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 nonsquamous 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.

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

“…In addition, recombinant human TRAIL and monoclonal agonist antibodies targeted DR4 and DR5 have been evaluated in the clinic. Some Phase 1/1b and Phase 2 studies provided clinical benefit in patients with advanced solid tumors (Ba‐Sang et al ., 2016; Huang and Sheikh, 2007; Tabernero et al ., 2015). Through investigating the mechanism of gastric cancer cells resistance to TRAIL, we may screen out the dominant population of TRAIL treatment for gastric cancer in the future.…”

Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer

“…The study was conducted at 19 study centers: Belarus (1), Hungary (3), Poland (1), Russia (6), and Ukraine (8). Before initiation of the study at each investigative site, the protocol, the informed consent form(s), the patient information sheet, details of patient recruitment, and any other relevant study document were submitted to the responsible ethics committees and written approvals were obtained.…”

“…The relatively high levels of free IGF-1 in adenocarcinoma (AC) and squamous cell carcinoma of the lung (SCC) suggest these cancers to be the potentially promising areas for development of drugs that target the (IGF-1R) signaling pathway [4][5][6][7][8][9]. AXL1717 (AXL) is an oral small-molecule pharmaceutical agent, originally developed as a targeted modulator of (IGF-1R) signaling [10].…”

Targeted therapy for soft tissue sarcomas in adolescents and young adults

“…Most of them showed great responses in singular patients, but no benefit overall in larger cohorts. These agents include R1507,146 AVE1642,147 MK-0646,148 and ganitumab alone or in combination with conatumumab (death receptor 5 agonist) 149. These results suggest that agents targeting IGF-1R might benefit a small subset of patients, but our current understanding of the biology of these tumors does not allow for selection of these patients yet.…”