Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.
Purpose
Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non-small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long term benefit.
Experimental Design
We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4 and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8 to 5.5 years).
Results
PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among five patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited.
Conclusion
In NSCLC patients treated with PD-1 blockade with long term follow up, TMB, PD-L1 and CD8 were each associated with benefit from PD-1 blockade. Pre-treatment PD-L1 expression was correlated with T lymphocyte infiltration as well as OS, while models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.
Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in advanced NSCLC patients. Experimental Design: We use high-dimensional mass cytometry (CyTOF) in baseline blood samples of advanced NSCLC patients treated with pembrolizumab. CyTOF data are analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (BGA). Results: We analyze 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, NK cells and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival and overall survival (OS). Additionally, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR=0.25 95%CI=0.12–0.51, p<0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in advanced NSCLC patients.
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