Addition of Anti–IGF-1R Antibody Ganitumab to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Metastatic Ewing Sarcoma

Get Permission

As reported in the Journal of Clinical Oncology by DuBois et al, the Children’s Oncology Group phase III AEWS1221 trial showed no event-free survival benefit with the addition of the anti–insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody ganitumab to interval-compressed chemotherapy in newly diagnosed patients with metastatic Ewing sarcoma.

The investigators noted that monoclonal antibodies directed against IGF-1R have shown activity in patients with relapsed Ewing sarcoma.

Study Details

In the multicenter trial, 298 patients were randomly assigned between December 2014 and March 2019 to receive ganitumab plus interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide (VDC/IE; n = 150) or VDC/IE alone (n = 148). All patients were to receive 14 cycles of chemotherapy; local control of the primary tumor was planned after the first six cycles, using investigator’s choice of surgery, radiation, or both. After completion of 14 cycles, patients were to receive radiotherapy to metastatic sites. Ganitumab at 18 mg/kg was given on day 1 of cycles 1 to 6 and 10 to 14, and at the same dose every 3 weeks for eight doses after completion of metastatic site radiation. The primary endpoint was event-free survival.

Early Closure

At the second data and safety monitoring committee (DSMC) interim monitoring point (at 50.5% observed information), the event-free survival hazard ratio (HR) for the ganitumab group vs the control group was 0.95 (95% confidence interval [CI] = 0.65–1.39). Although the protocol-defined inefficacy boundary was not crossed, the DSMC recommended early closure and early discontinuation of ganitumab in March 2019 based on observed outcome data and a potential increased risk of pneumonitis in the ganitumab group.

A total of 45 patients discontinued ganitumab early and crossed over to the control group. Patients were followed for 3 years from time of early closure for the current final primary analysis (data cutoff at end of March 2022).


  • The addition of ganitumab to interval-compressed chemotherapy did not improve event-free survival.
  • Event-free survival at 3 years was 39.1% in the ganitumab plus chemotherapy group vs 37.4% in the chemotherapy group.


Estimated event-free survival at 3 years was 39.1% (95% CI = 31.3%–46.7%) in the ganitumab group vs 37.4% (95% CI = 29.3%–45.5%) in the control group (HR = 1.00, 95% CI = 0.76–1.33, P = .50). Estimated overall survival at 3 years was 56.7% (95% CI = 48.3%–64.2%) in the ganitumab group vs 59.5% (95% CI = 50.8%–67.3%) in the control group (HR = 1.03, 95% CI = 0.75–1.42, P = .99). A post hoc analysis of the potential impact of crossover from the ganitumab group to the control group showed no significant effect on either event-free survival or overall survival.

Adverse Events

Rates of grade ≥ 3 nonhematologic toxicity were similar in the ganitumab group vs the control group, except for higher rates of febrile neutropenia (grade 3 in 48.0% vs 39.3%, grade 4 in 5.3% vs 3.4%) and increased alanine aminotransferase (grade 3 in 13.3% vs 3.4%, grade 4 in 0.7% vs 0.7%) in the ganitumab group. Among grade 3 or 4 adverse events of special interest, rates in both groups were similar and < 10% for allergic/infusion reactions, hyperbilirubinemia, hyperglycemia, and cardiac dysfunction. However, grade ≥ 3 pneumonitis occurred in 2.7% vs 0.7% of patients and resulted in death in one patient in the ganitumab group. All four patients with grade ≥ 3 pneumonitis in the ganitumab group had received radiotherapy to the thorax.

The investigators concluded, “Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of event-free survival events in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.”

Steven G. DuBois, MD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, St. Baldrick’s Foundation, QuadW Foundation, and Alex’s Lemonade Stand Foundation. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.