Abstract
We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance. Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains. Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK...Continue Reading
References
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Sep 8, 2010·The New England Journal of Medicine·Keith T FlahertyPaul B Chapman
Nov 25, 2011·Nature·Poulikos I PoulikakosDavid B Solit
Feb 24, 2012·The New England Journal of Medicine·Jeffrey A SosmanAntoni Ribas
Apr 27, 2012·PloS One·Christine M LovlyWilliam Pao
Jun 6, 2012·The New England Journal of Medicine·Keith T FlahertyUNKNOWN METRIC Study Group
Jun 28, 2012·Lancet·Axel HauschildPaul B Chapman
Oct 13, 2012·Expert Reviews in Molecular Medicine·Sarah Belden, Keith T Flaherty
Jan 8, 2013·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Ryan J Sullivan, Keith T Flaherty
Jan 12, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dennie T FrederickJennifer A Wargo
Nov 23, 2013·Cancer Discovery·Nikhil WagleLevi A Garraway
Feb 8, 2014·Annals of Oncology : Official Journal of the European Society for Medical Oncology·S TurajlicR Marais
Sep 24, 2014·The Surgical Clinics of North America·Charles W KimbroughEric G Davis
Sep 24, 2014·The Surgical Clinics of North America·Andrea M Abbott, Jonathan S Zager
Sep 30, 2014·The New England Journal of Medicine·James LarkinAntoni Ribas
Nov 18, 2014·The New England Journal of Medicine·Caroline RobertDirk Schadendorf
Citations
Feb 16, 2017·International Journal of Cancer. Journal International Du Cancer·William BerryDaniel Croagh
Feb 1, 2018·Cancers·William BerryBrendan J Jenkins
May 20, 2018·Pigment Cell & Melanoma Research·Deon B DoxieJonathan M Irish
Dec 28, 2018·Journal of Surgical Oncology·Jessica Y Liu, Michael Lowe
Apr 1, 2016·Critical Care Medicine·Joshua A SmithRick G Schnellmann
Jan 15, 2020·British Journal of Cancer·Manoela TiagoAndrew E Aplin
Apr 19, 2017·Oncotarget·Mengdong LiuDahai Hu
Apr 30, 2017·Oncology Letters·Lan DengXiuju Wang
Jul 25, 2018·American Journal of Clinical Dermatology·Meredith A McKean, Rodabe N Amaria
Nov 22, 2018·Melanoma Management·Marloes FautLukas B Been
Jan 4, 2019·Analytical and Bioanalytical Chemistry·Yen-Heng LinJau-Song Yu
Jul 6, 2015·Oncotarget·Ruiqin MaiGuohong Zhang
Oct 30, 2020·Cancer·Filip JankuFunda Meric-Bernstam
Nov 11, 2018·Cancer Immunology Research·Allison R GreenplateJonathan M Irish
Jun 2, 2021·Analytical Chemistry·Bernard EversBarbara M Bakker