Etrumadenant (AB928): A Comprehensive Monograph on a First-in-Class Dual Adenosine A2a/A2b Receptor Antagonist for Cancer Immunotherapy

I. Executive Summary

Etrumadenant (AB928) is an investigational, orally bioavailable, small molecule therapeutic agent representing a first-in-class dual antagonist of the adenosine A2a (A2aR) and A2b (A2bR) receptors. Developed by Arcus Biosciences, etrumadenant was designed to counteract a fundamental mechanism of tumor immune evasion by targeting the highly immunosuppressive adenosine signaling pathway within the tumor microenvironment (TME). The scientific rationale is robust: by blocking the effects of high concentrations of adenosine—a byproduct of tumor cell metabolism and death—etrumadenant aims to reinvigorate the anti-tumor activity of various immune cells, including T-lymphocytes and myeloid cells, thereby unleashing a more effective immune response against cancer.

The clinical development of etrumadenant has yielded a complex and dichotomous profile. The agent achieved a remarkable and unprecedented clinical success in the Phase 1b/2 ARC-9 trial, where its combination with chemotherapy and immunotherapy resulted in a statistically significant and clinically profound improvement in overall survival for patients with third-line metastatic colorectal cancer (mCRC). This result provided clear clinical validation for its mechanism of action. Conversely, the development program has faced significant setbacks. Trials in other indications, most notably metastatic castration-resistant prostate cancer (mCRPC) and EGFR-mutated non-small cell lung cancer (NSCLC), failed to demonstrate sufficient clinical benefit, leading to the discontinuation of development in those settings.