Olaratumab displayed anti-tumor activity both as a single-agent and in concert with standard of care chemotherapy in a study using human pediatric sarcoma cell-derived models and in human sarcoma cell transfected mice.
This may represent a successful first step towards olaratumab treatment being evaluated in pediatric patients with sarcoma. New agent to be used in children and adolescents with cancer are generally tested in clinical trials against a currently accepted SOC. Prior to conducting a trial in children, knowing whether a drug may be potentially better is usually extrapolated from results of clinical trial in adults and from pediatric models of disease.
Olaratumab, which is a human anti-PDGFRα monoclonal antibody, has received accelerated FDA and European Commission approval in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma in the frontline setting. The combination demonstrated an 11.8-month improvement in overall survival when compared with doxorubicin alone. The agent was the first therapy approved for the frontline setting in nearly 40 years.
“Platelet-derived growth factor receptor α (PDGFRα) is implicated in multiple types of carcinoma and sarcoma, where its expression and/or activation promote primary tumor growth and metastasis,” said Caitlin May, PhD, lead author of a poster compiled by a research team at Lily Oncology, Indianapolis, USA. “PDGFRα signalling has also been implicated in several pediatric sarcoma subtypes, rhabdomyosarcoma, osteosarcoma, synovial, and Ewing’s sarcoma.”
The investigators evaluated olaratumab and 1E10, a novel high affinity anti-mouse PDGFRα antibody for anti-tumor activity alone and combined with SOC in patients derived and cell-derived mouse models of pediatric bone and soft tissue sarcoma.
“Olaratumab has not yet been evaluated in pediatric patients; current efforts are focused on delineating the mechanism of action of olaratumab combined with standard of care in pediatric soft tissue sarcoma subtypes,” Dr. May remarked.
They established a pharmacokinetic relationship in the human Hu09 pediatric osteosarcoma cell model, wherein PDGFRα signaling was inhibited by olaratumab in a dose dependent fashion.
“Olaratumab plus the mouse surrogate antibody 1E10 and/or SOC chemotherapy delays tumor growth in mouse models of pediatric malignancies including osteosarcoma and rhabdoid tumors,” she commented.
In the human Hu09 pediatric osteosarcoma mouse model, tumor growth was delayed by olaratumab, both alone and in combination with SOC or with 1E10.
Single agent olaratumab inhibited tumor growth in the A-204 rhabdoid (rhabdomyosarcoma) cell line-derived mouse model compared to an IgG control for 4 weeks; stable disease was attained by 6 of 11 animals treated with olaratumab.
Based on these data, the investigators concluded: “PDGFRα signaling is blocked by olaratumab or 1E10 in mouse models of pediatric sarcoma, resulting in tumor growth inhibition. Furthermore, SOC reduces PDGFRα expression in bone and soft tissue sarcoma cell and tumor models.”
The investigators also showed that doxorubicin decreases expression of PDGF pathway members, explaining partially the mechanism of the greater activity seen with the combination.
The authors summarized that additional factors may play a role in olaratumab activity: “Interestingly, expression of pathway components did not necessarily predict sensitively to treatment, indicating that PDGFRα and ligand expression were necessary, but not sufficient, for olaratumab sensitivity.”
May C, Loizos N, Novosiadly R, et al. The anti-platelet-derived growth factor receptor α antibody olaratumab (ly3012207/imc-3g3) demonstrates anti-tumor activity in models of pediatric bone and soft tissue sarcoma. Presented at: Connective Tissue Oncology Society Annual Meeting; Lisbon, Portugal; November 9-12, 2016. Poster 118 2537944