title: Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer.
abstract: BACKGROUND
  KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway.
  
  
  METHODS
  Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out.
  
  
  RESULTS
  From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib.
  
  
  CONCLUSIONS
  This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.
authors.affiliation: John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda.
authors.forename: C A
authors.initials: CA
authors.lastname: Carter
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: A
authors.initials: A
authors.lastname: Rajan
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: C
authors.initials: C
authors.lastname: Keen
authors.affiliation: Lung & Upper Aerodigestive Cancer Research Group Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda.
authors.forename: E
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: S
authors.initials: S
authors.lastname: Khozin
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.affiliation: John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda.
authors.forename: C
authors.initials: C
authors.lastname: Brzezniak
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: U
authors.initials: U
authors.lastname: Guha
authors.affiliation: Cancer Therapy Evaluation Program, National Institutes of Health, Bethesda.
authors.forename: L A
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research.
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda.
authors.forename: L
authors.initials: L
authors.lastname: Xi
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda.
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Medical Oncology Branch, Center for Cancer Research.
authors.forename: J B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Department of Hematology and Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte.
authors.forename: K L
authors.initials: KL
authors.lastname: Reckamp
authors.affiliation: Department of Hematology and Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte.
authors.forename: S
authors.initials: S
authors.lastname: Koehler
authors.affiliation: Department of Internal Medicine, University of Southern California, Los Angeles.
authors.forename: B
authors.initials: B
authors.lastname: Gitlitz
authors.affiliation: Radiation and Cellular Oncology, University of Chicago, Medicine and Biological Sciences, Chicago.
authors.forename: R
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Division of Hematology and Oncology, University of California at Davis Cancer Center, Sacramento.
authors.forename: D
authors.initials: D
authors.lastname: Gandara
authors.affiliation: Radiation and Cellular Oncology, University of Chicago, Medicine and Biological Sciences, Chicago.
authors.forename: E
authors.initials: E
authors.lastname: Vokes
authors.affiliation: Medical Oncology Branch, Center for Cancer Research Lombardi Comprehensive Cancer Center, Georgetown University, Washington, USA gg496@georgetown.edu.
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D048728:MAP Kinase Kinase Kinase 1; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EGFR; KRAS; MEK; erlotinib; nonsmall-cell lung cancer; selumetinib