Exploring the Potential of Ozekibart in Relapsed Ewing Sarcoma

Ewing sarcoma is a rare and aggressive malignancy, usually characterized by a key fusion protein related to a gene translocation. Despite our understanding of this oncogene, it has been difficult to target, but the DR5 agonist ozekibart (INBRX-109) has shown promise in a phase 1 study (NCT03715933) with an impressive 64.5% response rate in relapsed/refractory patients when added to chemotherapy.¹

The favorable efficacy and tolerability have inspired hope that this agent could make a difference in patients who have a great need for targeted therapy. Ozekibart has already shown success in reducing disease progression of chondrosarcoma, another rare disease state, when compared with placebo in the ChonDRAgon trial (NCT04950075).²

As Ewing sarcoma often affects children and adolescents, expanding the patient population is a major goal of this research, Rashmi Chugh, MD, a medical oncologist at the University of Michigan, said in an interview with Targeted Oncology. She also noted that collaboration between many treating physicians and cancer centers is necessary to develop trials in rare disease states like this. “To try to capture enough patients to understand the benefit of treatment, we need to collaborate across the globe, across pediatric and adult medical oncology, and that’s an important part of this study.”

Chugh described the biological rationale and emerging clinical data for combining ozekibart with standard chemotherapy for Ewing sarcoma that were presented at the 2026 European Society for Medical Oncology Sarcoma and Rare Cancers Congress.¹ These findings indicate that this combination may significantly outperform historical outcomes for patients with relapsed or refractory disease. Looking forward, she discussed next steps to confirm the promising early findings while emphasizing the importance of cross-disciplinary collaboration to address the significant unmet needs of patients with Ewing sarcoma.

Targeted Oncology: What is the background for using targeted therapies for Ewing sarcoma?

Rashmi Chugh, MD: Ewing sarcoma is, by its very nature, a simplistic tumor. We know that the majority of Ewing sarcomas have a very characteristic driver fusion, where 2 genes come together abnormally, and the majority of the time, that’s EWS and FLI1. We recognize that this is the driver of this disease. Naturally, when we know the driver, there’s a desire to target that driver and do everything we can to stop that from perpetuating the cycle of this aggressive cancer. Unfortunately, because this oncogene encodes for a transcription factor, it’s a very difficult target, but that doesn’t stop us from wanting to target it and really trying to get to the root of going after this disease.

What were the goals and design of the trial of ozekibart and chemotherapy?

Ozekibart is a DR5 agonist, and this has a lot of rationale for use in a lot of different malignancies, with its behavior as a pro-apoptotic agent. The initial goals of the study were to first understand the safety and dose as a phase 1 study, and then over time, there were different combination cohorts that were added in that would help to see if we can get ozekibart to…work in and synergize with other agents in specific disease types where there’s rationale. One of the diseases that had particular rationale for this strategy [was] Ewing sarcoma. There was a dose-finding portion of this study where we looked at Ewing sarcoma in combination with one of our standard treatments, temozolomide and irinotecan, and adding ozekibart, initially looking at safety and dose finding, and then later expanding to a broader cohort of patients with Ewing [sarcoma].

What stood out about treating patients with Ewing sarcoma with this combination?

Even from the very start of the study, when it had been just dose finding and safety, we were seeing some remarkable responses out of proportion to what we might expect with just the combination of temozolomide and irinotecan which, based on historical controls, we often see tumor shrinkage and response rates on the order of 20%.³ But we were just anecdotally seeing more of that even in our dose-finding portion.¹ That’s what led to the rationale to expand it to more patients to see if we can get a better gauge, are we really doing better than our standard treatment by using it as a combination?

What were the key efficacy findings from the trial so far?

