International Trial Finds Best Regimen for Ewing Sarcoma

Sharon Worcester, MA

June 05, 2022

High-dose ifosfamide has shown superior survival benefit over three other chemotherapy regimens for patients with recurring or refractory primary Ewing sarcoma (RR-ES) in the practice-changing rEECur trial.

This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.

The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the American Society of Clinical Oncology (ASCO).

The results were presented June 5 during a plenary session here at the ASCO 2022 annual meeting.

Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester, UK. The incidence rate is 3.2 per million people under age 25 years, he said.

Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.

Dr Martin McCabe

This international trial set out to answer that question and compared four different regimens. Participating centers were "able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner," she said.

Earlier findings from this trial had shown that ifosfamide had improved survival compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.

At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.

Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, McCabe reported.  

Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. "Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival," he said.   

High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.

Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years compared with those aged 14 and older, McCabe noted.

As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.

Despite the practice-changing results, McCabe stressed that the "differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients."

The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.

Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.

Important Global Collaboration

Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. "In this really terrific collaboration...there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity."

"It's a really important concept in rare diseases: if we all work together, we actually can study them and get answers," she said.

"I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens]," she added.

Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial "could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data," she commented in an ASCO press release.  

Real-World Implications

The rEEcur trial results will change practice, invited discussant Katherine A. Janeway, MD, told the audience at the plenary session during which the results were presented.

Janeway is an associate professor of pediatrics at Harvard Medical School and a senior physician in pediatric oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts.

She illustrated the point by describing the case of a patient of hers who was diagnosed with Ewing sarcoma at 19 years of age.

The young woman presented with a primary tumor of the ilium, as well as pulmonary metastasis. She received upfront chemotherapy, underwent primary tumor resection, and received whole-lung radiation and radiation therapy to the pelvis for microscopic disease at the resection margins.

After 14 months, her disease recurred — she developed a single pulmonary nodule, which was surgically resected.

"Prior to the rEEcur trial results we had very limited evidence to drive pretreatment decisions for a patient like this," Janeway said. She said that all of the four commonly used chemotherapy regimens (that were tested in the trial) were considered for this patient, but there were either no prospective phase 2 trials or there were prospective phase 2 trials with small numbers that reported only on objective response rates.

"[The patient] received irinotecan-temozolomide, which, along with topotecan-cyclophosphamide, is the standard treatment for recurring Ewing sarcoma at my institution due to several retrospective studies showing good objective responses and reasonable progression-free survival," she said. "We have generally not considered high-dose ifosfamide because of the delivery of ifosfamide in upfront treatment."

Had the rEEcur findings been available, however, high-dose ifosfamide would have been considered as a treatment option, she said.

"That said, I would also continue to offer irinotecan and temozolomide as an alternative," she added. "Importantly, I would be able to provide her with the expected objective response rate, median event-free and overall survival, and toxicities for each treatment option to not only help her make an informed decision but also to help her plan for the future."

"Fortunately, it has now been over 10 years and this patient remains disease-free," Janeway commented.

The rEEcur trial results not only have the potential to benefit patients now, they will also help in the future with trial design and drug development efforts, Janeway commented. She agreed with the authors that new drugs are needed "given the poor outcomes even with high-dose ifosfamide."

"Recurring Ewing sarcoma is an aggressive, rapidly progressing disease with a difficult-to-target driver. For the foreseeable future, new drugs will need to be studied in combination with chemotherapy," she said. There are several ongoing phase 1 and 2 trials looking at newer, more targeted agents for Ewing sarcoma, but none are being studied in combination with ifosfamide, she noted.

Given the rEEcur results, it will be important to consider ifosfamide as a "potential chemotherapy backbone in combination with targeted agents," but the other regimens should also continue to be "considered as acceptable backbones in trials if needed in order to avoid overlapping toxicities or achieve therapeutic synergy," she said.

Remaining Questions

Future work should evaluate how outcomes with irinotecan-temozolomide and gemcitabine-docetaxel chemotherapy combinations compare with those in patients treated with high-dose ifosfamide, Janeway said.

It also remains unclear whether it will be feasible to conduct collaborative, international, multi-arm basket studies like rEEcur in rare cancers once novel agents from different industry partners are being studied and whether researchers can "achieve transcontinental collaborative trials to capture even more of the patient population."

The rEECur trial was funded by Cancer Research UK and the European Commission with additional funding from the Aamu Pediatric Cancer Foundation, Australia and New Zealand Children's Hematology and Oncology Group, Australia and New Zealand Sarcoma Association, Canteen, German Cancer Aid, Swiss Pediatric Oncology Group, and the Zoé4life foundation. McCabe has reported serving in a consulting/advisory role for Amgen. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health. Janeway has reported receiving honoraria from Foundation Medicine and Takeda, travel expenses from Bayer, and serving in consulting or advisory roles for Bayer and Ipsen.

ASCO 2022. Abstract LBA2. Presented June 5, 2022.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on Twitter: @SW_MedReporter

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