title: Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials.
abstract: BACKGROUND
  KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.
  
  
  METHODS
  Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.
  
  
  RESULTS
  Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).
  
  
  CONCLUSIONS
  MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX. Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Rabih
authors.initials: R
authors.lastname: Said
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gerald Steven
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Sarina Anne
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Internal Medicine, Moores Cancer Center - University of California San Diego, LaJolla, CA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Apostolia Maria
authors.initials: AM
authors.lastname: Tsimberidou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048369:MAP Kinase Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins