Novel therapeutics and surrogate endpoints in chondrosarcoma: a retrospective analysis of patients enrolled in phase I/II trials

Background Chondrosarcoma is a rare bone tumor with limited treatment options. Early-phase trials enable exploration of novel agents but defining meaningful endpoints remains challenging. The objective of this study was to evaluate the outcomes of the emerging therapeutics in chondrosarcoma and explore surrogate endpoints. Patients and methods This study included a retrospective single-institution cohort of patients with advanced chondrosarcoma treated in a dedicated phase I program at a tertiary cancer center between January 2010 and May 2025. Investigational agents from phase I/II trials were grouped by mechanism of action. The main parameters used were clinical benefit rate (CBR; stable disease, partial response, or complete response per RECIST 1.1), progression-free survival (PFS), overall survival (OS), and stable disease with any tumor reduction (SD-ATR; >0% to <30% reduction per RECIST 1.1). Kaplan–Meier and Cox models were used. Results Eighty-two patients were evaluated; 51 enrolled in ≥1 trial, yielding 76 enrollments. Among 69 evaluable cases, CBR was 56% (55% stable disease and 1% partial response). Median PFS was 2.7 months [95% confidence interval (CI) 1.8-4.7] and OS 10.6 months (95% CI 8.0-20.1). SD-ATR was associated with longer PFS [hazard ratio (HR) 0.02, 95% CI 0.00-0.11, P < 0.001] and OS (HR 0.25, 95% CI 0.07-0.94, P = 0.041). Death receptor 5 (DR5) agonists improved PFS (HR 0.4, 95% CI 0.2-0.9, P = 0.017) and favored OS (HR 0.6, 95% CI 0.2-1.2). SD-ATR was also seen with isocitrate dehydrogenase 1, transforming growth factor-β, methyltransferase 3, protein arginine methyltransferase 5 inhibitors, receptor tyrosine kinase-like orphan receptor 2 antibody–drug conjugates, and toll-like receptor 7 agonists. Conclusions These findings highlight DR5 agonists and support SD-ATR as a candidate surrogate endpoint for chondrosarcoma trials, underscoring the value of retrospective data in rare cancers.