title: Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.
abstract: Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, Barcelona, 08035, Spain, jtabernero@vhio.net.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Sant P
authors.initials: SP
authors.lastname: Chawla
authors.forename: Hedy
authors.initials: H
authors.lastname: Kindler
authors.forename: Karen
authors.initials: K
authors.lastname: Reckamp
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Cheng-Pang
authors.initials: CP
authors.lastname: Hsu
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Baker
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Pedro
authors.initials: P
authors.lastname: Beltran
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C554537:conatumumab; C545764:ganitumab