Resistance Biomarkers to PD-1/PD-L1–Targeted Immune Checkpoint Inhibitors: The PIONeeR Trial

Clinical studies have revealed several factors related to potential response to immune checkpoint inhibitors (ICIs), such as PD-L1 expression, tumor mutational burden, initial tumor size, history of steroid or antibiotic use, microsatellite instability status, and gut microbiota; however, robust predictive, validated biomarkers are still lacking.¹ The PIONeeR project, founded on a large biomarker program and a randomized umbrella clinical trial, aimed to understand, predict, and overcome resistance to ICIs.¹

The PIONeeR trial included >300 patients with advanced non–small-cell lung cancer (NSCLC). The biomarker analysis was focused on the first 137 patients with Eastern Cooperative Oncology Group performance status of 0 or 1 who received ≥2 lines of therapy.² Enrolled patients were treated with nivolumab, pembrolizumab, or atezolizumab monotherapy. Tumor tissue was collected at baseline and at 6 weeks of treatment, and blood samples were collected every cycle throughout the 24 weeks after the initiation of the first treatment cycle. Response to ICIs was assessed by RECIST version 1.1 every 6 weeks.² Immune cells were characterized in tumor and blood samples of each patient using flow cytometry for circulating immune-cell subtype quantification and endothelial activation and levels of soluble factors. In addition, dual- and multiplex-immunohistochemistry and digital pathology were used to quantify immune cells infiltrating the tumor. Whole exome sequencing was used to assess tumor mutational burden. A total of 331 biomarkers were measured in addition to routine clinical parameters.²

Multivariable logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histologic type, and PD-L1–positive tumor cells) with the risk of early progression.²

A total of 137 patients were included with tumors that were mainly nonsquamous (79%). Tumor cytotoxic T-cell density, especially PD-1–positive, were lower in patients with early progression (multivariable odds ratio [OR], 0.45; P = .022). Higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in early progression (multivariable OR, 3.8; P <.001). Among other biomarkers, regulatory T-cells (multivariable OR, 0.44; P = .018), natural killer cell subsets (multivariable OR, ≤0.44; P <.05), albumin (multivariable OR, 0.4; P <.01), and PD-L1 tumor cells percentage (multivariable OR, 0.27; P <.01) were decreased, whereas alkaline phosphatase was increased (OR, 3; P = .018) in patients with early progression. Multimodal data integration through supervised machine learning revealed a 37-biomarker signature that identified patients who may be resistant to anti–PD-1/PD-L1 prior to treatment initiation.³

In conclusion, the PIONeeR trial is the first study of comprehensive biomarker analysis that aimed at defining comprehensive predictive models of resistance in patients with advanced NSCLC treated with PD-1/PD-L1 ICIs. A signature of 37 biomarkers was seen in patients resistant to PD-1/PD-L1 ICIs before treatment initiation. In addition, the study demonstrated the complementary value of tumor and circulating biomarkers in predicting ICI efficacy and potential resistance.^2,3

References

1. Ciccolini J, Benzekry S, Barlesi F. Deciphering the response and resistance to immune checkpoint inhibitors in lung cancer with artificial intelligence-based analysis: when PIONeeR meets QUANTIC. Br J Cancer. 2020;123:337-338.
2. Greillier L, Monville F, Leca V, et al. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: the precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract LB120.
3. Greillier L, Monville F, Leca V, et al. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: the precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Late-Breaking Poster LB120.