Abstract CT137: Initial results from a phase 1 study of an A2a receptor antagonist, administered as monotherapy and in combination with anti-PD1 therapy in patients with advanced non-small cell lung cancer

Abstract Background: Immunotherapy is an important treatment option for patients with non-small cell lung cancer (NSCLC), however the majority of patients do not achieve durable responses with anti-PD1 treatment. The activity of anti-PD1 agents can be limited by adenosine in the tumor micro-environment (TME), which exerts immunosuppressive effects through A2a receptors on both adaptive and innate immune cells. Moreover, preclinical studies have demonstrated that adenosine suppresses T-cell function through mechanisms distinct from PD1 inhibition. Effective inhibition of the adenosine pathway may therefore potentiate current immunotherapy strategies, especially in combination with radiation. JNJ-86974680 is a small molecule selective A2a receptor (A2aR) competitive antagonist, exhibiting high in vitro potency (IC50= 0.01uM). Study NCT06116786 is a 2-part, first-in-human Phase 1 study, evaluating the safety, pharmacokinetics, and preliminary efficacy of JNJ-86974680 as a monotherapy, and in combination with anti-PD1 cetrelimab, in patients with NSCLC who progressed after prior therapy with anti-PD1 and chemotherapy. Methods: In the Part 1 Dose Escalation, participants were treated in sequential DLT periods, evaluating JNJ-86974680 safety first as a monotherapy, and then in combination with cetrelimab. Treatment continued after the DLT periods as combination therapy in 21 day cycles. Safety was evaluated through incidence of adverse events, lab abnormalities, and cardiac studies. Efficacy was evaluated per RECIST 1.1 criteria using CT scans every 6-12 weeks. Blood samples were collected at pre-specified timepoints for PK/PD and biomarker analyses. Results: As of 17 Oct 2024, 22 and 19 participants received JNJ-86974680 as monotherapy, and in cetrelimab combination, respectively, at doses of 5, 15, 30 and 60 mg JNJ-86974680. All dose levels were tolerable with no DLTs observed. The best response was Stable Disease in this anti-PD1 relapsed population, with longest duration of treatment 7.7 mos (ongoing). The most frequently reported TEAEs (>20%) were abdominal pain (26.1%), and nausea, fatigue, dizziness, cough, and headache (n=5, 21.7% for each). There were no treatment-related TEAEs of >Grade 2 severity reported. PK analyses revealed dose-proportional exposure, with an apparent half-life of 24 hours, and steady state achieved after 7 days. PD data showed consistent 90-100% A2aR inhibition in peripheral lymphocytes at trough concentrations with 15 and 30 mg doses. Preliminary biomarker data demonstrated immune effects with monotherapy and additive effects with cetrelimab combination. Conclusion: JNJ-86974680 demonstrated a favorable safety and tolerability profile as monotherapy and in combination with cetrelimab, with dose-proportional PK and near-complete A2aR inhibition in peripheral lymphocytes at clinically relevant doses (15-30 mg). Ongoing dose escalation aims to optimize intratumoral drug concentrations and maximize A2aR inhibition. Citation Format: Prantesh Jain, Alexander Spira, Seehoon Lee, Byoung Chul Cho, Enriqueta Felip, Andres Aguilar, Sarah Gordon, Sebastian Ochsenreither, Thomas Wehler, Amanda McGillivray, Ariel Chen, Raja Venkatasubramanian, Rajesh Bandekar, Shu Jin, Rosa Martín-Pérez, Aisha Nasreen Hasan, Brian Henick. Initial results from a phase 1 study of an A2a receptor antagonist, administered as monotherapy and in combination with anti-PD1 therapy in patients with advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT137.