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

Johnson AS, Crandall H, Dahlman K, Kelley MC
J Am Coll Surg. 2015 220 (4): 581-93.e1

PMID: 25797743 · DOI:10.1016/j.jamcollsurg.2014.12.057

BACKGROUND - 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.

STUDY DESIGN - 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.

RESULTS - 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 and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.

CONCLUSIONS - Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.

Copyright © 2015. Published by Elsevier Inc.

MeSH Terms (28)

Administration, Oral Adult Aged Biomarkers, Tumor Biopsy DNA, Neoplasm DNA Mutational Analysis Dose-Response Relationship, Drug Drug Therapy, Combination Feasibility Studies Female Follow-Up Studies Humans Imidazoles Male MAP Kinase Kinase 1 Melanoma Middle Aged Mitogen-Activated Protein Kinases Mutation Oximes Preoperative Care Prospective Studies Proto-Oncogene Proteins B-raf Pyridones Pyrimidinones Skin Neoplasms Young Adult

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