Abstract 7052: Istiratumab exhibits antiproliferative activity in Ewing sarcoma and rhabdomyosarcoma

Abstract Istiratumab (prior MM-141) is a fully human tetravalent bi-specific antibody that binds and co-inhibits IGF-1R and ErbB3 (HER3). Istiratumab inhibits ligand binding to abrogate PI3K/AKT signaling resulting in antiproliferative activity in various cancers alone and in combination with mTOR inhibitor everolimus or chemotherapy, including in a human Ewing sarcoma model. Following Phase I and Phase II trials in advanced solid and pancreatic cancer, the molecule was abandoned by Merrimack Pharmaceuticals and was subsequently acquired by Pegascy. To consolidate our decision to proceed with a pediatric study, we explored our MAPPYACTS sequencing data on recurrent or refractory pediatric cancers for alterations in both pathways. Mutations in IGF-1R and HER3 occur rarely in pediatric cancers, some tumors exhibit IGF-1R amplification. Most tumors expressed moderate levels of IGF-1R with high expression in neuroblastoma samples and amplified osteosarcoma; IGF-2R is expressed in most cancers. IGF1 was lowly expressed in neuroblastoma and sarcoma but highly in choroid plexus carcinoma whereas IGF2 was highly expressed in most tumor types, particularly rhabdomyosarcoma, hepatoblastoma and ependymoma that are known to exhibit LOH. HER3 was found expressed in RMS, hepatoblastoma, a proportion of high grade glioma and carcinomas, its ligand NRG1 was found high only in single samples of sarcoma subtypes. Moreover, we observed IRS2 and IRS1 overexpression in about 80% of Ewing sarcoma samples. Overall, the activity of these pathways encouraged us to explore further the antitumor activity of istiratumab in pediatric cancers. We evaluated antiproliferative activity in Ewing sarcoma (TC-71, TC-106, CHLA-99, TC-205), alveolar (Rh41, Rh30) and embryonal (RD) rhabdomyosarcoma of istiratumab alone and in combination with the IRS1/2 inhibitor NT219 or HDAC inhibitor panobinostat. Istiratumab exhibited antiproliferative activity at 0.1 and 1 µM against most cell lines as determined by WST-1 assay. Strong growth inhibition (60-70%) was noted in TC-71 and TC-106, moderate inhibition (26%) in CHLA-99, whereas TC-205 was not sensitive. 35-45% growth inhibition was achieved in rhabdomyosarcoma RD, Rh30 and Rh41, similar to EBV-positive nasopharynx carcinoma C666, which co-expresses both pathways. Antiproliferative effects of istiratumab were enhanced by addition of NT219 at 0.1 μM or panobinostat in the 3 Ewing sarcoma cell lines tested. Similarly, the addition of IGF1 but not NRG1 in low serum growing conditions reinforced the observed activity of istiratumab in Ewing sarcoma cell lines. Evaluations to determine biomarkers for sensitivity are ongoing. Conclusion: Istiratumab has antiproliferative activity in sarcomas and will be evaluated in molecularly selected pediatric malignancies and Ewing sarcoma within the AcSé-ESMART trial. Citation Format: Jerome Salmon, Sarah Cherkaoui, Floriane Braye, Raphael J. Morscher, Luc Friboulet, Alexandre Bobard, Jean-Paul Alves, Jean-Pierre Armand, Birgit Geoerger. Istiratumab exhibits antiproliferative activity in Ewing sarcoma and rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7052.