Abstract CT152: First in human study with EOS100850, a novel potent A2A antagonist, shows excellent tolerance and clinical benefit in immune resistant advanced cancers

Buisseret, Laurence;Rottey, Sylvie;de Bono, Johann;Mossakowski, Manon;Machiels, Jean-Pascal;et.al.
(2020) Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA — Location: Philadelphia

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Authors
  • Buisseret, Laurence
    Author
  • Rottey, Sylvie
    Author
  • de Bono, Johann
    Author
  • Mossakowski, ManonUCLouvain
    Author
  • Machiels, Jean-PascalUCLouvain
    Author
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Abstract
Adenosine is a strong immunosuppressive mediator often found at high extracellular levels in the microenvironment of most tumors. Blocking A2A receptors, predominantly expressed on tumor-infiltrating immune cells, is aimed at reversing the immunosuppressive effect of adenosine. EOS100850 is a potent and highly selective small molecule antagonist of the A2A receptor that remains active even at the high adenosine concentration found in tumors and that does not cross the blood-brain barrier. This multicenter FIH Phase I clinical trial (NCT02740985) assessed the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary clinical activity of EOS100850 monotherapy in subjects with refractory solid tumors. Pharmacodynamic assessments were performed in peripheral blood and tumor biopsies with simultaneous determination of plasma PK. Twenty-one adult participants with advanced malignancies were treated with EOS100850 monotherapy. Cohorts of 3 participants each were evaluated at 20 and 40 mg QD or 40 mg BID administration. Six participants were subsequently tested at doses of 80 mg BID and at the maximum administered dose of 160 mg BID. All subjects had at least 1 prior regimen (median 3). PK analysis indicated dose-proportional increase of EOS100850 plasma exposures up to 80 mg BID while PD evaluations revealed prolonged and maintained A2AR inhibition over the dosing interval. The most common adverse events (>15%) attributed to the investigational treatment included Grade 1-2 nausea, fatigue, vomiting, and liver enzyme abnormalities. No drug-related Grade 3-4 AEs and no dose-limiting toxicities were observed. As of the data cut off (15JAN20), stable disease was observed in 6 participants who remain on therapy, including head & neck cancers, endometrial cancers, and checkpoint inhibitor-refractory melanoma. Further evaluation is ongoing as monotherapy and in combination with pembrolizumab or chemotherapy in both immune checkpoint-naïve and -refractory patients.
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Buisseret, L., Rottey, S., de Bono, J., Mossakowski, M., Delafontaine, B., Manickavasagar, T., Kotecki, N., Martinoli, C., Schneider, M., De Henau, O., Chevron, P., Lager, J., & Machiels, J.-P. (2020). Abstract CT152: First in human study with EOS100850, a novel potent A2A antagonist, shows excellent tolerance and clinical benefit in immune resistant advanced cancers. American Association for Cancer Research. Proceedings of the Annual Meeting, 80(16). https://doi.org/10.1158/1538-7445.am2020-ct152 (Original work published 2020)