The Efficacy of PD-1/PD-L1 Inhibitors in Patients with Liver Metastasis of Non-Small Cell Lung Cancer: A Real-World Study

Abstract

Background: A controversy exists regarding the efficacy of programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors for patients with non-small cell lung cancer (NSCLC) and liver metastases. Our study retrospectively evaluated the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with liver metastases. Methods: This retrospective study included 1627 lung cancer patients who received immunotherapy. Among 648 patients who had advanced NSCLC and received PD-1/PD-L1 inhibitors, 61 had liver metastases and 587 did not have. We analyzed patient characteristics, progression-free survival (PFS) and overall survival (OS). An exploratory analysis of biomarkers including CD4, CD8 and CD68 for efficacy in patients with liver metastases was also performed. Results: In liver metastasis patients receiving PD-1/PD-L1 inhibitors, the objective response rate (ORR) was 29.5%, the disease control rate (DCR) was 72.1%, PFS was 6.4 months and OS was 15.2 months, which were all worse than those of patients without liver metastases (ORR: 35.8%; DCR: 81.8%; PFS: 7.9 months, p = 0.001; OS: 20.6 months, p = 0.008). When compared to non-liver lesions, the ORR (26.2 vs. 39.3%) and DCR (75.4 vs. 88.5%) of liver lesions were lower. During the analysis of PD-L1 expression, 27 PD-L1-positive patients had a longer PFS than 21 patients in the negative group (p = 0.012). Being PD-L1 positive was the independent prognostic indicators for PFS (p = 0.006). Additionally, the PD-L1 and CD8 dual-positive group responded favorably to PD-1/PD-L1 inhibitors. Conclusions: PD-1/PD-L1 inhibitors are effective in liver metastasis–NSCLC patients. However, the efficacy is inferior when compared to those of patients without liver metastases. In NSCLC patients with liver metastases, PD-L1 expression and CD8+ T cell infiltration can predict the response of PD-1/PD-L1-directed immunotherapy.

Progress of immune checkpoint inhibitors therapy for non-small cell lung cancer with liver metastases

“…Another retrospective study suggested that ICIs combined with cytotoxic agents may be more effective than ICIs alone in NSCLC with liver metastasis [ 19 ]. Another Real-World Study came to a similar conclusion [ 20 ], among 648 patients with advanced NSCLC treated with ICIs, 61 of whom developed LMs. The results showed that patients with LMs receiving PD-1/PD-L1 inhibitors were effective (ORR: 29.5%, disease control rate: 72.1%, PFS: 6.4 months, OS: 15.2 months).…”

“…Another study also found phenotypic changes of CD8+ tumour-infiltrating lymphocytes (TILs) in distal biopsy site of patients with liver metastasis, supporting the possibility that invasion of cancer cells into the liver may trigger liver-specific tolerance mechanisms, thereby reducing the efficacy of systemic antitumor immunotherapy [ 38 ]. Other studies have found that CD8+ T cell infiltration in liver lesions is significantly less than in non-liver lesions, suggesting that liver metastasis is related to CD8+ T cells and may influence treatment outcomes through liver-induced peripheral tolerance [ 3 , 20 ].…”

“…It was found in the liver metastasis subgroup of CheckMate227 that patients with different expression of PD-L1(cutoff 1%) had significant differences in their responses to immunotherapy [ 55 ]. Xie et al reported that immunotherapy significantly prolonged PFS in patients with LMs with positive PD-L1 expression [ 20 ]. In a retrospective analysis of Study 1108 and ATLANTIC [ 44 ], researchers found that durvalumab had better efficacy in LMs with high PD-L1 expression.…”

“…Tumehet et al found that CD8 + T cell count at the edge of invasive tumours was significantly reduced in patients with NSCLC liver metastasis [ 15 ]. Xie et al [ 20 ] also found that CD8+T cell infiltration in liver lesions was significantly less than that in non-liver lesions. These findings suggest that the poor efficacy of PD-1/PD-L1 inhibitors in the treatment of LMs may be related to the lack of CD8+ T cells.…”

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…Tumor mutation burden and programmed death receptor ligand-1 and 1 (PD-L1 and PD-1, respectively), as well as the number and percentage of lymphocytes, are biomarkers for the occurrence of metastasis in NSCLC. PD-1 and PD-L1 inhibitors are most studied and applied currently, and have good therapeutic effects in patients with brain, [10][11][12] liver, 13,14 and bone metastases. 15 Primarily, ICIs assist immune cells in eliminating tumor cells by obstructing their ability to evade the immune system, which thus amplifies their antitumor impact.…”