Liver metastases and the efficacy of immune checkpoint inhibitors in advanced lung cancer: A systematic review and meta-analysis

Abstract

BackgroundLiver metastasis is the most common type of lung cancer metastasis, and is a significant prognostic factor in lung cancer. However, the effect of liver metastases on the efficacy of immune checkpoint inhibitors (ICIs) remains inconsistent and controversial. The aim of this study was to explore the relationship between liver metastases and ICI efficacy in patients with advanced lung cancer based on data from randomized controlled trials (RCTs) and observational studies.MethodsPubMed, EMBASE, Cochrane Library databases, conference proceedings, as well as grey literature websites were searched for eligible studies without language restrict ion. Study quality was assessed using Cochrane tools and the Newcastle–Ottawa Quality Assessment Scale (NOS). Outcomes of interest were overall survival (OS) and progression-free survival (PFS). The difference in efficacy between patients with and without liver metastases was calculated by pooling ratios of hazard ratios (HR), as calculated using the deft approach.ResultsA total of 16 RCTs and 14 observational trials were included. Analyses of RCTs revealed a survival benefit for ICI treatment (i.e., ICI monotherapy, ICI + Chemotherapy, dual ICI therapy and dual ICI + Chemotherapy) versus standard therapies among non-small cell lung cancer (NSCLC) patients with liver metastases (PFS HR, 0.77; 95%CI, 0.61–0.97; OS HR, 0.78; 95%CI, 0.68–0.90). NSCLC patients with liver metastases achieved less PFS benefit and comparable OS benefit from ICI treatment compared with those without liver metastases (ratios of PFS–HRs, 1.19; 95%CI, 1.02–1.39; P=0.029; Ratios of OS–HRs, 1.10; 95%CI, 0.94–1.29; P=0.24). For patients with small cell lung cancer (SCLC), ICI treatment achieved a marginal effect on patients with liver metastases as compared with standard therapies (OS HR, 0.94; 95%CI, 0.73–1.23). SCLC patients with liver metastases benefited less from ICI treatment than patients without liver metastases (ratio of OS–HRs, 1.22; 95%CI, 1.01–1.46; P=0.036). In real-world data analysis, liver metastasis could be used as an independent prognostic risk factor, increasing the risk of death by 21% in lung cancer patients receiving ICI treatment compared with those without liver metastases (OS HR, 1.21; 95%CI, 1.17–1.27; P<0.0001). Subgroup analysis confirmed that this association was not modified by race (Asian vs. Western) or number of treatment lines.ConclusionsThe presence of liver metastases does not significantly influence the OS benefit of ICIs in patients with NSCLC. However, a small amount of data shows that liver metastasis restrains the magnitude of OS benefit in patients with SCLC. Liver metastasis has potential as an independent prognostic risk factor for lung cancer patients receiving ICI treatment in clinical practice.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022306449).

Assessing the Relationship Between Liver Metastases and the Survival of Patients With Non-Small Cell Lung Cancer After Immune Checkpoint Inhibitors Treatment: A Systematic Review and Meta-Analysis

“… 40 These are consistent with our findings, again suggesting that treatment combination options are one of the factors affecting the efficacy of immunotherapy. Additional studies 41 , 42 also assessed the relationship between liver metastasis and efficacy of immunotherapy. While these 2 studies were focusing on both NSCLC and small cell lung cancer, we only included and analyzed the data from RCTs conducted in NSCLC patients.…”

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

“…The response rates still exceeded those reported for other therapies, although the efficacy was worse than those without LMs. That meta-analysis of 12 RCTS [ 16 ] also showed that ICIs therapy (ICIs monotherapy, ICIs combined therapy) had a survival advantage in patients with LMs compared to standard therapy (PFS HR, 0.77; 95%CI, 0.61–0.97; OS HR, 0.78; 95%CI, 0.68–0.90). In a real-world retrospective study [ 21 ] of 1470 advanced NSCLC patients, 234 (15.9%) developed LMs at initial diagnosis.…”

“…Some studies have identified LMs as an independent poor prognostic factor in patients who received ICIs [ 3 , 15 , 16 ]. In a retrospective study receiving pembrolizumab for NSCLC, Tumeh et al discovered that NSCLC patients with LMs had a significantly shorter progression-free survival (PFS) (1.8 vs. 4.0 months, p = 0.0094) and lower objective response rate (ORR) (28.6 vs. 56.7%) than patients with non-liver metastasis, and they confirmed that LMs was predictive of reduced response and poor outcome independently [ 15 ].…”

“…The results showed that the ORR of patients with LMs was only 22.5%, and the PFS and OS were shorter. A meta-analysis [ 16 ] involving 12 RCTS showed that NSCLC patients with LMs obtained less PFS and OS benefit from ICIs treatment compared with patients without LMs, suggesting that liver metastasis could be considered an independent prognostic risk factor. But there are less consistent conclusions.…”

“…However, in patients with NSCLC with liver metastases, ICIs therapy still has a survival advantage over conventional therapy [ 6 , 16 , 18 – 21 ]. Pooled analyses of CheckMate017 and CheckMate057 showed that patients with LMs could benefit from second-line nivolumab over conventional docetaxel chemotherapy [ 6 ].…”