Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma

Journal of the American College of Surgeons
Adam S JohnsonMark C Kelley

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

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Citations

Feb 16, 2017·International Journal of Cancer. Journal International Du Cancer·William BerryDaniel Croagh
May 20, 2018·Pigment Cell & Melanoma Research·Deon B DoxieJonathan M Irish
Dec 28, 2018·Journal of Surgical Oncology·Jessica Y Liu, Michael Lowe
Jul 25, 2018·American Journal of Clinical Dermatology·Meredith A McKean, Rodabe N Amaria
Nov 11, 2018·Cancer Immunology Research·Allison R GreenplateJonathan M Irish

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