Liver metastases and the efficacy of the PD-1 or PD-L1 inhibitors in cancer: a meta-analysis of randomized controlled trials

Abstract

Objective: To explore the relations between liver metastases (LM) and the efficacy of the treatments with programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. Method: Pubmed, Embase, American Society of Clinical Oncology and the European Society for Medical Oncology were searched to select eligible studies about PD-1 or PD-L1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab, Avelumab, Durvalumab, and Atezolizumab). We included only the original randomized controlled trials (RCTs), including the hazard ratios (HR) of death in both patients with LM and patients without LM. Then the data were extracted for the meta-analysis. Subgroup analyses of cancer types and drug types were also performed. Results: 5293 patients [1246 (24%) patients with LM, and 4047 (76%) patients without LM] from the eight RCTs were included for the final analysis. The pooled hazard ratio (HR) of death in the patients with LM was 0.82 (95% CI, 0.71 to 0.93, P = .003) while the pooled HR in the patients without LM was 0.72 (95% CI, 0.66 to 0.79, P < .001). Additionally, no significant difference was found between the two groups (P = .137). Conclusion: No statistically significant association of liver metastases with the efficacy of treatments with PD-1 or PD-L1 inhibitors in the treatment of advanced or metastatic cancer was found in the stratified analyses. Moreover, future studies about the safety of the PD-1 or PD-L1 inhibitors in patients with or without liver metastases are warranted.

PD-L1 expression in liver metastasis: its clinical significance and discordance with primary tumor in colorectal cancer

“…In our study, a higher PD-L1 level in liver metastases suggested that PD-L1 expression might also be involved in liver tolerance. However, combining the relative resistance to PD-1/PD-L1 inhibitors in patients with liver metastasis, we proposed that the ability of PD-1/PD-L1 inhibitors to enhance the immune system's response may be partially counteracted by other mechanisms of liver tolerance, thus compromise the effectiveness of treatment [27].…”

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain

“…Patients who develop liver metastases have been found to have poorer outcomes than those with metastases to other sites, 23 and monoimmunotherapies and chemotherapies have mostly been ineffective in these patients. [24][25][26] In a previous study, patients with baseline liver metastases were found to have improved OS with bevacizumab plus carboplatin and paclitaxel. 9 Therefore, we hypothesized that the poor treatment outcomes with immunotherapy in patients with liver metastases could be attributed to tissue-specific immunoregulation, which might be reversed by combination treatment with bevacizumab.…”

TGF‐β signaling in liver metastasis

“…However, CD8 + T cell counts in the liver were lower compared to non-liver metastatic sites, which might contribute to the higher immune tolerance of the liver. 127,128 Therefore, combinational therapies targeting the immune system might be of added value specifically in the liver. As TGF-β shows a clear immune suppressive role, inhibition of TGF-β might elevate this suppression, and combining this inhibition with immunotherapy might improve the response rate of immunotherapy.…”