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Ref Type Journal Article
PMID (24816908)
Authors Tabernero J, Chawla SP, Kindler H, Reckamp K, Chiorean EG, Azad NS, Lockhart AC, Hsu CP, Baker NF, Galimi F, Beltran P, Baselga J
Title Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.
Journal Targeted oncology
Vol 10
Issue 1
Date 2015 Mar
URL
Abstract Text 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 (pā€‰<ā€‰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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Conatumumab AMG 655|AMG-655|AMG655 Conatumumab (AMG 655) is a monoclonal antibody that binds to and activates the TRAIL receptor 2 (TR-2), initiating caspase activation and inducing tumor cell apoptosis (PMID: 24816908).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lung non-small cell carcinoma not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II clinical trial, Ganitumab and Conatumumab combination treatment resulted in stable disease in 50% (11/22) of patients with non-small cell lung carcinoma (PMID: 24816908). 24816908
Unknown unknown sarcoma not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II trial, Ganitumab and Conatumumab (AMG 655) combination treatment resulted in stable disease in 33% (5/15) of patients with sarcoma, including one with leiomyosarcoma (PMID: 24816908). 24816908
Unknown unknown pancreatic cancer not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II clinical trial, Ganitumab and Conatumumab combination treatment resulted in stable disease in one patient out of sixteen with pancreatic cancer (PMID: 24816908). 24816908
Unknown unknown ovarian cancer not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II clinical trial, Ganitumab and Conatumumab combination treatment resulted in stable disease in 56% (5/9) of patients with ovarian cancer (PMID: 24816908). 24816908
Unknown unknown colorectal cancer not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II clinical trial, Ganitumab and Conatumumab combination treatment resulted in one unconfirmed partial response and stable disease in 38% (6/16) of patients with colorectal cancer (PMID: 24816908). 24816908
Unknown unknown Advanced Solid Tumor not applicable Conatumumab + Ganitumab Phase Ib/II Actionable In a Phase Ib/II trial, Ganitumab and Conatumumab (AMG 655) combination treatment resulted in stable disease in 36% (28/78) of patients with an advanced solid tumor (PMID: 24816908). 24816908