Emerging therapeutic strategies and clinical development of investigational agents for conventional chondrosarcoma.

INTRODUCTION: Conventional chondrosarcoma (cCS) is a malignant bone tumor withintrinsic resistance to cytotoxic therapy. Advances in genomic profiling have revealed recurrent alterations that are redefining the therapeutic landscape for these tumors. AREAS COVERED: Literature searches of PubMed and ClinicalTrials.gov for the terms conventional chondrosarcoma, systemic therapy, targeted therapy, immunotherapy, chemotherapy, molecular targets, and clinical trial through June 2026 were performed. Clinical and translational developments regarding treatment of cCS were summarized, emphasizing the following emerging targeted and immunotherapeutic agents: isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors, DR5 agonists, methylthioadenosine phosphorylase (MTAP)-deficient PRMT5 inhibitors, TP53 reactivators, histone deacetylase and BCL-2 modulators, immunotherapy approaches, multi-targeted tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates. EXPERT OPINION: Multi-targeted TKIs remain the most commonly used systemic therapies for advanced cCS; however, recent advances in DR5 agonism and IDH1 inhibition provide proof of concept that biologically informed therapeutic strategies can achieve meaningful clinical benefit. Continued progress will require comprehensive molecular profiling, rational combination strategies, and innovative clinical trial designs to accelerate drug development in this rare malignancy.