title: Phase II Study of the AKT Inhibitor MK-2206 plus Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Who Previously Progressed on Erlotinib.
abstract: OBJECTIVE
  Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients.
  
  
  METHODS
  Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild-type).
  
  
  RESULTS
  Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively, 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2.
  
  
  CONCLUSIONS
  Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC.
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, California. pnlara@ucdavis.edu.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.affiliation: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: USC Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gitlitz
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Mariana
authors.initials: M
authors.lastname: Koczywas
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reckamp
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt