title: Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.
abstract: BACKGROUND
  Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111.
  
  
  RESULTS
  Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group.
  
  
  CONCLUSIONS
  Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.
  
  
  BACKGROUND
  Eli Lilly and Company.
authors.affiliation: Instituto de Biomedicina de Sevilla-IBIS (Hospital Virgen del Rocío/Universidad de Sevilla/CSIC), Sevilla, Spain; Hospital Universitario Doce de Octubre and CNIO Lung Cancer Unit, Madrid, Spain. Electronic address: lpazaresr@seom.org.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: St Vincentius Kliniken, Karlsruhe, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mezger
authors.affiliation: Institute of Oncology and University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Tudor E
authors.initials: TE
authors.lastname: Ciuleanu
authors.affiliation: Klinik Löwenstein GmbH, Löwenstein, Germany.
authors.forename: Jürgen R
authors.initials: JR
authors.lastname: Fischer
authors.affiliation: Asklepios-Fachkliniken Mönchen-Gauting, Gauting, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Hospital Puerta de Hierro, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Provencio
authors.affiliation: Samodzielny Publiczny Zespól Gruźlicy i Chorób Pluc w Olsztynie, Olsztyn, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kazarnowicz
authors.affiliation: Semmelweis Egyetem, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Losonczy
authors.affiliation: Instituto do Cancer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Castro
authors.affiliation: Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szczesna
authors.affiliation: Ospedale Santa Maria della Misericordia, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crino
authors.affiliation: LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Poznan University of Medical Sciences, Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznan, Poland.
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.affiliation: Landesklinikum Horn, NÖ, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Ulsperger
authors.affiliation: Department of Internal Medicine II, University Clinic Ulm, Ulm, Germany; Klinik für Pneumologie, Thoraxonkologie, Schlaf-und Beatmungsmedizin, Kempten-Oberallgäu, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schumann
authors.affiliation: Hospital de Câncer de Barretos, Sao Paulo, Brazil.
authors.forename: Jose Elias A
authors.initials: JE
authors.lastname: Miziara
authors.affiliation: Hospital Santa Izabel-Santa Casa de Misericordia da Bahia, Nazare, Nazare, Brazil.
authors.forename: Álvaro E
authors.initials: ÁE
authors.lastname: Lessa
authors.affiliation: Institute of Oncology Bucharest, Bucharest, Romania.
authors.forename: Mircea
authors.initials: M
authors.lastname: Dediu
authors.affiliation: Csongrád Megye Mellkasi Betegségek Szakkórháza, Deszk, Hungary.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Bálint
authors.affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Depenbrock
authors.affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Soldatenkova
authors.affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.
authors.forename: Raffael
authors.initials: R
authors.lastname: Kurek
authors.affiliation: University of Colorado, Division of Medical Oncology, Aurora, CO, USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: The Christie Hospital, National Health Services Trust, Manchester, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Thatcher
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001938:Brazil; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D000068437:Pemetrexed; C527969:necitumumab; D006147:Guanine; D002945:Cisplatin