Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer

Abstract

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8⁺ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8⁺ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8⁺ expression might be the subset that would poorly benefit from such treatment.

Keywords: epidermal growth factor receptor tyrosine kinase inhibitor; non-small cell lung cancer; programmed cell death-1 ligand-1; programmed cell death-1 ligand-2; tumor microenvironment.

Figure 1

Representative images of the 4 tumor microenvironment subtypes of programmed cell death‐1 ligand‐1 (PD‐L1) and CD8⁺ immunostaining in non‐small cell lung cancer tissue. Scale bar = 100 μm. TIL, tumor‐infiltrating lymphocyte

Figure 2

Association between response to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) and the tumor microenvironment (TME) in non‐small cell lung cancer. A, Comparison of the response and disease control rates for first‐line EGFR‐TKIs, according to the TME subtypes. B, Waterfall plot of the best percentage change from baseline in the cumulative longest tumor diameters. †In the type 3 group, 1 patient had a nonmeasurable lesion (malignant pleural effusion) at the initiation of first‐line EGFR‐TKI; apparent reduction of malignant pleural effusion was confirmed after the initiation of therapy. ‡ In the type 1 group, the tumor was not measurable in 1 patient who had disease progression without response. §A case with programmed cell death‐1 ligand‐2 (PD‐L2) expression. PD, progressive disease; PR, partial response; SD, stable disease

Figure 3

Impact of programmed cell death‐1 ligand‐1 (PD‐L1) expression status and the tumor microenvironment on progression‐free survival (PFS) in patients with non‐small cell lung cancer after first‐line epidermal growth factor receptor‐ tyrosine kinase inhibitors (EGFR‐TKIs). A, Kaplan‐Meier curves for PFS in EGFR‐mutated NSCLC patients treated with first‐line EGFR‐TKIs, according to PD‐L1 expression. B, Comparison of the Kaplan‐Meier curves for PFS after first‐line EGFR‐TKIs, according to the tumor microenvironment subtype (Type 1‐4). Plus signs denote censoring. C, Swimmer plot shows duration of first‐line EGFR‐TKIs treatment for patients on this study. CI, confidence interval; TIL, tumor‐infiltrating lymphocyte

Figure 4

Representative case of non‐small cell lung cancer with altered tumor microenvironment and response to epidermal growth factor receptor‐tyrosine kinase inhibitor EGFR‐TKI) before and after developing acquired resistance to the initial EGFR‐TKI therapy. AF, allele frequency; ddPCR, droplet digital PCR; PD, progressive disease; PD‐L1/2, programmed cell death‐1 ligand‐1/2; TIL, tumor‐infiltrating lymphocyte; TPS, tumor proportion score