Other Therapies

Monoclonal antibody therapy. Monoclonal antibodies against the insulin-like growth factor 1 receptor (IGF1R) are reported to produce objective responses in approximately 10% of patients with metastatic recurrent Ewing sarcoma.[47-50][Level of evidence C3] These studies suggested that time-to-progression was prolonged compared with historical controls. Objective responses have been reported in studies combining the mTOR inhibitor temsirolimus with an IGF1R antibody. In a phase II trial of ten patients who were treated with an IGF1R antibody and a CDK4/6 inhibitor, no responses were reported.[51] Stratification by IGF1R expression (detected by immunohistochemistry) in one of the studies did not predict clinical outcome in patients with Ewing sarcoma.[52,53] Further studies are needed to identify patients who are likely to benefit from IGF1R therapy.

Immunotherapy. Immunotherapy with antigen-specific T cells is being studied in patients with Ewing sarcoma because immune-mediated killing attacks the tumor in a different way, unlike conventional therapies (that rely on pathways), which such tumors often resist. Several potential chimeric antigen receptors target antigens that have been identified for Ewing sarcomas. These include HER2 (human epidermal growth factor receptor 2),[54] GD2,[55] CD99 (MIC2 antigens),[56] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[57] Some of these therapies are in early-phase testing in patients with sarcomas.[54] Treatment with single-agent and combined immune checkpoint inhibitors has shown no activity in patients with recurrent Ewing sarcoma. There were no responses in five patients with Ewing sarcoma treated on a clinical trial with single-agent nivolumab or the combination of nivolumab and ipilimumab.[58] A trial of pembrolizumab included 13 patients with Ewing sarcoma whose cancer did not respond to the treatment.[59] Another trial of nivolumab reported that there were no responses in 11 patients with Ewing sarcoma.[60] The Children's Oncology Group (COG) conducted a phase I/II trial of the combination of nivolumab and ipilimumab in children with recurrent sarcomas.[61][Level of evidence B4] Only 1 of 14 patients with Ewing sarcoma exhibited a sustained partial response.

Multitargeted kinase inhibitors.

Multitargeted kinase inhibitors.

Regorafenib: A phase II study (SARC024 [NCT02048371]) evaluated regorafenib monotherapy in 30 patients with metastatic recurrent Ewing sarcoma and other translocation-positive tumors, including CIC::DUX4 sarcoma.[62] Modest activity was observed, with a 10% objective response rate by response evaluation criteria in solid tumors (RECIST). The median PFS was 14.8 weeks.A prospective, randomized, double-blind trial compared regorafenib with placebo in patients with recurrent Ewing sarcoma.[63] Of 36 patients who were evaluable for efficacy, 23 received regorafenib and 13 received placebo. The patients randomly assigned to regorafenib had an 8-week PFS rate of 56%, compared with 7.7% for patients randomly assigned to placebo. The median PFS was 11.4 weeks for patients who received regorafenib and 3.9 weeks for patients who received placebo. The response rate was 13% in patients treated with regorafenib. Ten patients in the placebo group crossed over to receive regorafenib after progression. Although the results were not significant, the authors suggested that this trial provided some evidence of benefit for the use of regorafenib in patients with relapsed Ewing sarcoma.In addition to this single-agent experience, regorafenib was shown to be tolerable on a sequential schedule with vincristine and irinotecan in 21 pediatric patients. Five patients with relapsed Ewing sarcoma were included as part of this phase I trial. Three of five patients had partial responses with this regimen.[64]

Multitargeted kinase inhibitors.

Anlotinib: A study completed in China evaluated treatment with anlotinib (an oral receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1–3, fibroblast growth factors 1–3, platelet-derived growth factor receptors alpha and beta, c-KIT, and RET) given along with vincristine and irinotecan for patients with relapsed or refractory Ewing sarcoma.[65][Level of evidence B4] Patients were treated in two cohorts. Cohort A included patients aged 16 years and older, and cohort B included patients younger than 16 years. At 12 weeks, patients in cohort A demonstrated an objective response rate of 62.5% (14 of 23 patients), and patients in cohort B demonstrated an objective response rate of 83.3% (11 of 12 patients). Anlotinib has not yet received approval from the U.S. Food and Drug Administration.

Multitargeted kinase inhibitors.

Cabozantinib: A real-world evidence analysis included 16 patients with relapsed or refractory Ewing sarcoma who were treated with cabozantinib. Four patients had objective responses (25% objective response rate).[66] Thirty-nine patients (older than 12 years) with relapsed Ewing sarcoma were assessable for response after cabozantinib monotherapy.[67] Patients younger than 16 years received 40 mg daily, and patients aged 16 years and older received 60 mg daily. Most patients were older than 18 years. Ten patients (26%) had responses (all partial responses).

Strategies to target fusion proteins.

Strategies to target fusion proteins.

Lurbinectedin: Lurbinectedin is structurally related to trabectedin, but it has been more effective in suppressing the activity of the oncogenic transcription factor EWS::FLI in mice in preclinical studies. In an open-label, single-arm, basket phase II trial, clinical antitumor activity was seen. In a cohort of 28 adult patients with confirmed Ewing sarcoma and relapsed disease, the objective response rate was 14.3%, the clinical benefit rate (response or disease stabilization for >4 months) was 39.3%, and the disease control rate (response or disease stabilization of any duration) was 57.1%.[68]

Strategies to target fusion proteins.

TK216: An agent known as TK216 is thought to interfere with interactions between the EWSR1::FLI1 fusion oncoprotein and key proteins critical for its oncogenic function, although it has also been shown to disrupt microtubules.[69] In a phase I/II trial of TK216 in combination with vincristine in patients with recurrent Ewing sarcoma, three responses were observed. However, the overall response rate was only 3.5% across the whole trial.[70]