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Multicenter Study
. 2022 Sep;113(9):3148-3160.
doi: 10.1111/cas.15464. Epub 2022 Jul 18.

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer

Kenji Nakahama  1 , Hiroyasu Kaneda  2 , Masahiko Osawa  3 , Mitsuru Fukui  4 , Motohiro Izumi  5 , Naoki Yoshimoto  6 , Akira Sugimoto  7 , Hiroaki Nagamine  7 , Koichi Ogawa  7 , Yoshiya Matsumoto  7 , Kenji Sawa  7 , Yoko Tani  2 , Shigeki Mitsuoka  2 , Tetsuya Watanabe  7 , Kazuhisa Asai  7 , Tomoya Kawaguchi  2   7
Affiliations
Multicenter Study

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer

Kenji Nakahama et al. Cancer Sci. 2022 Sep.

Abstract

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival, and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.

Keywords: immune checkpoint inhibitor; lung cancer; programmed death-ligand 1; tissue microarray; vascular endothelial growth factor receptor.

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Figures

FIGURE 1
FIGURE 1
Representative immunohistochemical staining for non–small cell lung cancer. (A,B) Vascular endothelial growth factor receptor 2 (VEGFR2) expression was observed in immune cells; arrows indicate the VEGFR2 positive immune cells. (C) VEGFR2 was negative for immune cells. (D,E) VEGFR2 expression was observed in tumor cells. F, VEGFR2 was negative for tumor cells. Original magnification: ×100 (A,D); ×200 (B,C,E,F)
FIGURE 2
FIGURE 2
Objective response rate based on VEGFR2 expression status. IC, immune cells, TC, tumor cells; VEGFR2, vascular endothelial growth factor receptor 2
FIGURE 3
FIGURE 3
Objective response rate based on VEGFR2 and PD‐L1 expression status. IC, immune cells; PD‐L1 TPS, programmed death‐ligand 1 tumor proportion score; TC, tumor cells; VEGFR2, vascular endothelial growth factor receptor 2
FIGURE 4
FIGURE 4
Progression‐free survival (PFS) and overall survival (OS) based on VEGFR2 expression status in patients treated with immune checkpoint inhibitor (ICI) monotherapy therapy. PFS and OS were analyzed according to IC‐VEGFR2 (A,C) and TC‐VEGFR2 (B,D) positivity in patients treated with ICI monotherapy. IC, immune cells; TC, tumor cells; VEGFR2, vascular endothelial growth factor receptor 2
FIGURE 5
FIGURE 5
Progression‐free survival (PFS) and overall survival (OS) based on VEGFR2 expression status in patients treated with immune checkpoint inhibitor (ICI) combination therapy. PFS and OS were analyzed according to IC‐VEGFR2 (A,C) and TC‐VEGFR2 (B,D) positivity in patients treated with ICI combination therapy. IC, immune cells; TC, tumor cells; VEGFR2, vascular endothelial growth factor receptor 2
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