Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group

Abstract

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

A phase II trial of regorafenib in patients with advanced Ewing sarcoma and related tumors of soft tissue and bone: SARC024 trial results

“…A second potential agent to consider in a regorafenib combination is an IGF1R inhibitor. While responses were seen in metastatic Ewing sarcoma using IGF1R inhibitors, Ewing sarcoma patients did not derive benefit from the use of IGF1R inhibitors as part of primary therapy 27 . As a result, combinations of any agent with regorafenib in Ewing sarcoma should be examined in model systems before moving into clinical trials, especially given many new targets that are emerging in preclinical studies.…”

Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype

“…In the light of the potential synergism between IGF1R inhibitors (IGF1Ri) and conventional chemotherapy, the addition of ganitumab to chemotherapy in newly diagnosed metastatic ES patients was investigated in a phase III trial [ 21 ].…”

“…Unfortunately, no event-free survival (EFS) benefit with the addition of the anti-IGFR1 mAb to interval-compressed chemotherapy, consisting of vincristine/doxorubicin/cyclophosphamide alternating once every two weeks with ifosfamide/etoposide (CDV/IE), was seen [ 21 ].…”

Children's Oncology Group's 2023 blueprint for research: Radiation oncology

“…A prospective study for metastatic Ewing sarcoma, AEWS1221 was also recently reported 33 . Despite evidence supporting consolidation of metastatic sites with RT, compliance with recommendations was poor, and no meaningful data were obtained to evaluate the efficacy of this approach 33 . AEWS1221 also utilized SBRT to allow definitive RT administered at higher doses in rapid time frame (five fractions) to improve compliance with RT recommendations for all metastatic bony sites.…”