figitumumab (CP-751,871)

We present the case of a 42-year-old female with recurrent ES with pulmonary metastases who, after progressing on anti-IGF-1R monotherapy with figitumumab (CP-751,871, NCT00560235), achieved complete remission in a phase I clinical trial (NCT00976508) that combined figitumumab IGF-1R-inhibition with growth hormone receptor antagonist pegvisomant. The impressive response observed highlights the clinical synergy of this combination which warrants further clinical exploration as well as the potential of IGF-1R inhibition for ES. Additionally, this case suggests that targeted therapy discontinuation might be an option for select patients with long-term complete remission.

Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary.

Initial anti-IGF-IR therapies like figitumumab were unsuccessful in a majority of patients in part due to the IR, which can bind the same ligands as IGF-IR and potentiate downstream signaling despite IGF-IR inhibition... Here, we confirm that OS and ES cells and PDXs preferentially express IR-A and that we can therapeutically modulate IR alternative splicing with our SSO in a dose-dependent manner. Additionally, our preliminary results indicate that AAVs, an FDA-approved methodology to deliver SSOs in a tissue-specific manner in pediatric diseases, are a promising approach for pediatric sarcomas as well. Targeting IR alternative splicing with splice-switching therapies and AAV delivery has the potential to address a key resistance mechanism that rendered previously developed anti-IGF-IR therapies ineffective in pediatric sarcoma patients.

Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.