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.

Trial registration: ClinicalTrials.gov NCT00819169.

Conflict of interest statement

Conflict of interest Josep Tabernero, Hedy Kindler, Karen Reckamp, E. Gabriela Chiorean, and A. Craig Lockhart received research funding for their respective institutions for the conduct of this study. Josep Tabernero was a paid consultant for Amgen, Bristol-Myers Squibb, Genentech, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, Imclone, and Bayer. Hedy Kindler was a paid consultant and received travel support from Amgen, and received consultancy fees from Bristol-Myers Squibb, OSI/Astellas, Genentech/Roche, Infinity, and Clovis. Sant P. Chawla and Karen Reckamp received consultancy fees from Amgen. Nilofer Azad had no relationships to disclose. José Baselga received consultancy fees from Astra Zeneca, Bayer Healthcare, Exelixis, Glaxo SmithKline, Intellikine, Janssen Oncology, Novartis, Merck, Roche/Genentech, and Sanofi Aventis. Cheng-Pang Hsu, Nigel F. Baker, and Pedro Beltran are employees of Amgen and hold Amgen stock. Francesco Galimi was an employee of Amgen while the study was conducted.

Figures

Fig. 1

Ganitumab and conatumumab in the Colo 205 human colorectal cancer xenograft model. RMANOVA: *p<0.015 vs conatumumab, *p<0.001 vs ganitumab

Fig. 2

CONSORT diagram; aReason for exclusion: did not receive treatment

Fig. 3

Individual patients’ best overall tumor response (maximum percentage decrease or minimum percentage increase from baseline in the sum of the longest diameter)

Fig. 4

Mean predose and end-of-infusion concentrations in part 2. a Mean ganitumab concentration; b Mean conatumumab concentration. n=the range of patient numbers at four time points