Association of Baseline and Pharmacodynamic Biomarkers With Outcomes in Patients Treated With the PD-1 Inhibitor Budigalimab

Abstract

Budigalimab, a novel anti-PD-1 monoclonal antibody, demonstrated efficacy and biomarker pharmacodynamics in patients with head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) consistent with those reported by other PD-1 inhibitors. Herein are presented additional outcomes of biomarker analyses from the phase 1 study of budigalimab monotherapy in patients with HNSCC and NSCLC (NCT03000257). PD-1 inhibitor naive patients with advanced HNSCC (n = 41) or NSCLC (n = 40) received budigalimab intravenously at 250 mg every 2 weeks (Q2W) or 500 mg Q4W until progression. Archival tumor specimens were evaluated by immunohistochemistry for CD8 and tumor PD-1 ligand 1 (PD-L1) expression, RNA, and wholeexome sequencing. Serum and whole blood samples were acquired at baseline and at select on-treatment time points. As of October 2019, best overall response of 15% in HNSCC and 18% in NSCLC was observed in all treated patients; both cohorts reported responses in PD-L1 + and PD-L1tumors. Treatment with budigalimab was associated with increases in multiple soluble biomarkers including interferon gamma-induced chemokines. Expanded overall T-cell counts, total CD8 T-cell counts, and percentages of CD8 + CD45RA -CD62Leffector memory T cells were observed at cycle 1, day 15 in responders. Univariate analysis demonstrated an association between prolonged progression-free survival and higher tumor mutational burden/neoantigen load, smaller tumor size, lower platelet-lymphocyte ratios, lower CCL23, lower colony-stimulating factor 1, and lower interleukin-6 levels at baseline. The biomarker analysis presented herein identified additional early pharmacodynamic biomarkers associated with anti-PD-1 activity and improved clinical responses to budigalimab in patients with advanced HNSCC and NSCLC.

Clinical predictive value of naïve and memory T cells in advanced NSCLC

“…Most studies have focused on the frequency of immune cells in blood or tumor-infiltrating lymphocytes (TILs) and served as biomarkers of prognosis (51-53). Liu C, et al reported that the percentage of CD4 + Tn and Tm in peripheral blood are prognostic indicators for patients with NSCLC (54)(55)(56). However, the "Tn" of these researches was a mixture of Tn and Tscm due to not using CD95 monoclonal antibodies to discriminate Tscm from Tn according to the methods of the papers (57), while Tn and Tscm in our research had distinguished by CD95 monoclonal antibody.…”

“…The "Tn" in these researches was completely different from the "Tn" of our manuscript. Meanwhile, this researches only analyzed the memory CD4 + and CD8 + T cells but did not fully analyze the subsets of memory cells, including Tscm, Tcm, Tem, and Tte (30,(54)(55)(56). More importantly, these studies did not analyze further the prognostic impact of each AC of the Tn/Tm subpopulation on patient survival.…”

Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade

“…In this study, a higher ORR (33.9% vs. 11.1%, p = 0.003) and disease control rate (DCR; 80.6% vs. 34.9%, p < 0.001) were also reported in patients with low IL-6 before treatment. In a recent study by Lambert and colleagues, low pre-treatment serum IL-6 associated with prolonged PFS ( p = 0.011) in a univariate analysis of the anti-PD-1 inhibitor budigalimab in patients with advanced NSCLC ( n = 40) or head and neck squamous cell carcinoma (HNSCC; n = 41) [ 28 ]. In another study using similar plasma cutoffs, a low baseline concentration of plasma IL-6 (< 11.150 pg/ml) associated with longer PFS ( p = 0.0142) following anti-PD-1 therapies in stage III-IV patients with NSCLC [ 29 ].…”

“…Several studies ( n = 8) involving 634 patients have reported on the association between peripheral CD4 + (Table 4 ) and CD8 + (Table 5 ) T lymphocytes at baseline and response of NSCLC patients to ICI. Specifically, higher levels of lymphocytes, including higher percentage and count of total T cells, percentage of Ki67 + CD8 + T cells and natural killer (NK) cell count prior to treatment with the anti-PD-1 inhibitor budigalimab were associated with improved clinical response and longer PFS in a phase I trial that included 40 patients with advanced NSCLC [ 28 ]. Miao et al reported similar findings, with higher baseline CD4 + T cell counts with a memory phenotype (lacking expression of CD45RA, > 311.3 × 10 6 cells/L), associating with longer PFS ( p < 0.001) [ 69 ].…”

“…An analysis of 231 NSCLC patients treated with anti-PD-(L)1 found that high peripheral lymphocyte counts 1-month post-treatment associated with longer PFS ( p < 0.001) and OS ( p < 0.001) [ 80 ]. Lambert et al also observed that 2 weeks post anti-PD-1 initiation, overall T-cell counts, CD8 + T-cell counts, and percentages of CD8 + CD45RA – CD62L – effector memory T cells were expanded in responding patients, and were associated with a longer duration of PFS ( p = 0.024, p = 0.021, and p = 0.014, respectively) [ 28 ]. Changes in additional peripheral lymphocyte subsets have been evaluated for association with outcome in NSCLC patients treated with ICI [ 81 , 82 ].…”