Ganitumab Plus Interval-Compressed Chemotherapy Fails to Improve EFS in Metastatic Ewing Sarcoma

R. Lor Randall, MD, FACS

The addition of the fully human monoclonal anti-IGF1R antibody ganitumab (AMG 479) to standard-of-care, interval-compressed chemotherapy did not significantly improve event-free survival (EFS) vs chemotherapy alone in patients with newly diagnosed metastatic Ewing sarcoma, according to data from a phase 3 trial (NCT02306161) published in the Journal of Clinical Oncology.

Findings showed that among patients treated with ganitumab plus chemotherapy (n = 150), the 3-year EFS rate was 39.1% (95% CI, 31.3%-46.7%,), compared with 37.4% (95% CI, 29.3%-45.5%) for those given chemotherapy alone (n = 148; HR, 1.00; 95% CI, 0.76-1.33; 1-sided P = .50). Moreover, the 3-year overall survival (OS) rate for the experimental arm was 56.7% (95% CI, 48.3%-64.2%) vs 59.5% (95% CI, 50.8%-67.3%) in the standard of care arm.

Patients were randomly assigned in a 1:1 fashion to interval-compressed chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide alternating once every 2 weeks with ifosfamide and etoposide (VDC/IE), or VDC/IE plus ganitumab. VDC/IE was given for 6 cycles, with or without ganitumab, as induction therapy. After local control, the chemotherapy regimen was administered for 8 cycles as consolidation, with or without ganitumab. Following metastatic site radiation, patients in the experimental arm received ganitumab maintenance.

Regarding safety, investigators observed more cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and elevated alanine transaminase in the ganitumab arm.

“This is a significant negative finding to know that [adding ganitumab] is not the right way to go [for patients with metastatic Ewing sarcoma],” said study co-author R. Lor Randall, MD, FACS. “We do have other biologic target agents for this cohort of patients in the future, so we are hoping to find something a little bit more therapeutic.”

In an interview with OncLive®, Randall expanded on the data from the phase 3 trial, the implications of these results, and how this study could help inform future trials exploring other targeted therapies for the treatment of patients with metastatic Ewing sarcoma. Randall is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.

OncLive^®: Can you provide an overview of the phase 3 trial of ganitumab with interval-compressed chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma?

Randall: This was a phase 3, randomized trial that [evaluated] standard chemotherapy with VDC/IE plus or minus the IGF-1R antibody [ganitumab]. We did compressed-interval therapy as usual, and [randomly assigned] the patients on the trial [in a 1:1 fashion].

What were the key efficacy results published in the Journal of Clinical Oncology?

Unfortunately, we found no added benefit with the [addition of] ganitumab. We did see a little bit of increased toxicity. The 3-year EFS [rate] for the standard [chemotherapy] arm was [37.4%] and the experimental arm [with] ganitumab [had a 3-year EFS of 39.1%]. The 3-year OS [rate] for the standard-of-care arm and the experimental arm was [59.5% vs 56.7%, respectively].

This was a bit of a disappointing result. There was some promise within some other tumor types [suggesting] that ganitumab might prove to be of some benefit [in metastatic Ewing sarcoma], but in this cohort, it did not. We did see a bit more toxicity [with ganitumab], therefore we do not recommend any further investigation with this drug.

Were there any previous data to support IGF-1R inhibition in Ewing sarcoma?

It was more that we had seen activity in other tumor types outside of [Ewing sarcoma]. However, I cannot speak to whether there were any preclinical data. Unfortunately, there are no potential biomarkers of response for this class of agents.

Do you see these data affecting interest in systemic therapy in this population?

We will still stay with the interval-compression backbone of VDC/IE. There are potentially some other agents in the pipeline that we will use with the same backbone for patients with relapsed disease.

Although the trial was negative, what did it tell clinicians about the treatment of this disease?

Metastatic Ewing sarcoma, unfortunately, is a devastating disease. Any metastatic cancer is a bad problem, but Ewing sarcoma is one of those diagnoses that has a very poor prognosis. The fact that we have reasonable frontline therapy with VDC/IE for nonmetastatic disease with good cure rates is helpful. Therefore, being able to build in other targeted agents with that backbone will be able to hopefully help this cohort of patients.

What is your main takeaway message to colleagues regarding this conversation?

There is a number of patients who will present with metastatic Ewing sarcoma when they first see their oncologist or their surgeon. It is important to realize that this is a very grim prognosis, but the Children’s Oncology Group is being very active in trying to find new agents. There are several agents in the pipeline that may yield some promise using this sort of structured study.

Are there any other areas of research in the treatment landscape of sarcomas that you’d like to highlight?

As a surgical oncologist, being able to build studies whereby we can potentially gain access to the metastatic clones, meaning the chest disease or the other bony sites, may yield some results.

There is an active trial right now through the Children’s Oncology Group looking at open vs thoracoscopic management for oligometastatic osteosarcoma. I bring this up as a sidebar because osteosarcoma is a different disease, but the beauty of that study is it will provide us with the actual metastatic tissue to unlock the mysteries of the metastatic clones.

We know from our data, as well as other data, that the disease that sets up remotely from the primary [tumor site] is biologically very distinct from the primary. Understanding the biology of those metastatic diseases has always been elusive to us because we have not had access to the [metastatic] tissue. There are potential studies afloat where we would be able to, in the best interest of the child and understanding the biology, gain access to that metastatic tissue.

Reference

1. DuBois SG, Krailo MD, Glade-Bender J, et al. Randomized phase III trial of ganitumab with interval-compressed chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. Published online January 20, 2023. doi:10.1200/JCO.22.01815