Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced Non-Small Cell Lung Cancer

Abstract

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 3.8-5.5 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 5 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.

Conclusions: In patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.

Figure 1.

Correlative factors and clinical characteristics. A, Scatter plot of correlative factors against clinical characteristics. B, Examples of PD-L1 expression on tumor vs. immune cells. C, Baseline PD-L1 expression in tumor vs. immune cells by best response per irRC (P = 0.007, Fisher exact test).

Figure 2.

Schematic presentation of the analyzed parameters in the correlative cohort per overall survival (OS). TMB: total mutational burden. PR: partial response. SD: stable disease. PD: progressive disease. △: mutation. LTB: Long term benefiter. Y1: year one. Y2: year two. Y3: year 3.

Figure 3.

OS and subgroup survival analysis of the correlative cohort (N = 38) by log-rank (Mantel–Cox) test. A, OS By PD-L1 categories (0%–49% n = 23 vs. >49% n = 9, P = 0.024). B, OS By TMB percentile (<25th percentile n = 6 vs. 25–50th percentile n = 7 vs. 50–75th percentile n = 6 vs. >75th percentile n = 6, P = 0.302). C, OS By CD8 categories (0%–5% n = 18 vs. 5%–25% n = 14, P = 0.222). D, OS By CD4 categories (0%–5% n = 21 vs. 5%–25% n = 9 vs. >25% n = 2, P = 0.540).