As reported in The Lancet Oncology by Gupta et al, the phase III Children’s Oncology Group ARST1431 trial showed no event-free survival benefit with the addition of temsirolimus to chemotherapy in previously untreated children, adolescents, or young adults with intermediate-risk rhabdomyosarcoma.
Study Details
In the open-label trial, 297 evaluable patients with intermediate-risk disease from sites in Australia, Canada, New Zealand, and the United States were randomly assigned between May 2016 and January 2022 to receive vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) without (n = 148) or with temsirolimus (n = 149), with all patients receiving maintenance therapy with cyclophosphamide plus vinorelbine. Intermediate-risk disease was defined as nonmetastatic FOXO1 fusion–positive rhabdomyosarcoma or unresected FOXO1 fusion–negative disease at unfavorable sites.
Treatment consisted of VAC/VI every 3 weeks for 14 cycles (42 weeks) followed by 6 cycles of maintenance therapy. Temsirolimus was given concurrently at weekly doses of 15 mg/m² or 0.5 mg/kg per dose for patients weighing less than 10 kg. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint of the study was 3-year event-free survival.
Survival Results
Patients had a median age of 6.3 years (interquartile range [IQR] = 3.0–11.3 years); 33 patients (11%) patients were aged ≥ 18 years. FOXO1-negative status was present in 73% of the temsirolimus group and 77% of the control group.
KEY POINTS
- The addition of temsirolimus to VAC/VI did not improve event-free survival in previously untreated children, adolescents, or young adults with intermediate-risk rhabdomyosarcoma.
- Event-free survival at 3 years was 66.8% vs 64.8%.
With a median follow-up of 3.6 years (IQR = 2.8–4.5 years), 3-year event-free survival was 66.8% (95% confidence interval [CI] = 57.5%–76.2%) in the temsirolimus group vs 64.8% (95% CI = 55.5%–74.1%) in the control group (hazard ratio [HR] = 0.86, 95% CI = 0.58–1.26, P =.44).
Overall survival at 3 years was 77.8% (95% CI = 69.7%–85.9%) in the temsirolimus group vs 78.7% (95% CI = 70.9%–86.4%) in the control group (HR = 1.15, 95% CI = 0.72–1.84, P = .56).
Adverse Events
All grade ≥ 3 adverse events were more common in the VAC/VI with temsirolimus group vs the VAC/VI alone group, except for anorexia and nausea. The most common in the temsirolimus group vs the control group were anemia (58% vs 41%), lymphopenia (48% vs 44%), neutropenia (70% vs 67%), and leukopenia (62% vs 58%). One treatment-related death occurred in the temsirolimus group, due to an otherwise unspecified cause.
The investigators concluded, “Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.”
Abha A. Gupta, MD, of the Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was supported by the Children’s Oncology Group, National Cancer Institute, and National Institutes of Health. For full disclosures of the study authors, visit thelancet.com.
