title: Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non-small-cell lung cancer: a randomized open-label phase II study.
abstract: Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel-induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC. Patients (N = 162) eligible for second-line NSCLC treatment (stage IIIB/IV) with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomized 2:1 to receive LY2181308 (750 mg intravenously, weekly) and docetaxel (75 mg/m intravenously, day 1) or docetaxel alone every 21 days. CTS from baseline to the end of cycle 2 was compared between the two treatment arms. The mean (SD) tumor size ratio for LY2181308/docetaxel and docetaxel was 1.05 (0.21) and 1.00 (0.15) (p = 0.200), respectively, suggesting no significant improvement in antitumor activity between the arms. Because there was also no significant difference between the two arms for progression-free survival (PFS) (2.83 months with LY2181308/docetaxel and 3.35 months with docetaxel [p = 0.191]), both arms were combined. Using the combined arms, CTS correlated with PFS (PFS = 4.63 months in patients with decreased CTS compared with 2.66 months in patients with increased CTS), supporting its use in early decision-making in phase II studies.
authors.affiliation: *Cedars-Sinai Medical Center, Los Angeles, California; †The Lung Cancer Group, The Christie and University Hospital of South Manchester, Manchester, United Kingdom; ‡Memorial Cancer Centre of Oncology and Institute Department of Lung Cancer and Chest Tumours, Warsaw, Poland; §Poznań University of Medical Sciences, Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznań, Poland; ‖Karmanos Cancer Center, Detroit, Michigan; ¶Lung Cancer Unit, IRCCS AOU San Martino IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; #Gemeinschaftspraxis für Haematologie, Onkologie und Palliativmedizin, Münster, Germany; **Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida; ††St. Vincentius-Kliniken gAG - Med. Klinik Abt. 2, Karlsruhe, Germany; ‡‡Sheffield Experimental Cancer Medicine Centre, Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom; §§Internal Medicine, Karmanos Cancer Institute, Detroit, Michigan; ‖‖Eli Lilly and Company, Windlesham, United Kingdom; ¶¶Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom; ##Eli Lilly and Company, Indianapolis, Indiana; and ***Department of Oncology, University of Oxford, Cancer and Haematology Center, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Ronald
authors.initials: R
authors.lastname: Natale
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.forename: Dariusz
authors.initials: D
authors.lastname: Kowalski
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Francesco
authors.initials: F
authors.lastname: Grossi
authors.forename: Christian
authors.initials: C
authors.lastname: Lerchenmüller
authors.forename: Mary
authors.initials: M
authors.lastname: Pinder-Schenck
authors.forename: Jörg
authors.initials: J
authors.lastname: Mezger
authors.forename: Sarah
authors.initials: S
authors.lastname: Danson
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Summers
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.forename: Valérie
authors.initials: V
authors.lastname: André
authors.forename: Mayukh
authors.initials: M
authors.lastname: Das
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
authors.forename: Denis
authors.initials: D
authors.lastname: Talbot
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage
chemical_list: C529350:LY 2181308; D009841:Oligonucleotides; D043823:Taxoids; D000077143:Docetaxel