Phase 1 trial of the adenosine A 2A receptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A 2A receptor within the tumor

Laurence Buisseret, Sylvie Rottey, Johann De Bono, Ariane Migeotte, Brant Delafontaine, Thubeena Manickavasagar, Chiara Martinoli, Noemie Wald, Maura Rossetti, Esha Gangolli, Erol Wiegert, Nicola McIntyre, Joanne Lager, Jean-Pascal Machiels

Research output: Contribution to journalMeeting Abstract

Abstract

Background: Tumors produce high levels of extracellular adenosine which suppress anti-tumor immune responses. Blocking A 2A receptors, predominantly expressed on tumor-infiltrating immune cells, can reverse the immunosuppressive effect of adenosine. Inupadenant is a non brain-penetrant, potent and highly selective small molecule antagonist of the A 2A receptor that remains active even at the high adenosine concentrations found in tumors. Methods: This is the phase I portion of an ongoing first-in-human, clinical trial (NCT02740985) to evaluate safety/tolerability, pharmacokinetic, pharmacodynamic and anti-tumor activity of inupadenant in adult patients with solid tumors who have exhausted standard treatment options. In addition, tumor biomarkers, including adenosine-pathway markers by immunohistochemistry (IHC), are being evaluated. We present updated results of the dose escalation, new results from the monotherapy expansion and new analysis of tumor biomarkers. Results: Overall, 42 patients (21 patients in the dose escalation and an additional 21 patients in a monotherapy expansion) with a median of 3 prior regimens were treated as of the data cut off (DCO, 30Nov20).The dose levels investigated, along with the most frequent (>20%) treatment-emergent adverse events (TEAEs) across all dose levels are presented in the table. 7 AEs led to discontinuation; 2 (atrial fibrillation and myocardial infarction) were considered possibly study drug-related by the investigator. No dose reductions were required. Two partial responses (PRs) were reported: melanoma (NRAS-mutant; received prior immunotherapy), and prostate cancer (received antiandrogen and chemotherapy). At the DCO, both PRs were ongoing with a duration of response >230 days. 12 patients had stable disease (SD) as best response and SD >6 months was observed in 3 patients. Response and stable disease were associated with a higher number of cells expressing the A 2A receptor within the tumor at baseline, as measured by IHC. Conclusions: Inupadenant monotherapy was generally well-tolerated as of the DCO at a dose of 80 mg twice daily with initial evidence of clinical benefit, including 2 durable PRs in patients who have exhausted standard treatment options. Analysis of pre-treatment tumor biopsies has identified the A 2A receptor as a biomarker which may be associated with clinical benefit
Original languageEnglish
JournalJournal of Clinical Oncology
Volume39
Issue number15
DOIs
Publication statusPublished - 2021

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