Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab

Josep Tabernero, Sant P. Chawla, Hedy Kindler, Karen Reckamp, E. Gabriela Chiorean, Nilofer S. Azad, A. Craig Lockhart, Cheng Pang Hsu, Nigel F. Baker, Francesco Galimi, Pedro Beltran, José Baselga

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

© 2014, Springer International Publishing Switzerland. 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.
Original languageEnglish
Pages (from-to)65-76
JournalTargeted Oncology
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • Apoptosis
  • Death receptor
  • Insulin-like growth factor receptor
  • Monoclonal antibodies
  • Targeted therapy
  • TRAIL

Fingerprint Dive into the research topics of 'Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab'. Together they form a unique fingerprint.

  • Cite this

    Tabernero, J., Chawla, S. P., Kindler, H., Reckamp, K., Chiorean, E. G., Azad, N. S., Lockhart, A. C., Hsu, C. P., Baker, N. F., Galimi, F., Beltran, P., & Baselga, J. (2015). Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab. Targeted Oncology, 10(1), 65-76. https://doi.org/10.1007/s11523-014-0315-z