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Adding the mTOR inhibitor temsirolimus (Torisel) to chemotherapy in the first-line setting failed to improve event-free survival (EFS) among young patients with intermediate-risk rhabdomyosarcoma, a phase III trial from the Children's Oncology Group showed.

The 3-year EFS rate was 66.8% for those who received temsirolimus and chemotherapy compared with 64.8% for those who received chemotherapy alone (HR 0.86, 95% CI 0.58-1.26, P=0.44), reported Abha A. Gupta, MD, of Princess Margaret Cancer Centre in Toronto, and colleagues in .

Three-year overall survival (OS) rates, a secondary endpoint, were 77.8% and 78.7%, respectively (HR 1.15, 95% CI 0.72-1.84, P=0.56).

"Novel strategies are required to improve outcomes in these patients," the authors concluded.

Rhabdomyosarcoma is a soft tissue sarcoma that primarily affects children and adolescents. These tumors are extremely rare, with only about 400 cases diagnosed in the U.S. each year.

In a , Ewa Koscielniak, MD, of the University of Tübingen in Germany, and Thomas Klingebiel, MD, of University Hospital Frankfurt in Germany, noted that this is one of many negative randomized rhabdomyosarcoma trials conducted in the U.S. and Europe.

"This method is unlikely to be effective for investigating new therapeutic approaches in a rare and genetically heterogeneous tumor such as rhabdomyosarcoma, especially when improvements in outcome with standard multimodal therapy have reached their limits," they wrote.

The only way to achieve progress in these patients is by stratifying them according to the molecular characterization of their tumors, and through the use of biomarkers "that allow the efficacy of a new drug to be demonstrated even in a small number of patients or through better assessment of residual or metastatic disease by measurement of circulating tumor DNA," they added.

In explaining the rationale behind their study design, Gupta and colleagues pointed to a previous in which patients with relapsed or refractory rhabdomyosarcoma had a 6-month EFS rate of 69.1% when treated with chemotherapy plus temsirolimus compared with 54.6% with chemotherapy plus bevacizumab (Avastin).

In addition, they noted that defined vincristine (Oncovin), actinomycin, and cyclophosphamide alternating with vincristine and irinotecan as the chemotherapy backbone for intermediate-risk rhabdomyosarcoma, which was used here, and that results from a phase III study showed an OS benefit following the addition of maintenance chemotherapy, thus leading them to add maintenance therapy to the current trial as well.

This study enrolled 325 patients across 210 centers in Australia, Canada, New Zealand, and the U.S. from May 2016 to January 2022.

Eligible patients were 40 and younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavorable sites. The study's 297 evaluable patients were randomized 1:1 to each of the two groups. Median age was 6.3 years, 11% were 18 and older, and 60% were male.

The primary endpoint of 3-year EFS was defined as time from study enrollment to the first occurrence of progression, relapse, second malignant neoplasm, death from any cause, or time to last contact for those without a previous event.

Post-hoc subgroup analyses showed no significant differences in EFS according to age or FOXO1 translocation status (in non-metastatic patients), although Gupta and colleagues acknowledged that the study was not sufficiently powered to evaluate the specific effects of temsirolimus on these subpopulations -- a limitation commonly seen in randomized trials in rare pediatric cancers.

The most common grade 3-4 adverse events included anemia (58% in the temsirolimus group vs 41% in the chemotherapy-alone group), lymphopenia (48% vs 44%), neutropenia (70% vs 67%), and leukopenia (62% vs 58%).

There was one treatment-related death in the temsirolimus group, categorized as not otherwise specified.

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