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01-03-2015 | Original Research

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

Authors: 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

Published in: Targeted Oncology | Issue 1/2015

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.

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Title: Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab
Authors: 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
Publication date: 01-03-2015
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 1/2015
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-014-0315-z

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