title: Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.
abstract: OBJECTIVE
  BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.
  
  
  METHODS
  This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.
  
  
  RESULTS
  In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.
  
  
  CONCLUSIONS
  Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. kkim@mdanderson.org
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Fecher
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Gardner
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Xu
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: DeMarini
authors.forename: Ngocdiep T
authors.initials: NT
authors.lastname: Le
authors.forename: Kiran
authors.initials: K
authors.lastname: Patel
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2