Ozekibart Plus Chemo Shows Promising Activity in R/R Ewing Sarcoma

Adding the investigational death receptor 5 (DR5) agonist ozekibart (INBRX-109) to irinotecan and temozolomide may produce substantial antitumor activity in patients with relapsed or refractory (R/R) Ewing sarcoma, a population with limited therapeutic options and historically poor outcomes, according to early-phase data presented at the ESMO Sarcoma and Rare Cancers Congress 2026.^1,2

In a phase 1 expansion cohort, the combination achieved an objective response rate (ORR) of 64.5% and a disease control rate (DCR) of 87.1% with a safety profile largely consistent with chemotherapy alone.²

Ewing sarcoma is a rare and aggressive small round blue cell tumor driven in most cases by EWS and ETS gene family rearrangements. Although intensive multimodal therapy has improved outcomes for localized disease, relapse occurs in approximately 30% to 40% of patients and is associated with a poor prognosis, particularly in those with metastatic or refractory disease.² Salvage regimens frequently include the combination of irinotecan and temozolomide, but response rates remain modest, and durable remissions are uncommon.³

Phase 1 Expansion Cohort Results

An ongoing open-label phase 1 trial (NCT03715933) is evaluating ozekibart, a tetravalent agonistic antibody targeting DR5, in combination with irinotecan and temozolomide in adolescents and adults with advanced or metastatic classical Ewing sarcoma. Ozekibart is designed to activate apoptotic signaling through DR5, a receptor commonly expressed on sarcoma cells, thereby inducing tumor-selective cell death.²

As of the data cutoff, 32 patients with unresectable or metastatic R/R Ewing sarcoma had received the triplet regimen. The median age was 31 years (range, 13-71), and patients had received a median of 2 prior lines of systemic therapy. Four patients had prior exposure to irinotecan and/or temozolomide.

Among 31 response-evaluable patients in the expansion cohort, ORR was 64.5% (20/31), with all responses classified as partial responses. The DCR reached 87.1.0% (27/31). Notably, 1 patient remained progression-free after more than 2 years of treatment.

The observed responses included patients whose disease had progressed despite prior irinotecan and temozolomide, highlighting the potential for ozekibart to enhance chemotherapy sensitivity.

Safety Profile

Treatment-related adverse events (AEs) were largely consistent with the established toxicity profile of irinotecan-temozolomide. The most frequently reported AEs of grade 3 or higher included diarrhea (35.9%), anemia (20.5%), vomiting (10.3%), and nausea (7.7%). Four patients discontinued ozekibart due to AEs.²

Importantly, no grade 3 or higher hepatotoxicity was observed, addressing a historical concern associated with earlier DR5-targeting therapies. Prior DR5 agonists demonstrated hepatotoxicity, which limited their clinical development.⁵ As of October 2025, 13 patients remained on treatment, and 14 had discontinued due to disease progression.¹

Clinical Context in Relapsed Ewing Sarcoma

Despite progress in frontline therapy, treatment of R/R Ewing sarcoma remains challenging. Standard salvage regimens include irinotecan-temozolomide, cyclophosphamide-topotecan, and high-dose ifosfamide, among others.³ Response rates for irinotecan-temozolomide typically range from approximately 15% to 30%, with relatively short progression-free survival (PFS) in most studies.³

Data from the randomized rEECur trial, which compared several salvage regimens in recurrent Ewing sarcoma, reported an ORR of approximately 20% with the irinotecan-temozolomide regimen, underscoring the need for improved therapeutic strategies.⁶

Ozekibart in Ewing Sarcoma and Beyond

Enrollment in the phase 1/2 trial is continuing; Inhibrx Biosciences stated its intention to meet with the FDA to discuss an accelerated approval pathway for this indication in the second quarter of 2026 if the trends shown in this analysis persist.⁷ Another expanded cohort of this trial has shown promising efficacy and tolerability in combination with standard chemotherapy in advanced colorectal cancer.

Ozekibart as monotherapy at 3 mg/kg every 3 weeks met its primary end point vs placebo in chondrosarcoma in the phase 2 ChonDRAgon trial (NCT04950075), showing a 52% improvement in PFS outcomes.⁸ The company stated its plan to file a biologics license application in the second quarter of 2026.

DR5 targeting combined with chemotherapy could represent a novel therapeutic approach for patients with R/R Ewing sarcoma, a setting where meaningful treatment advances have historically been limited.

REFERENCES

1. Chugh R, Wilky B, Alese O, 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. Ozekibart added to chemotherapy demonstrates robust activity in relapsed/refractory Ewing sarcoma. ESMO Daily Reporter. March 13, 2026. Accessed March 16, 2026. https://tinyurl.com/by3rmzsb

3. Grünewald TGP, Cidre-Aranaz F, Surdez D, et al. Ewing sarcoma. Nat Rev Dis Primers. 2018;4(1):5. doi:10.1038/s41572-018-0003-x

4. Wang BC, Xiao BY, Lin GH. Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies. BMC Cancer. 2022;22(1):349. doi:10.1186/s12885-022-09469-5

5. Forero A, Bendell JC, Kumar P, et al. First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Invest New Drugs. 2017;35(3):298-306. doi:10.1007/s10637-016-0420-1

6. McCabe M, Kirton L, Khan M, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). J Clin Oncol. 2022;40(suppl 17):LBA2. doi:10.1200/JCO.2022.40.17_suppl.LBA2

7. Inhibrx Biosciences provides progress updates on the INBRX-106 program and the expansion cohorts of the ozekibart (INBRX-109) program. News release. Inhibrx Biosciences. December 16, 2025. Accessed March 16, 2026. https://tinyurl.com/teksmb29

8. Inhibrx Biosciences reports positive topline results from its registrational trial of ozekibart (INBRX-109) in chondrosarcoma and provides updates on colorectal cancer and Ewing sarcoma expansion cohorts. News release. Inhibrx Biosciences. October 23, 2025. Accessed March 16, 2026. https://tinyurl.com/m8k6uurh