Clinical Efficacy of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients with Liver Metastases: A Network Meta-Analysis of Nine Randomized Controlled Trials

Abstract

Purpose: This network meta-analysis (NMA) was conducted to compare the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC) patients with liver metastases.

Materials and methods: English literature was retrieved from the PubMed, American Society of Clinical Oncology, and European Society for Medical Oncology databases from January 2015 to January 2021. We pooled the overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) using an NMA and ranked treatments by the surface under the cumulative ranking curve. Publication bias was evaluated by Begg's and Egger's tests. STATA 15.0 was used for the sensitivity analysis, and the remaining statistical analyses were performed using R 4.0.2.

Results: Nine eligible phase III randomized controlled trials were included, including 1,141 patients with liver metastases. Pembrolizumab+chemotherapy ranked highest, followed by atezolizumab+bevacizumab+chemotherapy and nivolumab. However, no significant difference in OS rates was observed across these three treatments (HR, 0.98; 95% confidence interval [CI], 0.43 to 2.22 for pembrolizumab+chemotherapy vs. atezolizumab+bevacizumab+chemotherapy; HR, 0.91; 95% CI, 0.52 to 1.57 for pembrolizumab+chemotherapy vs. nivolumab). Regarding the PFS rate, atezolizumab+bevacizumab+chemotherapy and pembro-lizumab+chemotherapy ranked highest and no significant difference was observed between them (HR, 0.79; 95% CI, 0.36 to 1.70 for atezolizumab+bevacizumab+chemotherapy vs. pembrolizumab+chemotherapy).

Conclusion: Pembrolizumab+chemotherapy, atezolizumab+bevacizumab+chemotherapy, and nivolumab were superior to other treatments in NSCLC patients with liver metastases. These new findings may help clinicians better select therapeutic strategies for NSCLC patients with liver metastases.

Keywords: Advanced non-small cell lung cancer; Immune checkpoint inhibitors; Liver metastases; Network meta-analysis; Overall survival; Progression-free survival.

Fig. 1

Flow chart of the literature search and research inclusion and exclusion criteria. ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; ICI, immune checkpoint inhibitor.

Fig. 2

Network plot: overall survival (A) and progression-free survival (B). The size of each dot represents the number of patients receiving the corresponding intervention. The width of each line represents the number of corresponding comparison studies. Atezo+Beva+Chemo, atezolizumab+bevacizumab+chemotherapy; Atezo+Chemo, atezolizumab+chemotherapy; Beva+Chemo, bevacizumab+chemotherapy; Chemo, chemotherapy; Nivo, nivolumab; Nivo+Ipi, nivolumab+ipilimumab; Pembro+Chemo, pembrolizumab+chemotherapy.

Fig. 3

Forest plot for the overall population. (A) Hazard ratios (HRs) of overall survival for patients treated with ICIs compared with those treated with Chemo. (B) HRs of overall survival for patients treated with ICIs compared with those treated with Beva+Chemo. (C) HRs of progression-free survival for patients treated with ICIs compared with those treated with Chemo. (D) HRs of progression-free survival for patients treated with ICIs compared with those treated with Beva+Chemo. Atezo+Beva+Chemo, atezolizumab+bevacizumab+chemotherapy; Atezo+Chemo, atezolizumab+chemotherapy; Beva+Chemo, bevacizumab+chemotherapy; Chemo, chemotherapy; CI, confidence interval; ICIs, immune checkpoint inhibitors; Nivo, nivolumab; Nivo+Ipi, nivolumab+ipilimumab; Pembro+Chemo, pembrolizumab+chemotherapy.

Fig. 4

Forest plot of subgroup analysis of histology: overall survival (A–D), progression-free survival (E–G). (A, E) Study of histology of SQ in contrast to Chemo. (B, C, F, G) Study of histology of No-SQ in contrast to Chemo and Beva+Chemo, respectively. (D) Study of histology of both SQ and No-SQ in contrast to Chemo. Atezo+Beva+Chemo, atezolizumab+bevacizumab+chemotherapy; Atezo+Chemo, atezolizumab+chemotherapy; Beva+Chemo, bevacizumab+chemotherapy; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; Nivo, nivolumab; Nivo+Ipi, nivolumab+ipilimumab; No-SQ, nonsquamous; Pembro+Chemo, pembrolizumab+chemotherapy; SQ, squamous.

Fig. 5

Forest plot of subgroup analysis for therapy line. (A, B) Study with therapy line=1 contrast to Chemo and Beva+Chemo, respectively. (C) Study with therapy line ≥ 2 contrast to Chemo. Atezo+Beva+Chemo, atezolizumab+bevacizumab+chemotherapy; Atezo+Chemo, atezolizumab+chemotherapy; Beva+Chemo, bevacizumab+chemotherapy; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; Nivo, nivolumab; Nivo+Ipi, nivolumab+ipilimumab; Pembro+Chemo, pembrolizumab+chemotherapy.