Background: Dedifferentiated chondrosarcoma (DDCS) is a rare aggressive CS subtype with a dismal prognosis and no standard of care systemic therapy. For those with advanced, metastatic disease, retrospective chemotherapy studies demonstrate short-term median progression-free survival (PFS) of around 3 to 5.5 months. Benefit from checkpoint and tyrosine kinase inhibitors has been reported, however clinical trial data is scarce, and endpoints are not well defined, thus benchmarking outcomes is challenging. The IMMUNOSARC I master-trial exploring sunitinib plus nivolumab in multiple sarcoma subtypes, detected potential activity in DDCS leading to a specific cohort within the phase II trial IMMUNOSARC II (NCT03277924). Methods: Patients (pts) with ECOG 0-1, centrally confirmed and progressive, measurable DDCS were eligible and treated with sunitinib 37.5 mg/d for 14 days (induction phase), followed by 25 mg/d, in combination with nivolumab 240 mg every 2 weeks until progressive disease (PD) or intolerance. Imaging assessments were performed every 8 weeks. Main endpoint was 6-m PFSR with one-arm survival design (type I error α 0.05, power 0.90, H0 40%, H1 70%) and a Brookmeyer-Crowley like test was assumed with at least 14 of 23 pts required without progression at 6 months. Results: Between December 2019 and October 2023, 24 pts with a median age of 60 years (38-76) were enrolled in 7 centres. Sixteen pts (66%), were male. Pts had received a median of 1 (0-2) prior lines of therapy. In total, 23 pts were evaluable with a median follow-up of 20.1 months (95%CI: 11.6-28.6). Median PFS, according to local site assessment, was 5.6 months (95%CI: 4.5-6.7); the 6m-PFSR was 10 of 23 pts (46%); (95%CI: 23-66) and median overall survival 10.3 months (95%CI: 6.7-13.9). In 19 pts with RECIST measurable response, 5 pts (26.3%) achieved a partial response; 10 (52.6%) stable disease and 4 (21.1%) PD. End-of-treatment reasons were PD in 21 pts (87%), toxicity 1 pt (4.2%) with two pts (8.4%) ongoing. For safety population, the most relevant study drug-related G3-4 toxicities were neutropenia (20.9%), anemia (16.7%), and increased ALT (12.5%). Conclusions: Sunitinib and nivolumab demonstrated encouraging activity in advanced DDCS that did not meet the primary endpoint, but compares favourably with previous analyses of cytotoxic and targeted therapy. The combination is worthy of further exploration in conjunction with reaching a consensus on clinically meaningful endpoints in this challenging population. Translational studies to identify potential predictive biomarkers are ongoing. Clinical trial information: NCT03277924.