A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

Abstract

BackgroundRobatumumab (19D12; MK‐7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin‐like growth factor receptor‐1 (IGF‐1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3).ProcedureRobatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients.ResultsLow disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET‐CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25–115 doses of robatumumab with remissions of >4 years duration (N = 6).ConclusionsThese findings show that although the IGF‐1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF‐1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

“…A particular focus of research has been IGF1R that has been targeted in phase I/II clinical trials of IGF1R inhibitors in osteosarcoma161718. Given this prior interest, we assessed IGF1R copy number in an extension cohort of 87 cases of childhood and adult osteosarcoma.…”

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

“…Outcomes in these trials were extremely disappointing due to an overall infrequency of objective responses and a lack of any accurate predictive biomarkers of response. The most promising patient subgroup who might benefit from IGF1R‐targeted therapy are Ewing's sarcoma patients, where a minority have sustained durable responses lasting several years without major side effects (Anderson et al ., ). The inability to select which patients are likely to respond has severely hampered efforts to employ IGFR1‐targeted agents in mainstream treatment.…”

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

“…Previous studies of monoclonal antibodies and TKIs targeting IGF-1R in patients with a range of solid tumors have yielded mixed, mostly negative, results, both as monotherapy and when combined with established therapies (see Supplementary Table S1 for details). Objective responses have been low and mainly limited to studies in osteosarcoma, Ewing sarcoma, and other soft tissue sarcomas (71)(72)(73)(74)(75). The failure of IGF-1Rinhibitory drugs to impact tumor growth in unselected patients may be attributable to compensatory activation of other signaling pathways, including those involving the epidermal growth factor receptor (EGFR; ref.…”