The tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) in conventional chondrosarcoma (CS): Secondary efficacy endpoints from the randomized, registrational, phase 2 ChonDRAgon study.

11504 Background: Clinical outcomes for unresectable/metastatic CS are poor. There are no approved therapies, and systemic treatment options are limited. Ozekibart (INBRX-109), a novel tetravalent DR5 agonist, was evaluated in ChonDRAgon (phase 2; NCT04950075), the largest randomized, placebo (PBO)-controlled trial in advanced conventional CS. ChonDRAgon met its primary endpoint: ozekibart significantly prolonged median progression free survival (PFS) vs PBO (5.52 vs 2.66 mo; stratified HR, 0.479; 95% CI, 0.335-0.684; P <.0001) (Jones et al. CTOS 2025). We present additional efficacy data. Methods: Eligible patients (pts) were ≥18 y with unresectable/metastatic conventional CS; those ≥65 y required a BMI <30 kg/m 2 . Pts with liver conditions associated with increased risk of hepatotoxicity were excluded. Pts were randomized 2:1 to ozekibart 3 mg/kg IV Q3W or PBO and stratified by grade (2 vs 3), IDH mutation status, and prior systemic therapy (No vs Yes). Pts could cross over from PBO to open-label ozekibart upon progression. The primary endpoint was PFS per RECIST 1.1 assessed by real time central independent radiology review (CIRR) in the intention-to-treat population; inter-arm comparison used a stratified log-rank test. The study was powered to detect a HR of 0.571 (90% power; 1-sided family-wise α, 0.025). Secondary efficacy endpoints included overall survival (OS), overall response rate (ORR) per CIRR, quality of life (QOL; EORTC QLQ-C30 pain symptoms and physical functioning scales), duration of response (DOR), and disease control rate (DCR; response, stable disease ≥84 days, non–complete response/non–progressive disease). Results: Overall, 137 pts were randomized to ozekibart and 69 to PBO; median duration of follow-up was 10.2 and 9.0 mo at the primary analysis (data cutoff: Sep 30, 2025). Median age for ozekibart and PBO was 54.0 y (range, 20-82 y) and 50.0 y (19-91 y), respectively; 70.1% and 60.9% of pts were male. Most pts had grade 2 CS (ozekibart, 70.1%; PBO, 69.6%) and ≈40% received prior systemic therapy (42.3%; 40.6%). 18.2% of pts in the ozekibart arm and 4.3% in the PBO arm remain on treatment. Ozekibart demonstrated a manageable safety profile (Jones et al. CTOS 2025) and led to a significantly greater DCR than PBO (54.0% vs 27.5%; P =.0005). ORR was 5.8% (8/137; all partial responses) with ozekibart and 0 with PBO ( P =.0433); median DOR was 11.1 mo. OS data were immature. Ozekibart significantly delayed QOL deterioration vs PBO, in both pain (median time to deterioration, 2.76 vs 1.41 mo; HR, 0.605; P =.0033) and physical functioning (2.56 vs 1.41 mo; HR, 0.561; P= .0007). Conclusions: In addition to a PFS benefit, ozekibart significantly improved DCR and delayed QOL deterioration vs PBO in advanced CS. Ozekibart has the potential to become the first standard of care for a population with high unmet need. Clinical trial information: NCT04950075 .