Key Ideas

Conventional chondrosarcoma has historically had no approved systemic therapy given its resistance to chemotherapy and radiation. A DR5 agonist antibody, ozekibart, is now under FDA review after becoming the first agent to show a statistically significant progression-free survival benefit in a randomized trial. IDH1/2 inhibitors also show meaningful, if more modest, activity in this molecularly defined subset of patients.

Rewriting the Playbook for a Historically Untreatable Sarcoma

Sarcoma comprises more than 100 recognized sarcoma subtypes are being refined further as next-generation sequencing becomes routine, but this discussion focuses on chondrosarcoma, a cartilage-producing tumor divided into conventional, dedifferentiated, mesenchymal, and clear cell subtypes. Conventional chondrosarcoma, the most common subtype at 85% to 90% of cases, is notoriously resistant to both chemotherapy and radiation, leaving advanced disease with historically dismal outcomes and no approved systemic therapy. That is beginning to change.

Localized Disease: Surgery Remains the Cornerstone

For conventional chondrosarcoma, complete surgical resection with oncologically negative margins is still the standard for localized disease. Radiation is not typically used for resectable disease but may have a role in technically difficult locations such as the skull base and spine. There is no established role for adjuvant cytotoxic chemotherapy given the tumor's inherent chemoresistance. Dedifferentiated and mesenchymal subtypes are the exceptions, where perioperative systemic therapy is considered on a case-by-case basis, generally borrowing osteosarcoma-based regimens for dedifferentiated disease and Ewing sarcoma-type regimens (such as VDC-IE) for the more chemosensitive mesenchymal subtype, which carries a characteristic HEY1-NCOA2 fusion and tends to affect younger patients.

Early referral to a sarcoma center is worthwhile for tumors in difficult-to-access locations such as the pelvis or axial skeleton, suspected dedifferentiation on imaging, recurrent disease, or cases likely to require complex reconstruction. Biopsy trajectory planning in close coordination with the treating surgeon and interventional radiologist is essential, since the entire biopsy tract must be excised at the time of definitive surgery.

Ozekibart: The First Randomized PFS Benefit in Chondrosarcoma

Advanced conventional chondrosarcoma has historically produced a median progression-free survival of only two to four months with any available chemotherapy or targeted therapy. The phase 2 registrational ChonDRAgon trial tested ozekibart (INBRX-109), a tetravalent death receptor 5 (DR5) agonist antibody, against placebo in 206 patients with unresectable or metastatic conventional chondrosarcoma, randomized 2:1 with crossover permitted after centrally confirmed progression. DR5 is a component of the TRAIL apoptotic signaling pathway, and chondrosarcoma is known to have relatively high DR5 expression, providing rationale for this approach.

The trial met its primary endpoint: median progression-free survival improved from 2.66 months with placebo to 5.52 months with ozekibart, a 52% reduction in the risk of progression or death (hazard ratio 0.479). The benefit was consistent across IDH-mutant and IDH-wild-type subgroups. Disease control rate improved from 27.5% to 54%, and updated results presented at ASCO also showed improvement in pain and physical function, though the objective response rate remained modest at 5.8% versus 0% with placebo, and overall survival data are still pending.

Hepatotoxicity is the most important safety signal to know: grade 3 or higher adverse events occurred in 39% of patients on ozekibart versus 25% on placebo, with hepatic adverse events in 11.8% versus 4.5%, concentrated early in treatment among patients with underlying hepatic impairment. Risk mitigation now includes excluding patients with severe hepatic impairment, more frequent liver enzyme monitoring, dose reduction for patients over 65, and avoiding concurrent acetaminophen. The FDA has accepted a biologics license application for ozekibart in this indication, with a target review date in 2027; if approved, it would be the first systemic therapy ever cleared specifically for conventional chondrosarcoma.

IDH1/2 Inhibitors: A Smaller but Real Signal

IDH1 and IDH2 mutations occur in roughly half of conventional chondrosarcomas, most often in central, conventional tumors. In a phase 1 study, ivosidenib, an IDH1 inhibitor familiar to oncologists from leukemia treatment, produced an objective response rate of 23% (including one complete response) among 13 patients with conventional chondrosarcoma, with a median progression-free survival of 7.4 months and a notably durable median duration of response of 53.5 months in responders. This activity supported the ongoing phase 3 CHONQUER trial, a randomized, placebo-controlled study of ivosidenib in IDH1-mutant, locally advanced or metastatic conventional chondrosarcoma with 0 to 1 prior systemic regimens.

