title: Melanoma patients in a phase I clinic: molecular aberrations, targeted therapy and outcomes.
abstract: BACKGROUND
  The purpose of the study was to assess the outcome of patients with advanced melanoma treated with matched molecularly targeted therapy.
  
  
  METHODS
  We reviewed 160 consecutive patients with metastatic melanoma treated in the phase I program (N = 35 protocols). Treatment was considered to be 'matched' (N = 84) if at least one drug in the regimen was known to inhibit the functional activity of at least one of the patient's mutations.
  
  
  RESULTS
  Of 160 patients, 134 (83.7%) had adequate tissue for molecular analysis; 69% (110 of 160) had ≥1 mutation: 61.2% (82 of 134), BRAF; 20.7% (23 of 111), NRAS; 2.6% (2 of 77), KIT; 2.3% (1 of 44), KRAS; 20% (1 of 5), GNAQ; 11.1% (1 of 9), P53 and 2.6% (1 of 39), coexisting mutations in BRAF and PIK3CA. Eighty-four patients (52.4%) were treated with matched-targeted agents, most of whom had BRAF mutations (N = 74). Twenty-six percent of patients (41 of 160) achieved a complete or partial remission (CR/PR) [40% (34 of 84)) on a matched phase I protocol versus 9.2% (7 of 76) for those on a non-matched study (P ≤ 0.0001)]. The median progression-free survival (PFS) (95% CI) was longer for patients treated on a matched phase I trial than on their prior first standard treatment [5.27 (4.10, 6.44) versus 3.10 (1.92, 4.28) months, P = 0.023], but not on non-matched phase I treatment. Multivariable analysis showed that matched therapy was an independent predictor of higher CR/PR rates, prolonged PFS and survival.
  
  
  CONCLUSIONS
  For melanoma patients, especially those with BRAF mutations, administering molecularly matched agents can be associated with better outcomes, including longer PFS compared with their first-line systemic therapy.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
authors.forename: H
authors.initials: H
authors.lastname: Henary
authors.forename: D S
authors.initials: DS
authors.lastname: Hong
authors.forename: G S
authors.initials: GS
authors.lastname: Falchook
authors.forename: A
authors.initials: A
authors.lastname: Tsimberidou
authors.forename: G C
authors.initials: GC
authors.lastname: George
authors.forename: S
authors.initials: S
authors.lastname: Wen
authors.forename: J
authors.initials: J
authors.lastname: Wheler
authors.forename: S
authors.initials: S
authors.lastname: Fu
authors.forename: A
authors.initials: A
authors.lastname: Naing
authors.forename: S
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: F
authors.initials: F
authors.lastname: Janku
authors.forename: K B
authors.initials: KB
authors.lastname: Kim
authors.forename: P
authors.initials: P
authors.lastname: Hwu
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D005260:Female; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D057285:Precision Medicine; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013534:Survival; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D020558:GTP Phosphohydrolases; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019009:Proto-Oncogene Proteins c-kit; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C554061:GNAQ protein, human; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human
keywords: matched therapy; melanoma; metastatic melanoma; phase I; targeted therapy