The effect of smoking status on efficacy of immune checkpoint inhibitors in metastatic non-small cell lung cancer: A systematic review and meta-analysis

Abstract

Background: It remains uncertain whether smoking status can effect efficacy of immune checkpoint inhibitors (ICIs) in metastatic non-small cell lung cancer (NSCLC). We performed a meta-analysis to address this issue.Patients and methods: PubMed, Embase, Cochrane Library, Web of Science, and international meetings were searched until April 1, 2021, for phase 2 and 3 randomized controlled trials (RCTs) which compared ICIs with chemotherapy (CT) and reported overall survival (OS) and/or progression-free survival (PFS) data according to smoking status. This meta-analysis was registered in INPLASY platform (#INPLASY202140025). The random-effect model was used for statistical analysis. Findings: Twenty-eight articles from 24 RCTs including 13918 patients were eligible. ICIs significantly prolonged OS than CT in smokers (hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.69-0.81), but not in never-smokers (HR = 0.87, 95% CI: 0.74-1.04); while there was no significant treatment-smoking interaction (P interaction = 0.11). Significant heterogeneity was observed for both smokers (OS: I 2 = 60%, P = 0.0002; PFS: I 2 = 74%, P < 0.0001) and never smokers (PFS: I 2 = 69%, P < 0.0001). Subgroup analyses revealed that ICIs monotherapy significantly improved OS in smokers (HR = 0.76, 95% CI: 0.69-0.85) but not in never-smokers (HR = 0.93, 95% CI: 0.77-1.12, P interaction = 0.07), and treatment-smoking interaction was significant in patients with PD-L1 50% (HR, 0.61 vs 1.18; P interaction = 0.005). ICIs plus CT achieved better OS either in smokers or never-smokers (HR, 0.76 vs 0.61; P interaction = 0.39), while dual ICIs combination prolonged OS only in smokers but never-smokers (HR, 0.68 vs 1.02; P interaction = 0.02). Interpretation: Either ICIs monotherapy or combination therapy was superior to CT in smokers. While ICIs monotherapy and dual ICIs combination were less effective in never-smokers, and ICIs plus CT might be the optimal selection. Nevertheless, given the limitation of the high heterogeneity of studies included, the findings need to be confirmed by future RCTs focusing on this subject.

Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer

“…Our results are supported by other studies. A recent meta-analysis by Dai et al [ 100 ] found that ICI monotherapy and dual ICIs improved survival in ever smokers but not never smokers, regardless of PD-L1, and that the addition of chemotherapy was able to improve survival for both groups. Several real-world studies and analyses further support these observed associations [ 101 , 102 , 103 ].…”

Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition

“…Further trials are needed as there are no RCTs yet that specifically focus on the value of immunotherapy in the subgroup of ALK-positive NSCLC, probably due to small patient numbers. In contrast, there are numerous RCTs that have shown the lacking benefit of immunotherapy in never smokers [29,30]. The patient in this case report stopped smoking twenty years ago and had only a ten pack-year history of tobacco smoking.…”

The use of immunotherapy in older patients with advanced non-small cell lung cancer

“…Overall, considering that a single biomarker, even though it may be crucial for posing the indication for a specific agent, is not able to catch the complexity of a patient, all known prognostic and predictive factors should be considered during the pretreatment evaluation (Fig. 2), including some parameters that are fairly easy to assess, such as the tumor burden, both radiologically and laboratory evaluated [103], the ECOG PS [104] and the tobacco smoking status [105]. Among immunoinflammatory indexes, the Lung Immune Prognostic Index (LIPI) score [106,107] was retrospectively tested in a cohort of 191 patients aged ≥ 70 with advanced tumors (27% NSCLC) treated with ICBs.…”