title: Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer.
abstract: SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.
  
  
  
  Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m(2) i.v., days 1 and 8) and cisplatin (75 mg/m(2) i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors.
  
  
  
  A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine-cisplatin group than in the gemcitabine-cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%).
  
  
  
  In line with SQUIRE ITT, addition of necitumumab to gemcitabine-cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors.
  
  
  
  NCT00981058.
authors.affiliation: Department of Medical Oncology, Hospital Universitario Doce de Octubre & CNIO, Madrid, Spain lpazaresr@seom.org.
authors.forename: L
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Socinski
authors.affiliation: Oncology Clinical Development, Eli Lilly and Company, Bridgewater, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shahidi
authors.affiliation: Oncology Patient Tailoring, Eli Lilly and Company, Indianapolis, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Hozak
authors.affiliation: Global Statistical Science, Oncology, Eli Lilly and Company, Bad Homburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Soldatenkova
authors.affiliation: Oncology Clinical Development, Eli Lilly and Company, Bad Homburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kurek
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA.
authors.forename: M
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Department of Medical Oncology, The Christie Hospital, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C527969:necitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000093542:Gemcitabine
keywords: EGFR expressing; SQUIRE; necitumumab; squamous NSCLC