# Multi-Targeted TKIs in Patients with Advanced Ewing Sarcoma: A Systematic Review and Single-Arm Meta-Analysis

## TL;DR

This study reviews and combines data from multiple studies to evaluate how well tyrosine kinase inhibitors work in treating advanced Ewing sarcoma, finding moderate effectiveness with some drugs showing better results.

## Contribution

The study provides a meta-analysis of tyrosine kinase inhibitors in relapsed Ewing sarcoma, highlighting the most effective drugs available in Western countries.

## Key findings

- Tyrosine kinase inhibitors showed an objective response rate of 23% and a disease control rate of 61.1% in Ewing sarcoma patients.
- Cabozantinib and regorafenib demonstrated the most consistent benefits among FDA-approved drugs.

## Abstract

Ewing sarcoma is a rare and aggressive cancer that often relapses after treatment. There is no clear standard therapy for patients whose disease progresses. Tyrosine kinase inhibitors have recently shown promising results. We reviewed and pooled data from published clinical trials and real-world studies to better evaluate the efficacy and safety of tyrosine kinase inhibitors in relapsed Ewing sarcoma patients. In our pooled analyses of 14 studies, we found an objective response rate of 23% and a disease control rate of 61.1%. Cabozantinib and regorafenib showed the most consistent benefits among drugs available in Western countries. These findings suggest the potential of tyrosine kinase inhibitors in the treatment of such a challenging population.

Background/Objectives: Standard treatment of multiply relapsed Ewing sarcoma remains to be established. Recent studies evaluating tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties have shown encouraging results. Therefore, we conducted a systematic review and meta-analysis to explore the efficacy and safety of TKIs in patients with Ewing sarcoma. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials (CTs) and cohort studies assessing TKIs in the treatment of advanced Ewing sarcoma patients who received at least one prior line of therapy. The main outcome was objective response rate (ORR). All analyses were conducted using R software (v.4.2.2), employing random effects models with 95% confidence intervals (CIs). Results: We included 14 studies (seven phase II CT and seven retrospective cohorts), comprising 257 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib, sorafenib, lenvatinib, sunitinib, fruquintinib, and imatinib. In a pooled analysis of all Ewing sarcoma patients treated with TKIs, the ORR was 23% (95% CI, 11.2–37.1%) and the DCR was 61.1% (95% CI, 47.3–74.2%). Responses were numerically higher but statistically nonsignificant between clinical trials and real-world studies. The analysis including only single-agent TKIs showed better responses for anlotinib and apatinib, yet these drugs are not available in Western countries. Among the FDA-approved TKIs, superior outcomes were noted with single-agent cabozantinib. (ORR: 21.6%) and regorafenib (ORR: 11.3%). Several studies did not report toxicity data exclusively for Ewing sarcoma patients; thus, conclusions about toxicity are mostly based on the general population of studies and may not be fully representative of Ewing sarcoma patients. Conclusions: Anti-angiogenic TKIs have shown important anti-tumoral activity in patients with Ewing sarcoma. Efficacy was consistently seen in both clinical trials and real-world studies. Nonetheless, there are important differences in study design and population that may limit our interpretation of efficacy and toxicity findings.