhide Yamada, Martijn P Lolkema, Jason E Faris, Ferry A L M Eskens, Sunil Sharma, Rona Yaeger, Heinz-Josef Lenz, Zev A Wainberg, Emin Avsar, Arkendu Chatterjee, Savina Jaeger, Eugene Tan, Kati Maharry, Tim Demuth, Jan H M Schellens
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF V600E colorectal cancer models. Patients with refractory BRAF V600 -mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with ( n = 28) or without ( n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose...
June 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28277830/can-binimetinib-encorafenib-and-masitinib-be-more-efficacious-than-currently-available-mutation-based-targeted-therapies-for-melanoma-treatment
#16
REVIEW
Megan C Turner, Kara Rossfeld, April K S Salama, Douglas Tyler, Georgia Beasley
Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT...
April 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27639128/liquid-chromatography-tandem-mass-spectrometric-assay-for-therapeutic-drug-monitoring-of-the-b-raf-inhibitor-encorafenib-the-egfr-inhibitors-afatinib-erlotinib-and-gefitinib-and-the-o-desmethyl-metabolites-of-erlotinib-and-gefitinib-in-human-plasma
#17
Rolf W Sparidans, Hilde Rosing, Johannes J M Rood, Jan H M Schellens, Jos H Beijnen
No abstract text is available yet for this article.
October 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27220786/-current-progress-and-feasibility-of-using-molecular-targeted-agent-combinations-for-metastatic-colorectal-cancer
#18
Toshiki Masuishi, Kei Muro
The efficacy of molecular-targeted agent combinations for the treatment of metastatic colorectal cancer has become increasingly evident over recent years, although none of these combinations have been recognized yet as a standard therapy. The intention here is to provide a synopsis of current progress in this developing area by reviewing existing publications and ongoing clinical trials. While bevacizumab plus anti-EGFR agents exhibit detrimental effects in first-line setting , a combination of bevacizumab with erlotinib has been suggested as an effective maintenance therapy...
April 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27116335/pyogenic-granuloma-in-patients-treated-with-selective-braf-inhibitors-another-manifestation-of-paradoxical-pathway-activation
#19
Benjamin Henning, Pascale Stieger, Jivko Kamarachev, Reinhard Dummer, Simone M Goldinger
Cutaneous toxicities under therapy with selective BRAF inhibitors such as vemurafenib or encorafenib (LGX818) are frequent, including plantar hyperkeratosis, squamous cell carcinoma, and second primary melanoma. Pyogenic granuloma is a benign, rapidly growing, eruptive hemangioma that often bleeds and ulcerates. Common causes are mechanical trauma and cast immobilization, as well as multiple drugs such as retinoids and antineoplastic agents. However, the development of pyogenic granuloma under treatment with encorafenib (LGX818) has not yet been reported...
June 2016: Melanoma Research
https://www.readbyqxmd.com/read/27028853/comparative-profiles-of-braf-inhibitors-the-paradox-index-as-a-predictor-of-clinical-toxicity
#20
COMPARATIVE STUDY
Charles H Adelmann, Grace Ching, Lili Du, Rachael C Saporito, Varun Bansal, Lindy J Pence, Roger Liang, Woojin Lee, Kenneth Y Tsai
BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation...
May 24, 2016: Oncotarget
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