Phase 1 dose escalation trial of the selective adenosine A2B antagonist PBF-1129 in patients with metastatic non-small cell lung cancer

The adenosinergic pathway represents a critical immunometabolic checkpoint within the tumor microenvironment of non-small cell lung cancer (NSCLC), contributing to immune suppression and therapeutic resistance. PBF-1129, an oral, selective A2B adenosine receptor (A2BAR) antagonist, was evaluated in a phase 1, open-label, dose-escalation trial (NCT03274479) in patients with advanced/metastatic NSCLC who had progressed on standard therapies. All patients had previously received chemotherapy and immune checkpoint blockade. Twenty-one patients received escalating doses (40-320 mg once daily), with no dose-limiting toxicities observed. The most frequently reported treatment related adverse events of any grade were lymphocytopenia (n = 8, 38.1%), vomiting (n = 8, 38.1%), anorexia (n = 6, 28.5%), and fatigue (n = 6, 28.5%). PBF-1129 showed dose-proportional pharmacokinetics and maintained plasma concentrations above the 90% maximal inhibitory concentration (IC₉₀) of A2BAR at 320 mg for 24 h, which was determined to be the recommended phase 2 dose (RP2D). Best response was stable disease in 3 out of 21 patients including 2 of 6 treated at RP2D. Immunophenotyping revealed post-treatment reductions in programmed cell death protein 1 (PD-1) expression on CD8⁺ T cells, which correlated with improved survival. The reduction of PD-1 expression on CD4⁺ T cells and decreased myeloid-derived suppressor cells were also associated with better outcomes. These findings suggest PBF-1129 is safe and modulates the systemic immune parameters, warranting further evaluation in combination with immune checkpoint blockade.