Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis

Abstract

Background: Immune checkpoint inhibitors, which are a milestone in anti-cancer therapy, have been applied in the treatment of multiple malignancies. Real-world data have suggested that smoking status may be associated with the efficacy of anti-PD-1/PD-L1 therapy. Hereby, to evaluate "smoking benefit or not", we included numerous high-quality randomized controlled clinical trials (RCTs) without any restriction on category. Methods: A systematic search of online database was performed from July 2010 to July 2019. Eligible studies included phase II/III RCTs comparing PD-1/PD-L1 inhibitors with chemotherapy in the treatment of multiple carcinomas and contained subgroup analysis of smoking status. Then, related hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) were pooled.Results: In the initial meta-analysis, compared with chemotherapy, the OS of non-smokers (HR, 0.81; 95% CI, 0.67-0.98) and smokers (HR, 0.77; 95% CI, 0.71-0.83) were significantly prolonged with PD-1/PD-L1 inhibitors. Outcomes from subgroup analysis showed that in anti-PD-1/PD-L1 monotherapy groups, non-smokers showed no significant improvement in OS (HR, 0.94; 95% CI, 0.83-1.06), while the OS of smokers was significantly prolonged (HR, 0.79; 95% CI, 0.74-0.85); in groups of PD-1/PD-L1 inhibitors combined with chemotherapy, the OS of non-smokers (HR, 0.45; 95% CI, 0.28-0.71) and smokers (HR, 0.72; 95% CI, 0.61-0.85) were significantly prolonged. Combined ipilimumab and chemotherapy showed no significance in both groups. Conclusion:Smokers benefit from either anti-PD-1/PD-L1 monotherapy or the combined regimen compared with chemotherapy. Considering cost-effectiveness, monotherapy was recommended to smokers. For non-smokers, only the combined regimen was feasible in non-small cell lung cancer.

Surprising impact of stromal TIL’s on immunotherapy efficacy in a real-world lung cancer study

“…Others have reported on the association of the smoking status and the efficacy of nivolumab, a notion which can be supported biologically through the fact that the tumor mutational burden is higher in smokers [20]. However, in our data smoking history was not predictive for ICI efficacy, this may be due to low number of never smokers.…”

The Confounders of Cancer Immunotherapy: Roles of Lifestyle, Metabolic Disorders and Sociological Factors

“…In a phase III randomized control trial with 1981 NSCLC patients, PD-1 inhibitors worked more efficaciously in patients with a smoking history while nonsmoking patients showed no survival benefit [ 121 ]. A similar meta-analysis in NSCLC, urothelial cancer and HNSCC showed that smokers benefited from anti PD-1/PD-L1 mono or combination therapy while nonsmokers benefitted from a combination of chemo- and immunotherapy [ 122 ]. One possible mechanism behind the increase in response to CPI treatment in smokers is related to an increase in PD-L1 expression by dendritic cells.…”

Recognizing Prognostic and Predictive Biomarkers in the Treatment of Non-Small Cell Lung Cancer (NSCLC) with Immune Checkpoint Inhibitors (ICIs)

“…For OS of chemoimmunotherapy compared to chemotherapy, both smokers and nonsmokers received a benefit with HRs of 0.72 (95% CI 0.61–0.85) and 0.45 (95% CI 0.28–0.71) respectively. 56 …”