Olutasidenib, another IDH1 inhibitor, was evaluated in a phase 1b/2 trial of patients with IDH1-mutant chondrosarcoma; among response-evaluable patients, 52% achieved stable disease with a median progression-free survival of 2.0 months, a more modest signal than ivosidenib's. Notably, no benefit was seen in dedifferentiated chondrosarcoma in this study, underscoring that this remains a significant unmet need distinct from conventional disease.

Practical Takeaways

Molecular profiling, including IDH1/2 testing, should be obtained for all patients with advanced conventional chondrosarcoma, since IDH-mutant patients may be eligible for targeted therapy trials such as CHONQUER. For dedifferentiated chondrosarcoma, an osteosarcoma-type regimen remains the standard approach, whether used in the neoadjuvant or adjuvant setting, generally for disease-free survival benefit rather than proven overall survival benefit. For mesenchymal chondrosarcoma, early identification, particularly in younger patients, and use of a Ewing sarcoma-type regimen is appropriate. Anti-angiogenic agents such as pazopanib and cabozantinib have shown anecdotal activity and disease stabilization in the broader chondrosarcoma space but not significant objective responses, and immunotherapy approaches remain immature. Given the rarity and biologic complexity of this disease, clinical trial enrollment should be considered whenever appropriate, and histology should be reviewed at a sarcoma center given how consequential subtype misclassification can be for treatment selection.

For Patients

Chondrosarcoma is a rare cancer that forms in cartilage-producing cells, most often around the pelvis, hip, or shoulder. Because these tumors generally do not respond well to standard chemotherapy or radiation, surgery has long been the only truly effective treatment, and once the disease spreads or cannot be removed surgically, options have historically been extremely limited. That is starting to change. A new antibody-based drug called ozekibart recently showed, for the first time in a randomized study, that it can meaningfully slow tumor growth in advanced chondrosarcoma, more than doubling the time before the cancer progressed compared to placebo. It is currently under FDA review and not yet approved, though it may become available through clinical trials. Separately, about half of chondrosarcomas carry a genetic change called an IDH mutation, and drugs that target this mutation, including one already used in certain leukemias, have shown encouraging, though more modest, activity, with a larger study now underway. If your chondrosarcoma is advanced or has spread, it is worth asking your care team whether genetic testing of the tumor and a referral to a sarcoma-focused center or clinical trial might be appropriate.

Key Takeaways

  • Conventional chondrosarcoma is chemotherapy- and radiation-resistant; surgery remains the standard for localized disease, with no established adjuvant chemotherapy role.

  • Ozekibart (INBRX-109), a DR5 agonist antibody, is the first agent to show a statistically significant progression-free survival benefit in a randomized chondrosarcoma trial (ChonDRAgon: median PFS 5.52 vs 2.66 months; hazard ratio 0.479), currently under FDA review with hepatotoxicity as the key safety consideration.

  • IDH1/2 mutations occur in roughly half of conventional chondrosarcomas; ivosidenib showed a 23% response rate and durable responses in a phase 1 study, now being tested in the phase 3 CHONQUER trial.

  • Dedifferentiated and mesenchymal chondrosarcoma are managed differently from conventional disease, borrowing osteosarcoma- and Ewing sarcoma-type regimens respectively.

  • Molecular testing and sarcoma-center referral are essential given the rarity, subtype complexity, and evolving treatment landscape of this disease.

References

  1. Wang V, Doherty M, Sebio A, et al. The tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) in conventional chondrosarcoma: secondary efficacy endpoints from the randomized, registrational, phase 2 ChonDRAgon study. Presented at ASCO 2026.

  2. Inhibrx Biosciences. Inhibrx Biosciences reports positive topline results from its registrational trial of ozekibart in chondrosarcoma. Press release, October 23, 2025; FDA BLA acceptance June 15, 2026.

  3. Tap WD, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: long-term safety and clinical activity in patients with conventional chondrosarcoma. Clin Cancer Res. 2025.

  4. Wagner AJ, et al. Phase 3 study of ivosidenib vs placebo in locally advanced or metastatic IDH1-mutant conventional chondrosarcoma (CHONQUER). J Clin Oncol. 2025.

  5. Olutasidenib in recurrent/relapsed locally advanced or metastatic IDH1-mutated chondrosarcoma: phase 1b/2 trial. Nature Communications. 2026.