Cemiplimab in locally advanced and/or metastatic secondary angiosarcomas (CEMangio): A phase II clinical trial.
Authors: van Ravensteijn Stefan , De Haan Jacco J. , Gelderblom Hans , Hillebrandt-Roeffen Melissa H.S. , de Voer Richarda M. , Speetjens Frank M. , Kaal Suzanne E.J. , Smits Minke , van Herpen Carla M.L.- , Versleijen-Jonkers Yvonne M.H. , Desar Ingrid M.E. 
Published: June 2024

11513 Background: Angiosarcomas (AS) are rare and aggressive vascular sarcomas that can be subdivided in primary (de novo; pAS) and secondary AS (sAS). Secondary AS arise due to DNA damaging factors like radiotherapy (RT) and UV radiation or due to chronic lymphedema (Stewart Treves AS). Prognosis of locally advanced and metastatic AS is very poor and treatment options are limited. sAS differ from pAS in clinical behavior, genetic and molecular background. Instead, sAS show similarities to cutaneous squamous-cell carcinoma, for which the immune checkpoint inhibitor (ICI) cemiplimab showed impressive results. The high T-cell infiltrated tumor microenvironment and frequent DNA damage response mutations in sAS indicate susceptibility to ICI. Based on these tumor characteristics and anecdotical reports of responses to ICI in UV associated secondary AS, a clinical trial was designed with cemiplimab in sAS. Methods: In this prospective single arm multicenter phase II trial, the efficacy and safety of ICI cemiplimab 350 mg iv 3-weekly was investigated in patients with locally advanced or metastatic sAS. Using a Simons two-stage design, a total of 18 patients (pts) were included. The primary outcome is best overall response rate (BORR) after 24 weeks of cemiplimab treatment. Secondary outcomes include median time to response (mTTR), duration of response (mDOR), progression-free survival (mPFS), and overall survival (mOS) as well as translational biomarkers for response. Tumor mutational burden (TMB) and microsatellite instability (MSI) are investigated using “TruSight Oncology 500” (Illumina) sequencing (n = 16). In samples with high TMB (≥10 mutations / Megabase (Mb)), the mutational signature is analyzed. Results: At the cutoff date (23-Jan-24) all 18 projected pts have been included (12 RT-sAS, 3 UV-sAS, 3 Stewart Treves sAS). Cemiplimab was first line treatment in 10 pts (55.6%), second line in 6 pts (33.3%) and third line in 2 pts (11.1%). Median follow-up time was 8.0 months. The BORR at 24 weeks was 27.8%, with partial response (PR) in 4 patients (2 RT-sAS and 2 UV-sAS) and 1 complete response (CR) in a RT-sAS. One patient with a PR at 24 weeks (UV-AS) developed a CR. In both patients CR is ongoing. The mTTR was 2.6 months (range 1.2-5.4) and mDOR 6.2 months (range 0.43-N/A). The mPFS was 4.1 months (95% CI 1.2-6.4) and mOS was not reached. The toxicity profile was as expected. Three patients stopped treatment due to ICI related toxicity (1 pt with hepatitis grade 3, 1 pt with hepatitis grade 4, and 1 pt with dermatitis grade 2). High TMB was observed in 3 pts with UV-sAS, all showing single-base substitution signature 7a, associated with UV damage. The 2 pts with the highest TMB (60 and 125 mut/Mb) showed PR as BORR at 24 weeks. None of the patients showed MSI. Results of the additional biomarkers will be available at the ASCO meeting. Conclusions: Cemiplimab shows promising effectivity in secondary angiosarcomas. Clinical trial information: NCT04873375 .