Systemic Treatment of Advanced Chordoma With Molecular Targeted Therapies: A Large Multicentre European Retrospective Case Series

BACKGROUND: This retrospective series reports outcomes and prognostic factors for advanced chordoma (AC) treatment with molecular targeted therapies (MTTs) in different treatment lines. METHODS: This is a retrospective series of 57 patients with AC treated between 2004 and 2023 at one of seven participating sarcoma centres. Demographics, previous treatment, treatment details and outcomes were recorded. RESULTS: 57 patients were treated with 7 different MTTs. Treatment was received in first (n = 57), second (n = 16), third (n = 5) or fourth (n = 1) line. The most frequently administered agent in first line was imatinib (84.2%) and in second line imatinib + sirolimus (35.7%). Overall median progression free survival (PFS) and overall survival (OS) in first-line treatment was 6.5 (95% CI 4.0-9.0) and 29.5 months (95% CI 24.0-40.4) and in second-line 10.0 (95% CI 4.0-22.0) and 37.2 months (95% CI 9.4-45.9). Partial response according to RECIST 1.1 was seen in 5/79 treatments (6.3%). Dose reductions and interruptions were reported in 19.0% and 27.8% of treatments. CONCLUSIONS: PFS and response rates with these MTTs were in line with previous phase II trials and retrospective series. Although the efficacy does not meet the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) criteria for single arm studies in orphan diseases, MTTs are frequently used off-label due to the high unmet need and lack of other systemic treatment options. The toxicity profile and limited efficacy rate should be taken into account when counselling patients. Further research is needed to explore other systemic treatment options including (combinations with) immunotherapy.