Predicting the response of secondary angiosarcomas to cemiplimab

Predicting the response of secondary angiosarcomas to cemiplimab Angiosarcomas (AS) are rare and aggressive tumors that arise from the vascular endothelium. AS can present anywhere in the body and can either develop spontaneously (primary AS) or due to previous radiotherapy, chronic lymphedema, or exposure to UV radiation (secondary AS). AS treatment didn’t change for decades and the prognosis for AS patients is still poor with a 5-year survival of only 30-40%. Although immune checkpoint inhibition (ICI) is now standard of care for many forms of cancer, for AS this is not the case. In our previous project sponsored by the Sarcoma Foundation of America, we have analyzed the genetic and immune landscape of AS. In this project we found that mainly secondary AS can be considered immunogenically “hot”, due to the high number of mutations which makes them potentially more sensitive to ICI and the higher amounts of tumor infiltrating CD8+ T cells (TILs). The complex genetic background resembles that of cutaneous squamous cell carcinoma, for which the PD-1 inhibitor cemiplimab is registered as first line treatment, and proved to be very effective. Based on our preclinical results we succeeded to start a clinical phase II trial with cemiplimab in patients with locally advanced and metastatic secondary AS. This clinical trial provides us with the unique opportunity to prospectively conduct translational research in a rare sarcoma subgroup. A clear predictive biomarker(set) for response to ICI treatment is lacking in all solid cancers, causing unnecessary toxicity for non-responding patients a high societal financial burden. In the current proposal we aim to indentify such a biomaker(set), predicting the response of secondary AS patients to cemiplimab. For this purpose, we will collect baseline and on treatment samples of tumor, blood and feces. Our primary objective is to determine whether a high pretreatment number of TILs is related with clinical benefit from treatment with ICI. The secondary objectives are to define a predicitive immunogenomic profile based on a set of biomarkers that differ between responding and non-responding patients, correlate them with duration of response, and to investigate changes over time in the immunogenomic profiles. Ultimately, after this project we have identified the most relevant immunogenomic and microbiome-related biomarkers for predicting response to treatment with ICI in secondary AS patients.