LAUSR

Background: Programmed cell death 1 (PD-1) is a receptor upregulated on activated lymphocytes that mediates a dominant-negative checkpoint signal limiting antigen receptor-driven cellular activation. PD-1 immune checkpoint inhibitors have shown durable clinical responses in patients with non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Budigalimab (formerly ABBV-181) is a blocking humanized recombinant anti-PD-1 monoclonal antibody, currently under evaluation in multiple studies such as phase 1 clinical trial (NCT03000257) in patients with solid tumors including HNSCC and NSCLC. Multiple clinical biomarker assessments have been incorporated into this study to accommodate pharmacodynamic (PD) and predictive analyses. Methods: Patients with previously treated, advanced HNSCC (n=41) or NSCLC (n=40) that were PD-1 inhibitor naive received budigalimab IV at 250 mg every two weeks or 500 mg every four weeks to progression, with responses assessed every 8 weeks. Archival tumor FFPE specimens from patients with HNSCC (n=37) and NSCLC (N=33) were evaluated for CD8 infiltration and tumor PD-L1 expression by Dako 28-8 IHC assay, with remaining samples processed for RNA sequencing and whole-exome sequencing. Serum (for soluble biomarkers) and whole blood (for flow cytometric analysis of T cell biomarkers) were taken at baseline and selected on-treatment time points. Univariate analysis of biomarkers associated with the best overall response (BOR) and progression-free survival was conducted. Results: As of July 2019, responses per response evaluation criteria in solid tumors (RECIST) v1.1 or iRECIST were observed at the expected rates for a PD-1 inhibitor (BOR of partial or complete response of 15% in HNSCC and 19% in NSCLC), with responses in PD-L1+ and PD-L1- tumors in both groups. Budigalimab dosing was associated with rapid complete PD-1 receptor saturation, transient decreases in circulating lymphocytes, upregulation of proliferation (Ki67) biomarkers in T cells, and upregulation of multiple soluble biomarkers, including IFNγ-induced chemokines. Differential neoantigen burden and lymphocyte-associated gene expression in tumors were observed in responders versus non-responders. Preliminary univariate analysis of biomarkers found that baseline tumor size, serum IL-6, and T cell counts were significantly associated with outcomes. Conclusions: Our biomarker analysis of budigalimab-treated HNSCC and NSCLC patients has identified early PD biomarkers consistent with PD-1 inhibitor activity as well as pre-treatment tumor and peripheral biomarkers associated with observed clinical responses. These findings confirm that budigalimab is a biologically active PD-1 inhibitor. Citation Format: Stacie Lambert, Chun Zhang, Stefan Englert, Claire Guo, Tolga Turan, Catherine Tribouley, David Masica, Robert T. McLaughlin, Gregory S. Vosganian, Daniel E. Afar. Pharmacodynamic and predictive biomarkers of clinical responses to PD-1 inhibitor budigalimab from the first-in-human clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4464.