Martin McCabe, MD, PhD

High-dose ifosfamide extended event-free and overall survival in patients with recurrent or primary refractory Ewing sarcoma compared with other commonly used chemotherapy regimens, according to the results of a randomized trial reported at the 2022 ASCO Annual Meeting by lead author Martin McCabe, MD, PhD, Clinical Senior Lecturer at the University of Manchester and pediatric oncologist at the Christie Hospital, United Kingdom.¹ Median event-free survival was 5.7 months with ifosfamide vs 3.5 months with topotecan plus cyclophosphamide, and median overall survival was 15.4 months with ifosfamide vs 10.5 months with topotecan plus -cyclophosphamide. These gains in survival are modest but are considered important, since they inform treatment choices and designs of future clinical trials, experts said.

The phase III rEECur study is the first randomized trial to compare different chemotherapy regimens in recurrent and primary refractory Ewing sarcomas. Previous studies were single-arm or case series.

“The rEECur study has, for the first time, accrued randomized data for four widely used chemotherapy regimens and is now accruing data for a fifth regimen. Prior to rEECur, the basis for choosing drugs for patients with relapsed or refractory Ewing sarcoma was weak, and randomized clinical trials were lacking to inform clinicians and patients about which treatments were the most effective and/or most toxic,” said Dr. McCabe. “There was no standard of care before this trial,” he added.

Ifosfamide is an older drug that works by breaking DNA strands and inhibiting cell proliferation. The 5-year survival rate for this relatively uncommon cancer is about 15%. About 300 children, teenagers, and young adults in the United States are diagnosed with the disease each year.

Study Details

The study was designed as a multiarm, multistage, seamless phase II/III “drop-a-loser” randomized trial, Dr. McCabe explained. The four treatments compared were topotecan plus cyclophosphamide, irinotecan plus temozolomide, gemcitabine plus docetaxel, and high-dose ifosfamide. These regimens were the most widely used in Europe at the time the trial was initiated. The primary endpoint was event-free survival, and secondary endpoints included toxicity, progression-free survival, overall survival, and quality of life.

“Patients were between the ages of 2 and 50 [median age, 19] and were randomly assigned among two, three, or four arms depending on their eligibility,” he explained.

Of the original four treatment arms, two arms were dropped—irinotecan plus temozolomide and gemcitabine plus docetaxel—at the first and second interim analyses based on response rates and event-free survival. In phase III, high-dose ifosfamide was compared with topotecan plus cyclophosphamide, with 73 patients in each arm. Patients were treated with intravenous ifosfamide at a dose of 3,000 mg/m² on days 1 through 5 by continuous infusion. Topotecan was given at 0.75 mg/m² and cyclophosphamide at 250 mg/m², both intravenously, on days 1 through 5.

At baseline, 85% of patients were in their first episode of disease progression. Two-thirds were male. Most had received previous treatment with ifosfamide, and most had a good performance status. About 70% of patients had bone as their initial disease site.

Key Results

At a median follow-up of 47 months, median event-free survival was 3.5 months with topotecan plus cyclophosphamide and 5.7 months with high-dose ifosfamide. The 6-month event-free survival rates were 37% and 47%, respectively. Median overall survival was 10.5 months with topotecan plus cyclophosphamide vs 15.4 months with high-dose ifosfamide. There was a 96% probability that ifosfamide was better than topotecan plus cyclophosphamide in terms of event-free survival.

“The vast majority of events occurred early,” Dr. McCabe stated. “There was about a 5-month difference in median overall survival and a 10% difference in 1-year and 2-year overall survival favoring high-dose ifosfamide, which was 94% more likely to be effective than topotecan plus cyclophosphamide for overall survival.”

The event-free and overall survival differences were greater with ifosfamide vs topotecan plus cyclophosphamide in younger patients than for those aged 14 and older.

There were more treatment discontinuations overall on the topotecan-plus-cyclophosphamide arm, but more discontinuations due to toxicity on the ifosfamide arm; the study protocol allowed dose reductions for topotecan plus cyclophosphamide but did not allow dose reductions for ifosfamide. The rates of neurotoxicity and nephrotoxicity were higher with ifosfamide as well, but they were less than 10% in both arms. The main grade 3 or 4 adverse events with topotecan plus cyclophosphamide vs high-dose ifosfamide were febrile neutropenia (about 25% in both groups); infections (8% vs 14%, respectively); vomiting (1% in both groups) and nausea (0% vs 3%, respectively); diarrhea (1% in both groups); encephalopathy (0% vs 7%, respectively), and renal toxicity (0% vs 8%, respectively).

The investigators used different measures for quality of life in children and adults. Children reported improved quality of life with ifosfamide but not with topotecan plus cyclophosphamide. There were no clear differences between the arms in quality of life in adults on either regimen.

What Next?

The study is still open and recruiting patients to the ifosfamide arm plus a fifth arm that includes carboplatin plus etoposide. A new arm that will include a molecularly targeted agent will be introduced later in 2022.

“This is the first randomized, controlled trial of chemotherapy in this disease setting,” Dr. McCabe concluded. “Importantly, we now have data both to inform patients and to develop future studies. The differences [between these regimens] are quite subtle. What we need are better drugs to cure more patients.” 

DISCLOSURE: Dr. McCabe has served as a consultant or advisor to Amgen.

REFERENCE

1. McCabe M, Kirton L, Khan M, et al: Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur. 2022 ASCO Annual Meeting. Abstract LBA2. Presented June 5, 2022.