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. 2020 Apr 15;26(8):2037-2046.
doi: 10.1158/1078-0432.CCR-19-2027. Epub 2020 Jan 14.

Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer

Kohsuke Isomoto #  1   2 , Koji Haratani #  2 , Hidetoshi Hayashi  3 , Shigeki Shimizu  4 , Shuta Tomida  5 , Takashi Niwa  1   6 , Toshihide Yokoyama  6 , Yasushi Fukuda  6 , Yasutaka Chiba  7 , Ryoji Kato  2 , Junko Tanizaki  8 , Kaoru Tanaka  2 , Masayuki Takeda  2 , Takashi Ogura  1 , Tadashi Ishida  6 , Akihiko Ito  4 , Kazuhiko Nakagawa  2
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Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer

Kohsuke Isomoto et al. Clin Cancer Res. .

Abstract

Purpose: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.

Experimental design: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing.

Results: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months.

Conclusions: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

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