Phase 1 trial of the adenosine A2A receptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A2A receptor within the tumor.

Abstract

2562 Background: Tumors produce high levels of extracellular adenosine which suppress anti-tumor immune responses. Blocking A2A 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 A2A 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 A2A 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 A2A receptor as a biomarker which may be associated with clinical benefit. Clinical trial information: NCT03873883. [Table: see text]