Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer

Abstract

Background: Immune checkpoint inhibitors (ICIs) offer durable progression-free survival (PFS) benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, the predictors of long-term PFS (LTPFS) remain unclear.

Methods: Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and August 2022 were identified. Predictive value of different characteristics was evaluated in LTPFS (PFS ≥ 24 months) compared with short-term PFS (STPFS, PFS ≤ 3 months). Circulating cytokine levels were evaluated in paired peripheral blood samples collected before and after ICIs treatment.

Results: Among 202 patients identified and 171 included (median follow-up: 41.0 months), 44 (25.7%) experienced LTPFS, associated with a 5-year overall survival (OS) rate of 81.2%. Squamous NSCLC, intermediate or poor lung immune prognostic index (LIPI) score, and liver metastases, were negatively associated with LTPFS. High tumor mutational burden (TMB, ≥ 10 mutations/megabase) was enriched in LTPFS compared to STPFS (P = 0.002). Patients with both high TMB and PD-L1 demonstrated the greatest survival benefit from first-line ICIs monotherapy (median PFS: 24.5 months, median OS: 67.0 months). Thirty-eight peripheral blood samples were collected before and after ICIs treatment from 10 patients with LTPFS and 9 with STPFS, which revealed increased CCL11 (P = 0.013) and decreased IL1RA (P = 0.001) and IL17A (P = 0.003) levels in LTPFS after ICIs treatment.

Conclusion: Distinct clinical characteristics, including TMB, PD-L1, pathologic subtypes, LIPI score, number of organs involved, metastatic sites, and dynamic circulating cytokines profile features, can distinguish NSCLC patients achieving LTPFS from those with STPFS following first-line ICIs monotherapy.

Keywords: Cytokine; Immunotherapy; Long-term; Non-small cell lung cancer; Predictive; Survival.

Fig. 1

Flow diagram and grouping of the clinical analysis cohort. NSCLC: non-small cell lung cancer; PFS: progression-free survival; PD: progressive disease

Fig. 2

Clinical outcomes in advanced NSCLC receiving first-line immunotherapy monotherapy. a Kaplan–Meier curves for PFS in the total population. b Kaplan–Meier curves for OS in the total population. c Percentage of patients with LTPFS, STPFS, and non-STPFS/non-LTPFS. d Kaplan–Meier curves for PFS among patients with LTPFS, STPFS, and non-STPFS/non-LTPFS. e Kaplan–Meier curves for OS among patients with LTPFS, STPFS, and non-STPFS/non-LTPFS

Fig. 3

Clinical characteristics of LTPFS. a Stacked bar graphs showing the percentage of patients with PR, SD, PD, and NA as the best response in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Forest plots of univariate and multivariate analyses assessing the association of clinical characteristics with LTPFS compared to STPFS. PR: partly response; SD: stable disease; PD: progressive disease; NA: not available

Fig. 4

Predictive value of PD-L1 and TMB in LTPFS. a Stacked bar graphs showing the percentage of patients with TMB ≥ 10 mut/Mb and < 10 mut/Mb in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Kaplan–Meier curves for PFS stratified by TMB. c Kaplan–Meier curves for OS stratified by TMB. d Stacked bar graphs showing the percentage of patients with different TMB and PD-L1 statuses in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. e Kaplan–Meier curves for PFS stratified by the combination of TMB and PD-L1 status. f Kaplan–Meier curves for OS stratified by the combination of TMB and PD-L1 status

Fig. 5

Circulating biomarkers in predicting LTPFS. a Pre-treatment neutrophil–lymphocyte ratio in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. b Pre-treatment platelet-lymphocyte ratio in the LTPFS, STPFS, and non-STPFS/non-LTPFS groups. c Changes in circulating cytokines after ICIs treatment between STPFS and LTPFS