title: A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer.
abstract: BACKGROUND
  Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.
  
  
  RESULTS
  One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%-42.1%] with GC versus 20.0% (95% CI 11.9%-30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8-5.6) months with GC and 5.7 (95% CI 4.6-6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56-1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9-17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48-1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3-4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).
  
  
  CONCLUSIONS
  Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.
  
  
  BACKGROUND
  ClinicalTrial.gov Identifier NCT01086254.
authors.affiliation: Department of Oncology, University of Turin, AOU San Luigi, Orbassano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Novello
authors.affiliation: Thoracic Cancer Unit, Department of Medicine, Gustave-Roussy, Villejuif, France. Electronic address: benjamin.besse@gustaveroussy.fr.
authors.forename: B
authors.initials: B
authors.lastname: Besse
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Felip
authors.affiliation: Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille.
authors.forename: F
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Department of Pneumology and Allergies, CHU Toulouse Hôpital Larrey, Toulouse.
authors.forename: J
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Department of Pneumology, CHU Côte de Nacre, Caen, France.
authors.forename: G
authors.initials: G
authors.lastname: Zalcman
authors.affiliation: Department of Oncology, Asklepios Fachkliniken München-Gauting, Gauting.
authors.forename: J
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Thoracic Oncology, LungenClinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.affiliation: Department of Medical Oncology, Istituto Toscano Tumori-Ospedale Civile, Livorno, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Department of Oncology, New Cross Hospital, Wolverhampton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Ferry
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Carcereny
authors.affiliation: Department of Medical Oncology, Humanitas Cancer Center IRCCS, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Oncology Division, Sanofi Aventis, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Garcia-Ribas
authors.affiliation: Department of Oncology, University of Turin, AOU San Luigi, Orbassano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Scagliotti
authors.affiliation: Thoracic Cancer Unit, Department of Medicine, Gustave-Roussy, Villejuif, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D003841:Deoxycytidine; C090712:iniparib; D002945:Cisplatin; D000093542:Gemcitabine
keywords: advanced disease; first-line therapy; iniparib; non-small-cell lung cancer