Efficacy and safety of DR4/DR5 agonist aponermin monotherapy in advanced chondrosarcoma: Preliminary report from a prospective, multicenter study.

11532 Background: Reported median progression-free survival (mPFS) of Chondrosarcoma is less than 4 months for patients receiving first-line systemic therapy. Aponermin, a recombinant circularly permuted human Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), induces tumor cell apoptosis by activating the extrinsic apoptotic pathway. This study aimed to evaluate the efficacy of Aponermin in patients with advanced chondrosarcoma. Methods: This prospective, multicenter, single-arm study (Registration No: ChiCTR2500104488) was approved by an independent ethics committee. The planned enrollment was 32 patients aged 18-75 years with histologically confirmed advanced chondrosarcoma, documented evidence of disease progression within 6 months prior to enrollment, ECOG performance status ≤2, and measurable disease per RECIST 1.1. Patients received intravenous Aponermin 10 mg/kg (days 1-5, every 14 days as one cycle) until disease progression, unacceptable toxicity, or investigator's decision to discontinue. The primary endpoint was objective response rate (ORR). Secondary endpoints included 4-month PFS rate, disease control rate (DCR), overall survival (OS), and safety. Results: As of January 23, 2026, 21 patients were enrolled and treated. Median age was 51 years (range: 26-70), with a median of 2 prior surgeries (range: 1-6). Eight patients had received prior drug therapy. Histopathological subtypes included: conventional grade 1, 19% (4/21); conventional grade 2, 47.6% (10/21); conventional grade 3, 4.8% (1/21); mesenchymal, 9.5% (2/21); and one case each (4.8%) of myxoid, dedifferentiated, clear cell, and unknown subtype. Twenty patients were evaluable for efficacy. Median treatment duration was 3.6 months (range: 0.5-14.0), with 4 patients still on treatment. Although no objective responses were observed，80.0% (16/20) of DCR was achieved. Median PFS was 4.2 months (95% CI: 2.9-5.5), and the 4-month PFS rate was 57.9%. Median OS was not reached. Notably, Among patients achieving DCR, 50% maintained clinical benefit for over 4 months, including one patient with conventional grade 3 chondrosarcoma with SD lasting 7.4 months, two patients with conventional grade 2 with SD exceeding 10.0 months, and one patient with clear cell subtype with SD lasting 14 months. Aponermin demonstrated a favorable safety profile. Treatment-related adverse events occurred in approximately 9.5% (2/21) of patients, including one case (4.8%) of grade 1 allergic reaction and one case (4.8%) of hand-foot syndrome, both alleviated with symptomatic treatment. Conclusions: Aponermin monotherapy demonstrated promising disease control and a favorable safety and tolerability profile in advanced chondrosarcoma. Given the limited sample size and ongoing enrollment, final efficacy and safety assessments await study completion. Clinical trial information: ChiCTR2500104488.