Ifosfamide Demonstrates Superiority For Recurrent, Primary Refractory Ewing Sarcoma

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The first phase III randomised controlled trial of chemotherapy for recurrent and primary refractory Ewing sarcoma (RR-ES) points to better event-free survival (EFS) and overall survival (OS) with high-dose ifosfamide than with topotecan plus cyclophosphamide (TC). 

Martin McCabe, from the University of Manchester in the UK, reported the rEECur results at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA, observing that “for the first time, we have randomised efficacy and toxicity data to inform patients and, importantly, us” in the treatment of this patient population. 

The presenter explained that the multi-arm, multi-stage, phase II/III study was designed to address the poor-quality evidence and absence of a standard of care for patients aged 2–50 years and to provide a consensus backbone for future comparisons with novel agents. 

Although initially four drug regimens were included, the gemcitabine plus docetaxel (GD) and the irinotecan plus temozolomide (IT) arms were discontinued after the first and second interim EFS assessments, leaving the ifosfamide and TC arms to continue to phase III. 

Analysis of the 73 patients in each of these arms showed that 17% had primary refractory disease, 52% and 14% had experienced a first recurrence within 2 years or at 2 years or later, respectively, and 16% had two or more recurrences. 

Disease progression was local in 13% of cases, pleuropulmonary metastases in 35% and metastatic to other sites in 52%, Martin McCabe said. And although not stratified, the trial arms were similar with regards to sex, age, pubertal stage, prior treatment with ifosfamide or cyclophosphamide, and performance status, the presenter added. 

After a median follow-up of 47 months, the median EFS in the whole cohort was 4.9 months and the median OS was 14.7 months. 

The primary outcome of EFS rate per treatment group at the latest analysis in April 2022 was 14% for ifosfamide-treated patients versus 8% for those given TC, giving a nonsignificant hazard ratio of 0.73. 

The probability density plot indicated that there is a 96% likelihood that ifosfamide therapy offers better EFS than TC, the presenter explained. 

The median EFS durations for the ifosfamide and TC arms were 5.7 and 3.5 months, respectively, with corresponding 6-month survival rates of 47% and 37%. 

At time of analysis 27% of patients given ifosfamide and 22% given TC were alive, with median OS durations of 15.4 and 10.5 months, respectively, and 1-year OS rates of 55% and 45%. Again the hazard ratio of 0.73 was not significant but there was a 94% likelihood that ifosfamide offered better OS than TC. 

Exploratory analysis indicated that ifosfamide offered better EFS for children aged 14 years or younger than older patients, and this was also true for OS, the presenter noted. 

Discussing toxicity, the investigator said that ifosfamide was associated with higher rates of grade 3 or more severe adverse events than TC (57 vs 44%) and a higher rate of infections or infestations (14 vs 8%), as well as more encephalopathy (8 vs 3%) and renal/urinary disorders (8 vs 0%). Rates of febrile neutropenia were comparable in the groups (25 vs 26%). 

Around a quarter (26%) of patients discontinued ifosfamide due to toxicity compared with none of their TC-treated counterparts, although the investigator noted that dose reductions were only permitted for the TC arm. 

He also said that the rate of grade 3 or more severe events was comparable in the GD (51%) and IT (55%) arms and although these regimens had lower rates of febrile neutropenia (18% and 11%, respectively), 34% of IT-treated patients had gastrointestinal issues, including diarrhoea in 25%.  

Quality of life as reported by children and their parents was “improving” with ifosfamide but not with TC, although no such difference was noted in adult participants, the researcher commented. 

“These data allow us to move forward with patient management and with trial design based on empirical data rather than supposition”, commented Martin McCabe, noting that as most patients were on first progression, “the results are applicable to standard care”. 

He concluded that the trial continues to recruit patients to the ifosfamide and carboplatin plus etoposide treatment arms, and a combination arm of ifosfamide plus lenvatinib will be introduced later in 2022. 

Session discussant Katherine Janeway, from the Dana–Farber Cancer Institute in Boston, Massachusetts, USA, praised the international collaboration required to obtain the “high quality evidence” for OS, toxicity and quality of life in the rEECur trial. 

She mentioned the need to determine the outcomes of the IT and TG arms compared with the ifosfamide cohort, and noted difficulties with conducting international rare cancer basket studies for novel agents with different pharmaceutical partners.  

While ifosfamide might be considered the chemotherapy backbone of choice for combinations, other agents might be preferred because of overlapping toxicity or synergy, commented Katherine Janeway. Agents under phase I and II trial investigation in Ewing sarcoma with other chemotherapy backbones include trabectedin, palbociclib, cabozantinib and seclidemstat, she said. 

Reference 

McCabe MG, Kirton L, Khan M, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomised controlled trial of chemotherapy for treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). J Clin Oncol 2022; 40 (suppl 17; abstr LBA2). doi: 10.1200/JCO.2022.40.17_suppl.LBA2