The registrational ChonDRAgon study (NCT04950075; n= 206) investigating ozekibart (INBRX-109; Inhibrx Biosciences) as a single agent versus placebo in patients with advanced or metastatic, unresectable chondrosarcoma shows positive topline results.
Chondrosarcomas are a heterogeneous group of primary bone cancers. They are characterized by hyaline cartilaginous neoplastic tissue, and are the second most common primary bone malignancy.[1]
Most chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential [1][2]
Grade I lesions rarely metastasize, rarely recur, and have, on average, a 10-year survival rate of >80%. By contrast, grade III lesions are associated with a poor prognosis, a lung metastasis rate of >50%, and a 10-year survival rate of <30%.[2]
The standard treatment of high-grade conventional chondrosarcoma is complete surgical resection with wide margin. However, low-grade lesions may be amenable to curettage with or without adjuvant local treatment [2]
Because of high resistance to currently available conventional (anticancer) therapies, the disease progression in patients with metastatic or unresectable chondrosarcoma is difficult to control, hence, there is an urgent medical need for new strategies for optimal treatment.[2][3]
A different approach
Ozekibart is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to exploit the tumor-biased cell death induced by DR5 activation. Death receptor 5 (DR5) is a receptor for the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL).
DR5 activation selectively induces programmed cell death in damaged and/or neoplastic cells with minimal impact on normal tissues.
In preclinical studies, ozekibart demonstrated antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase 1 study, ozekibart was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. Ozekibart also demonstrated a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. This outcome resulted in the randomized, placebo-controlled, phase 2 ChonDRAgon study which was designed to further evaluate ozekibart in conventional chondrosarcoma.[3]
Study results
The ChonDRAgon study met its primary endpoint of a statistically significant and clinically meaningful median progression-free survival (PFS) for patients with advanced or metastatic chondrosarcoma treated with ozekibart compared to placebo.
Ozekibart achieved a 52% reduction in the risk of disease progression or death compared to placebo (stratified Hazard Ratio [HR] 0.479; 95% CI: 0.33, 0.68); P<0.0001), more than doubling median PFS to 5.52 months versus 2.66 months for placebo. Importantly, ozekibart is the first investigational therapy to demonstrate a significant PFS benefit in a randomized trial for chondrosarcoma, a disease with no approved systemic options.
The benefit of ozekibart was consistent across all pre-specified subgroups, including patients with IDH-wild-type and IDH-mutant tumors. Other key secondary endpoints, including disease control rate (54% vs 27.5%), and delay to deterioration in pain and physical function, further supported the clinical benefit observed with ozekibart.
Ozekibart was generally well tolerated, with a manageable safety profile. The most common treatment-related adverse events were fatigue, constipation, and nausea. Hepatotoxicity, a known risk for this mechanism of action, occurs during the first treatment cycle and is in patients with underlying hepatic impairment.
One hepatotoxicity-related fatal event occurred early in the study, prior to the implementation of mitigation measures. Over the course of the ChonDRAgon study, this risk was effectively mitigated by excluding patients with severe liver impairment and by implementing close monitoring during early treatment cycles, allowing for prompt management of liver enzyme elevations. This approach resulted in a low overall incidence of treatment-related hepatic adverse events, 11.8% compared to 4.5% in the placebo arm, the majority of which were Grade 1 or 2 in severity.
“I am very encouraged and enthusiastic about ozekibart and the impact I have seen on my sarcoma patients,” said Professor Robin Jones, MD, medical oncologist specializing in the treatment of bone and soft tissue sarcomas and Head of the Sarcoma Unit at The Royal Marsden in London, United Kingdom.
“With no approved treatments available, we have observed that ozekibart helps to keep the cancer from growing, improves how patients feel, and restores a sense of hope for my patients,” Jones added.
Beyond chondrosarcoma
in addition to the chondrosarcoma data, Inhibrx also reported updates on the ongoing expansion cohorts investigating ozekibart in combination with FOLFIRI in late-line colorectal cancer and in combination with irinotecan and temozolomide in refractory Ewing sarcoma.
