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 whole-exome 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-L1- tumors. 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-CD62L- effector 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.

Conflict of interest statement

AbbVie Inc. provided financial support for the study (NCT03000257) and participated in the design, study conduct, as well as the writing, review, and approval of the manuscript. Data analysis and interpretation was conducted by employees of AbbVie Inc.

S.L.L., C.Z., C.G., T.T., D.L.M., S.E., Y.F., J.S., R.T.M., C.T., and D.A.: AbbVie employees and may own stock. G.V.: former employee of AbbVie and may own stock.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1

Immunohistochemical detection of PD-L1 percentage positive in tumor cells (A), PD-L1 intensity in inflammatory cells (B), and CD8 percentage positive (C) expression in archival tumor samples of patients with HNSCC and NSCLC treated with budigalimab monotherapy. A total of 71 patients (38 HNSCC and 33 NSCLC) were included in these analyses. Purple: EGFR mutated; blue: ALK rearrangement. + indicates positive; CR, complete response; HNSCC, head and neck squamous cell carcinoma; iPR, immune partial response; NSCLC, non–small cell lung cancer; PD, progressive disease; PD-L1, programmed cell death protein 1 ligand 1; PR, partial response; SD, stable disease.

FIGURE 2

Exome sequencing showed a relationship between tumor mutational burden (TMB) and best overall response (A); weak association of TMB with PFS was also observed, with a hazard ratio of 0.77 and a P-value of 0.126 (B). The optimized (sensitivity plus specificity) cutoff of 4.895, shown by the solid line, and an optimized (maximal sensitivity) cutoff of 2.47, shown by the dotted line were determined by performance as shown in Supplemental Digital Content Figure 1 (Supplemental Digital Content 1, http://links.lww.com/JIT/A666). A total of 32 patients (22 HNSCC and 10 NSCLC) were included in these analyses. BOR indicates best overall response; CR, complete response; HNSCC, head and neck squamous cell carcinoma; iPR, immune partial response; mono, monotherapy; NSCLC, non–small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIGURE 3

RNAseq analysis of the ∼40,000 transcripts that are nonzero in at least one sample detected multiple unique features with significant expression differences between responders and nonresponders in the indication-specific HNSCC, n=32 (A) and NSCLC, n=12 (B) data sets, as well as the combined (C) data set, n=44. Orange and green dots represent significantly differentially expressed transcripts (|FC| >2, P-value <0.05, FDR <0.25), with orange indicating higher expression in responders and green indicating lower expression in responders. Qiagen Ingenuity Pathway Analysis of differential gene expression by responders and nonresponders showed significantly upregulated pathways (orange) and downregulated pathways (blue) in responding patients with HNSCC (D). In the combined data set, EDIL3 was associated with both BOR (E) and PFS (F). AUC indicates area under the concentration-time curve; BOR, best overall response; CR, complete response; FC, fold change; FDR, false discovery rate; HNSCC, head and neck squamous cell carcinoma; HR, hazard ratio; iPR, immune partial response; NSCLC, non–small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; RNAseq, RNA sequencing; SD, stable disease.

FIGURE 4

Immunophenotyping detected pharmacodynamic changes induced by budigalimab, including the percentages of Ki67+ CD4 and CD8 T cells [mean and SE shown from a total of 44 patients (24 HNSCC and 20 NSCLC) with baseline and postbaseline Ki67 assessments, with 9 responders] (A), circulating cell counts of CD3–, CD4–, and CD8+ T-cell counts (mean and SE shown from a total of 71 patients with baseline and postbaseline total T cells, helper T cells, cytotoxic T cells, B cells, and NK cells assessments, with 13 responders) (B), and percentages of CD8 T-cell subsets on the basis of CD28 and CD95 expression (mean and SE shown from a total of 49 patients with baseline and postbaseline memory subset assessments, with 10 responders) (C). – indicates negative; +, positive; C, cycle; D, day; HNSCC, head and neck squamous cell carcinoma; mem, memory; NK, natural killer; NSCLC, non–small cell lung cancer.

FIGURE 5

Budigalimab treatment induced soluble biomarkers of T-cell activity associated with differential response. Data shown are from a total of 65 patients with baseline and postbaseline assessments including 12 responders and 43 nonresponders. Longitudinal analysis of significantly upregulated biomarkers across all patients shows IFN-γ peak expression at the C1D2 time point (A), while CXCL9 (MIG), CXCL10, CXCL11, GZMH, TNFRSF4, and TNFRSF9 peak at the C2D1 time point (B, C). Significant PFS differences were observed between patients with the highest and lowest induction at C1D2 of IFN-γ (D), IL-8 (E), or CXCL9 (MIG) (F). C indicates cycle; D, day; FC, fold change; HSNCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; INF, inflammatory; IO, immuno-oncologic; MIG, mitogen-inducible gene; NSCLC, non–small cell lung cancer; TNF, tumor necrosis factor.