The study is still ongoing, so we have a lot more data to secure, but we recently presented on the ongoing results, and so far, of the 31 patients we’ve analyzed, the response rates were about 64%, so [it is] impressive compared to historical controls.¹ Of course, it’s difficult to compare [with] historical controls, but I think seeing that glimmer of improved response rates comparatively has given a lot of promise to us in the community, as well as to our patients. The other remarkable thing is, in terms of [adverse events (AEs)], we haven’t seen a dramatic difference in [AEs] [from what] we see historically from temozolomide and irinotecan in combination. Again, it’s, it’s difficult to compare [with] historical controls rather than a randomized study, but just based on our impression, it is comparable in terms of toxicity.

Were these findings on the combinations’ tolerability expected?

Not necessarily. We know that sometimes when we combine agents, we there’s a lot of unexpected things that you might run into. With this combination, temozomide and irinotecan, we see a fair amount of nausea, vomiting, diarrhea, tough [AEs] that we’ve learned to manage well. We see maybe a slight increase in that. But again, it’s difficult to say, but it is not meaningfully so in my personal experience,

What do these findings suggest based on the treated patients who had already received the same chemotherapies?

When the study started, any number of prior therapies were allowed, and so there were many patients that had received prior irinotecan-based therapy, or maybe even the same combination chemotherapy, and many of those still had some benefit from this combination. In this later phase of the study, we’ve narrowed it down to have a more homogeneous population where there is 1 to 2 prior systemic treatments. That is the limit. But again, these are patients [who] have relapsed disease after going through our standard chemotherapy, and finding levels of tumor shrinkage rates that are better than we have historically is certainly promising and hopeful for us.

What are the next steps for research into this therapy?

As with any really promising therapy, first, we want to better understand why it works and who it works best in, so trying to understand that [and] partnering with some of our laboratory scientists in the field is going to be helpful for us to understand it. Also, doing a direct comparison at some point would be helpful in trying to understand the additive benefit. This is obviously still a single-arm study that we’re just doing our best to compare with historical controls, and being able to compare the efficacy and toxicity.

The other important next step is expanding it to all populations. Ewing sarcoma is a unique disease because it really does span the ages. We have the pediatric population, the adolescent/young adult population, then even an older population. The study started within the adults in phase 1. A lot of our patients initially on were adults, and slowly, we’ve been expanding the age [range] so we can try to treat as many patients as we can, including the adolescent, young adult and soon, in the pediatric population.

Generally, what are the greatest unmet needs in Ewing sarcoma?

Over the decades, we’ve made incredible progress in curing patients with localized disease, but patients [who] have disease that has spread or relapses despite our treatment have, unfortunately, poor outcomes. Focusing on this relapsed and refractory population is important. Also, [so is] being better able to understand who’s at highest risk for relapse. The treatment course is long for initial diagnosis, and there are a lot of long-term toxicities that we need to better be able to predict who we need to treat for as long [with] a therapy and [with the] intensive therapy duration that we are doing right now.

What else do you have to say about the work you’ve done on this study?

This study represents an amazing collaboration and partnership, which we often see in the Ewing sarcoma world with pharmaceutical companies really eager to make a difference in an orphan disease, along with a group of dedicated pediatric and medical oncologists [who] know that we have to come together as a community to really get studies that are large enough to better understand the difference.

The exciting part of this study is, it started as a hypothesis, and once we saw some efficacy, the sponsor is committed to expanding the study so we can gather more patients, even though this is a difficult diagnosis; it’s a rare disease. To try to capture enough patients to understand the benefit of treatment, we need to collaborate across the globe, across pediatric and adult medical oncology, and that’s an important part of this study.

REFERENCES

1. Chugh R, Wilky B, Alese O, et al. et al. Phase I study of the tetravalent death receptor 5 (DR5) agonist ozekibart combined with irinotecan and temozolomide in adolescents and adults with Ewing sarcoma. Presented at: ESMO Sarcoma and Rare Cancers Congress 2026; March 12-14, 2026; Lugano, Switzerland. Abstract 84MO.

2. McCabe MG, et al. Randomized phase III rEECur trial comparing chemotherapy regimens for recurrent Ewing sarcoma. J Clin Oncol. 2022;40(15_suppl):11500. doi:10.1200/JCO.2022.40.15_suppl.11500