Colorectal Cancer
Based on initial results from the Phase 1 trial of ozekibart in combination with FOLFIRI for the treatment of advanced or metastatic, unresectable colorectal cancer (CRC), Inhibrx initiated an expansion cohort enrolling 44 patients, as a fourth line of therapy for approximately 70% of patients and as a third line of therapy for approximately 30% of patients. 80% of patients had been previously treated with regimens containing irinotecan.
Efficacy, based on RECIST v1.1 criteria, was assessed in 26 evaluable patients to date who had at least one post-baseline scan. The results show a 23% overall response rate (ORR) and an overall disease control rate of 92%. These outcomes are highly encouraging in a heavily pretreated CRC population, where responses are rare (5-6%) and outcomes are generally poor with the current standard of care.
The study results demonstrated that ozekibart, in combination with FOLFIRI, was well tolerated. The most common treatment-emergent adverse events included anemia, diarrhea, nausea, and fatigue, with the majority being low-grade and consistent with the known safety profile of FOLFIRI.
Ewing Sarcoma
Based on initial results from the Phase 1 trial of ozekibart in combination with irinotecan and temozolomide (IRI/TMZ) for advanced or metastatic, unresectable, relapsed, or refractory Ewing sarcoma, Inhibrx initiated an expansion cohort which is expected to enroll up to 50 patients.
Of the 33 patients recruited to date, more than half were third or fourth line patients. Among the 25 evaluable patients to date, Inhibrx observed a 64% overall response rate (ORR), and a disease control rate of 92%, with the majority of patients experiencing measurable tumor reduction. These outcomes are highly encouraging in this difficult-to-treat patient population as compared to the response rate typically observed with standard IRI/TMZ (15-30%).
Overall, ozekibart in combination with IRI/TMZ was well tolerated. The most common adverse events were diarrhea, nausea, anemia, and fatigue, all consistent with the known safety profile of IRI/TMZ.
“We are excited by these results which suggest the potential of ozekibart to expand not only in sarcomas but also in high unmet need solid tumor indications,” said Mark Lappe, Chief Executive Officer and Co-Founder of Inhibrx.
“We look forward to working with the FDA to deliver ozekibart to patients as swiftly as possible.”
Regulatory status
In January 2021, the FDA granted Fast Track designation to ozekibart for the treatment of patients with metastatic or unresectable conventional chondrosarcoma, and, in November 2021, the US Foof and Drug Administration FDA granted orphan drug designation to ozekibart for chondrosarcoma.
Detailed results from this trial will be presented at the Connective Tissue Oncology Society (CTOS) Annual Meeting on November 14, 2025.
Clinical trials
Study of INBRX-109 in Conventional Chondrosarcoma (ChonDRAgon) – ClinicalTrials.gov ID NCT04950075
Phase 1 Study of INBRX-109 in Subjects with Locally Advanced or Metastatic Solid Tumors Including Sarcomas – ClinicalTrials.gov ID NCT03715933
Reference
[1] Chow WA. Chondrosarcoma: biology, genetics, and epigenetics. F1000Res. 2018 Nov 20;7:F1000 Faculty Rev-1826. doi: 10.12688/f1000research.15953.1. PMID: 30519452; PMCID: PMC6248264.
[2] Weinschenk RC, Wang WL, Lewis VO. Chondrosarcoma. J Am Acad Orthop Surg. 2021 Jul 1;29(13):553-562. doi: 10.5435/JAAOS-D-20-01188. PMID: 33595238.
[3] Subbiah V, Chawla SP, Conley AP, Wilky BA, Tolcher A, Lakhani NJ, Berz D, Andrianov V, Crago W, Holcomb M, Hussain A, Veldstra C, Kalabus J, O’Neill B, Senne L, Rowell E, Heidt AB, Willis KM, Eckelman BP. Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma. Clin Cancer Res. 2023 Aug 15;29(16):2988-3003. doi: 10.1158/1078-0432.CCR-23-0974. PMID: 37265425; PMCID: PMC10425732.
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DOI
 investigating ozekibart (INBRX-109; Inhibrx Biosciences) as a single agent versus placebo in patients with advanced or metastatic, unresectable chondrosarcoma shows positive topline results.Chondrosarcomas are a heterogeneous group of primary bone cancers. They are characterized by hyaline cartilaginous neoplastic tissue, and are the second most common primary bone malignancy.){kind=link}