title: Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial.
abstract: OBJECTIVE
  Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development.
  
  
  OBJECTIVE
  To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma.
  
  
  METHODS
  Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy.
  
  
  METHODS
  Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600.
  
  
  METHODS
  The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points.
  
  
  RESULTS
  A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients.
  
  
  CONCLUSIONS
  The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01619774.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McQuade
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.affiliation: Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Hudgens
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Xinmeng Jasmine
authors.initials: XJ
authors.lastname: Mu
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Samira
authors.initials: S
authors.lastname: Bahl
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Judit
authors.initials: J
authors.lastname: Jané-Valbuena
authors.affiliation: Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Khalida M
authors.initials: KM
authors.lastname: Wani
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Caitlyn A
authors.initials: CA
authors.lastname: Creasy
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston.
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authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
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authors.lastname: Roszik
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Bassett
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston.
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Simpson
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Rosalind D
authors.initials: RD
authors.lastname: Mouton
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Isabella C
authors.initials: IC
authors.lastname: Glitza
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Sapna P
authors.initials: SP
authors.lastname: Patel
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Rodabe N
authors.initials: RN
authors.lastname: Amaria
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Adi
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authors.lastname: Diab
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Patrick
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authors.lastname: Hwu
authors.affiliation: Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston7Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Departments of Pathology and Translational and Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Massachusetts General Hospital, Boston.
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authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco.
authors.forename: Kevin B
authors.initials: KB
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston11Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston.
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mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage; D010766:Phosphorylation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016827:CD8 Antigens; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D038601:Ribosomal Protein S6; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C561627:dabrafenib