Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses.

Abstract

Angiosarcomas (AS) are rare vascular sarcomas. Secondary AS (sAS) arise from DNA-damaging factors such as radiotherapy and UV radiation (UV-AS) or due to chronic lymphedema. The prognosis for advanced AS is poor, with limited treatment options. Immune checkpoint inhibition is not approved for AS, but high intratumoral T-cell density and frequent mutations in sAS may support efficacy. This prospective, single-arm, multicenter phase II trial assessed the efficacy and safety of cemiplimab (350 mg, intravenously every 3 weeks) in patients with locally advanced or metastatic sAS using a Simon's two-stage design. The primary outcome was the best overall response rate within 24 weeks of treatment. Secondary outcomes included time to response, duration of response, progression-free survival, overall survival, and predictive biomarkers for treatment response. Eighteen patients (12 with AS from radiotherapy, 3 with UV-AS, and 3 with AS due to chronic lymphedema) were treated with cemiplimab. The best overall response rate was 27.8% (4 partial responses, 1 complete response), with a time to response of 2.6 months and a duration of response of 6.9 months. The median progression-free survival was 3.7 months, and the median overall survival was 13.1 months. Grade ≥3 immune-related adverse events occurred in 33.3% of patients. High tumor mutational burden was observed in three patients with UV-AS, two of whom showed a response. High intratumoral CD3+ (P = 0.019), CD4 (P = 0.046), CD8+ (P = 0.026), and FoxP3+ (P = 0.026) T-cell densities; low platelet-to-lymphocyte ratio (P = 0.026); and Colidextribacter abundance were associated with response. Cemiplimab shows promising effectivity in sAS and warrants further investigation. Promising predictive blood and tissue biomarkers were identified, indicating potential for improved patient selection.