Adam S Johnson1, Holly Crandall2, Kimberly Dahlman3, Mark C Kelley4. 1. Department of Pathology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. 2. Department of Clinical Trials Shared Resource, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. 3. Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. 4. Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. Electronic address: mark.kelley@vanderbilt.edu.
Abstract
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 receiveddabrafenib 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.
RCT Entities:
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.
Authors: Allison R Greenplate; Daniel D McClanahan; Brian K Oberholtzer; Deon B Doxie; Caroline E Roe; Kirsten E Diggins; Nalin Leelatian; Megan L Rasmussen; Mark C Kelley; Vivian Gama; Peter J Siska; Jeffrey C Rathmell; P Brent Ferrell; Douglas B Johnson; Jonathan M Irish Journal: Cancer Immunol Res Date: 2018-11-09 Impact factor: 11.151
Authors: Deon B Doxie; Allison R Greenplate; Jocelyn S Gandelman; Kirsten E Diggins; Caroline E Roe; Kimberly B Dahlman; Jeffrey A Sosman; Mark C Kelley; Jonathan M Irish Journal: Pigment Cell Melanoma Res Date: 2018-06-28 Impact factor: 4.693
Authors: Marloes Faut; Mathilde Jalving; Gilles F Diercks; Geke A Hospers; Barbara L van Leeuwen; Lukas B Been Journal: Melanoma Manag Date: 2018-05-16