Background: Involvement of tumor immune microenvironment including programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) in biological properties of EGFR-mutant non-small cell lung cancer (NSCLC) remains elusive. Correlation of EGFR mutational status and PD-L1 expression and its impact on anti-PD-1/PD-L1 therapies have been intensively investigated but the relationship between pretreatment EGFR T790M (preT790M) and PD-L1 status has not yet been tackled. We have previously reported that EGFR-TKI-naïve patients with high preT790M had significantly shorter progression-free survival (PFS) upon EGFR-TKI treatment. In this study we investigated the association between preT790M status of tumor and immune microenvironment and its impact on efficacy of EGFR-TKI.

Materials and methods: We had previously assessed preT790M by droplet digital PCR in 44 advanced NSCLC patients harboring activating EGFR mutations treated with first-line EGFR-TKIs at Osaka City University Hospital between August 2013 and July 2016. For the current study, tumor proportion score (TPS) for PD-L1 and PD-L2 expression was assessed immunohistochemically using 28-8 antibody and D7U8C antibody, respectively. CD8-positive tumor-infiltrating lymphocytes (TILs) in tumor specimens were also evaluated.

Results: PD-L1/PD-L2 TPS and CD8-positive TILs were evaluable in 39 of 44 pretreatment tumor specimens. PD-L1 TPS of ≥50%, 1-49% and <1% were observed in 9 (23.1%), 10 (25.6%) and 20 patients (51.3%), respectively. PD-L2 TPS of ≥50%, 1-49% and <1% were observed in 1 (2.6%), 8 (20.5%) and 30 patients (76.9%), respectively. Significantly more PD-L1 high cases (TPS of ≥50%) were detected in subgroup of tumor with preT790M (41.2%, n=7/17) than in that without preT790M (9.1%, n=2/22) (p=0.026). In non-preT790M subgroup, CD8-positive TILs density was significantly higher in PD-L1 high than in PD-L1 low (median: 1298/mm2 vs. 331/mm2, p=0.035), while in preT790M subgroup, there was no significant difference regardless of PD-L1 level (median: 329/mm2 vs. 226/mm2, p=0.19). The median PFS and response rate for initial EGFR-TKIs were 13.6 months and 95% in non-preT790M/PD-L1 low, 1.6 months and 0% in non-preT790M/PD-L1 high, 11.4 months and 80% in preT790M/PD-L1 low, and 6.7 months and 57% in preT790M/PD-L1 high, respectively. No correlation was observed between preT790M and PD-L2 expression levels.

Conclusion: Results of our study suggest that there may exist the subtypes in EGFR-mutated NSCLC according to PD-L1 status and tumor immune microenvironment. Differential efficacy of EGFR-TKIs based on these subtypes further implies the potential impact of PD-L1 status and tumor immune microenvironment in EGFRblockade along with preT790M.

Citation Format: Yoshiya Matsumoto, Kenji Sawa, Mitsuru Fukui, Jun Oyanagi, Motohiro Izumi, Koichi Ogawa, Tomohiro Suzumura, Tetsuya Watanabe, Hiroyasu Kaneda, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Tomoya Kawaguchi, Yasuhiro Koh. Association between low-frequency pretreatment EGFR T790M mutation and tumor immune microenvironment in patients with EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4906.