Abstract 732: Targeting adenosine A2B receptor using PBF-1129 in treating patients with metastatic non-small cell lung cancer

Abstract Background: Immunotherapy has improved lung cancer treatment drastically, but its effectiveness is limited by the immunosuppressive tumor microenvironment (TME). In the TME, adenosine accumulates from ATP breakdown by ectonucleotidases like CD39 and CD73, recruiting immunosuppressive cells such as Tregs and MDSCs. Adenosine regulates immune cell function by activating four cell surface receptors, with A2B being the only low-affinity receptor primarily triggered by high adenosine levels in cancer, which makes it a favorable drug target. We previously reported the results of a phase 1 dose escalation trial of PBF-1129, a first-in-class A2BAR inhibitor in patients with mNSCLC who progressed on chemotherapy and immune checkpoint inhibitors (ICI, NCT03274479). Patients received escalating doses of PBF-1129 orally daily (40 mg, 80 mg, 160 mg, 320 mg) until disease progression or intolerability. Primary objective was safety and tolerability, followed by PK, ORR, PFS, OS, and immunophenotyping analysis. Here we report correlative analysis of immunophenotyping of peripheral blood changes during treatment. Blood was collected before treatment started, after the first cycle of treatment, and after the second cycle/end of treatment. PBMC was isolated using ficoll gradient. Results: 21 patients (9 female), median age 61 years (range 49-75) were enrolled, median line of therapy was 4th (range 3-6). As previously reported, no dose-limiting toxicities were observed at any dose level and no maximum tolerated dose was identified. Best response of stable disease was observed. Flow cytometry analysis revealed that the PD-1 exhaustion marker was downregulated in CD8+ T cells following one to two treatment cycles (p=0.03*). Nonsignificant changes indicated a reduction in CD73 expression on various immune subpopulations, in addition to MDSCs and Tregs percentage reduction was observed in most patients. Conclusions: PBF-1129 was safe and tolerable in patients with heavily pretreated mNSCLC, although limited single-agent activity was observed. The treatment improved immune cell function by alleviating PD-1 levels in cytotoxic T cells. Citation Format: Ruohan Wu, Dwight Owen, Lai Wei, Mikhail Dikov, Shankar Suman, Joseph Amann, Shuxiao Guan, Po-Lan Su, Catherine Schweitzer, Michael B. Smith, Sarah Ferguson, Julio Castro, Daniel Spakowicz, Erin Bertino, Peter Shields, Kai He, Carolyn J. Presley, Gregory A. Otterson, William E. Carson, David P. Carbone. Targeting adenosine A2B receptor using PBF-1129 in treating patients with metastatic non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 732.