Analyzing the Predictive Effects of PD-L1 Expression, Early Changes of bTMB and Circulated CD8+T Cells during Treatment for Responses of RT Combined with ICI in NSCLC

Abstract

The beneficial role of immunotherapy and the clinical relevance of current biomarkers remain inconclusive; thus, appropriate strategies and reliable predictors need further definition. A rational combination of biomarkers is needed. Here, we estimated potential predictive factors for responses of radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) in a phase II trial to determine the efficacy and safety of combination of moderate hypofractionated RT with ICI in patients with oligometastatic NSCLC (NCT03557411). Pretreatment tumor tissue samples and longitudinal blood were collected for immune and tumor biomarker analysis. We examined pre-treatment (pre-ICI) PD-L1 expression in tumor cells. Circulating tumor cell (CTC), PD-L1+CTC, blood tumor mutation burden (bTMB), CD8+T cells, CD4+T cells, NK cells, B cells in circulation were acquired pre-ICI and 1 month after ICI starting (1-mth). In addition, early changes of CTC (CTC), PD-L1+CTC (PD-L1+CTC), bTMB (bTMB), CD8+T cells (CD8+T cells), CD4+T cells (CD4+T cells), NK cells (NK cells), B cells (B cells) were also analyzed to estimate the predictive effects for treatment. High pre-ICI bTMB and increased CD8+T cells at 1 month was associated with better PFS (p = 0.016; p = 0.006). Interaction analyses revealed that each combination of two markers in the 5 markers including PD-L1, pre-ICI bTMB, 1-mth bTMB, 1-mth CD8+T cells and CD8+T cells was significantly associated with PFS, except for CTC, PD-L1+CTC, CD4+T cells, NK cells and B cells in circulation due to low power. Unsupervised cluster analysis based on these markers revealed three sub-cohorts. Cohort-1 was overrepresented by patients with progressive disease (81%) of whom were negative for 3-4 of the 5 biomarkers. Cohort-3 was overrepresented by patients with partial response (70%) of whom were positive for 3-4 of the 5 biomarkers. Survival analyses of the 3 cohorts indicated a significant association with PFS (p = 0.017). This study suggests that a combination of PD-L1 expression, early changes of bTMB and circulated CD8+T cells as a better predictive biomarker for response to RT combined with ICI. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.