High-dose ifosfamide outperforms topotecan-cyclophosphamide in the treatment of patients with recurrent/refractory Ewing sarcoma
rEECur is the first randomized trial comparing two chemotherapy regimens in patients with recurrent and primary refractory Ewing sarcoma (RR-ES). Results of this trial, presented as a late breaking abstract at ASCO 2022, show that high-dose ifosfamide (IFOS) was associated with a better event-free (EFS) and overall survival (OS) compared to doublet chemotherapy with topotecan and cyclophosphamide (TC). However, this survival benefit did come at the cost of a higher rate of encephalopathy and kidney toxicity, and IFOS treated patients were also more likely to discontinue treatment due to toxicity compared to TC.
Introduction
The prognosis for patients with RR-ES is poor, with a 5-year OS of about 15%. Today, multiple chemotherapy regimens are being used after progression to fist line therapy, but these regimens are not supported by strong, randomized evidence. As a result, there is also no established backbone to compare novel agents in clinical trials. To address this, rEECur was designed as the first randomized controlled trial in this setting, with the objective to define the standard care, balancing efficacy, and toxicity.
Study design
The rEECur study was set up as a multi-arm mutli-stage seamless phase II/III ‘drop a loser’ randomized trial. The trial began with the 4 most used treatments for RR-ES at the time: IFOS, TC, irinotecan and temozolomide (IT), and gemcitabine and docetaxel (GD). The phase II protocol was designed to drop the least successful treatment arms after 50 and then 75 patients had been randomly assigned and evaluated, however small the difference. In the first interim analysis, the GD arm was discontinued, and enrollment stopped in the IT arm after the second interim analysis. Of note, the results obtained with the 3 best-performing arms were quite similar, and the differences are quite small.
Results
The entire study cohort of rEECur included 439 patients, with a median age of 19 years. Of these patients, 85% were in 1st progression (18% primary refractory, 52% suffered a first disease recurrence within 2 years after the start of therapy, 15% recurrence ≥2 years). Progression was local in 15% of patients, pleuropulmonary in 33% and involved other metastatic sites in 52% of patients. The vast majority of patients (87%) had measurable disease at baseline. Overall, 92% of patients in the trial was pretreated with ifosfamide, while 58% previously received cyclophosphamide. For the phase III comparison in this trial, both the TC and the IFOS cohort contained 73 patients. The baseline patient and disease characteristics for these two patient groups were similar and in line with the overall study cohort.
In the randomized comparison between IFOS and TC, both the EFS and the OS were better with IFOS. The median EFS with IFOS and TC were reported at 5.7 and 3.5 months, respectively, with corresponding 6-month EFS rates of 47% and 37%. In terms of OS, IFOS treated patients reached a median of 15.4 months with a 1-year OS rate of 55%, whereas TC-treated patients had a median OS of 10.5 months, with 45% of patients being alive at 1 year, Subgroup analyses suggested a better survival in younger patients (< age 14) than for older children and adults, but the reason for this difference remains elusive and patient numbers are too limited to draw firm conclusions.
Comparing the IFOS arm to the TC arm, participants experienced more events of grade 3/4 encephalopathy (7% vs. 0%) and kidney toxicity (8% vs. 0%), and they were more likely to discontinue treatment due to toxicity (26% vs. 0%). Also infections were slightly more common with IFOS than with TC at 14% and 8%, respectively. Febrile neutropenia occurred at similar rates for both IFOS and TC (25% vs. 26%).
Conclusions
rEECur represents the first randomized comparison of chemotherapy regimens in patients with RR-ES. In this analysis, IFOS proved to be more effective than TC, with a superior EFS and OS. This benefit obtained with IFOS may be more pronounced in children, but this requires further validation. These data provide a foundation and path forward in designing clinical trials of new therapies, which are desperately needed for this disease. As future clinical trials in ES will evaluate combinations of chemotherapy and targeted treatments, these results also provide input on the best chemotherapy backbone based on toxicity (given the fairly similar outcome in terms of efficacy). The rEECur trial is currently recruiting patients to compare IFOS to a combination of carboplatin and etoposide regimens, and an additional arm with IFOS and lenvatinib is planned.
Reference
McCabe M, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). Presented at ASCO 2022; Abstract LBA2.
