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

Sep 28, 2026

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Adenosinergic signaling acts as an immunometabolic checkpoint in the tumor microenvironment of non-small cell lung cancer (NSCLC), promoting immune suppression and treatment resistance. PBF-1129, an oral selective A2B adenosine receptor antagonist, was evaluated in a Phase 1 open-label dose-escalation study in advanced/metastatic NSCLC after progression on standard therapies. Twenty-one patients received 40–320 mg once daily with no dose-limiting toxicities, dose-proportional pharmacokinetics, and systemic immune modulation.

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CategoryHealthcare

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Investigational New Drugs (2025) 43:1211–1221 [https://doi.org/10.1007/s10637-025-01591-y](https://doi.org/10.1007/s10637-025-01591-y) Phase 1 dose escalation trial of the selective adenosine A2B antagonist PBF-1129 in patients with metastatic non-small cell lung cancer Dwight H. Owen1,2 · Ruohan Wu1 · Lai Wei3 · Mikhail Dikov1 · Shankar Suman1,8 · Po‑Lan Su1,4 · Joseph Amann1 · Shuxiao Guan1 · Daniel Spakowicz1,2 · Catherine Schweitzer5 · Carly Pilcher5 · Michael B. Smith6 · Sarah Ferguson5 · Julio Castro Palomino7 · Santiago Figueroa Pérez7 · Erin M. Bertino1 · Peter G. Shields1,2 · Kai He1,2 · Carolyn J. Presley1 · Gregory A. Otterson1 · William E. Carson1,2 · David P. Carbone1,2 Received: 22 July 2025 / Accepted: 17 October 2025 / Published online: 3 December 2025 © The Author(s) 2025 Summary The adenosinergic pathway represents a critical immunometabolic checkpoint within the tumor microenvironment of nonsmall 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. Keywords Non-small cell lung cancer · Phase 1 clinical trial · Adenosine receptor · Immunotherapy | Dwight H. Owen and Ruohan Wu contributed equally to this work. | | --- | | [ClinicalTrials.gov:NCT03274479](ClinicalTrials.gov:NCT03274479) | * Dwight H. Owen [Dwight.owen@osumc.edu](Dwight.owen@osumc.edu) 1 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 1800 Cannon Drive, 12th Floor, Columbus, OH, USA 2 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 3 Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA 4 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Check Kung University, Tainan, Taiwan 5 Clinical Trials Office, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 6 Department of Pharmacy, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 7 Palobiofarma S.L., Pamplona, Spain 8 Department of Oncology, Mayo Clinic, Rochester, MN, USA Introduction Despite recent progress in treating metastatic non-small cell lung cancer (mNSCLC), only a subset of tumors respond to currently available immunotherapy treatments; those that do respond eventually develop treatment resistance. A possible barrier to durable responses is the immunosuppressive tumor microenvironment (TME), which involves several immunosuppressive factors and cells. To develop a

FAQs

What does the study evaluate?

The trial evaluates PBF-1129, an oral selective A2B adenosine receptor antagonist, in metastatic non-small cell lung cancer patients using a Phase 1 dose-escalation design.

How was dosing administered and what safety signal was observed?

Patients received escalating once-daily doses of 40–320 mg. No dose-limiting toxicities were observed.

What biological and clinical responses were reported?

Pharmacokinetics were dose-proportional with plasma concentrations above IC90 at 320 mg for 24 hours. Stable disease occurred in some patients, and post-treatment reductions in PD-1 expression on CD8+ T cells correlated with improved survival.

Sep 28, 2026

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