Efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer patients with different metastases

BACKGROUND: To investigate the significance of metastatic sites and their numbers to the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 232 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified from January 2016 to February 2019. Six metastatic sites (brain, liver, bone, adrenal gland, contralateral lung, pleura) were included to analyze their significance to ICI efficacy. To explore the association between liver metastasis (LM) and tumor T cell infiltration, 46 patients with available tumor specimens were tested for PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) density. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves. RESULTS: More metastatic organs involved were associated with significantly worse PFS (0–1 organ: 5.7 months, 2–3 organs: 3.5 months, ≥4 organs: 2.7 months, P<0.001) and lower ORR (36% vs. 29.8% vs. 18.2%, P<0.001). Patients with brain metastasis (BM) had shorter PFS and OS than those without (P=0.002, P=0.021; respectively). Notably, patients with LM had the shortest PFS (2.3 months, P=0.005) and numerically shortest OS (9.8 months, P=0.238) compared with those with other organ metastases. Multivariate analysis revealed that LM was independently associated with inferior PFS (P<0.001). Immunostaining showed that patients with LM tended to have lower proportions of PD-L1+CD8+TIL+ tumors compared with those without LM (0% vs. 30.8%, P=0.088). Interestingly, ICI-based combination therapy could effectively control LM with improved intrahepatic PFS (P=0.056) and ORR (41.7% vs. 6.7%, P=0.030). CONCLUSIONS: More metastatic organs involved were associated with poorer response to ICIs. LM was a negative predictive factor for patients treated with ICI monotherapy and the combination strategy might effectively control LM.