The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

Abstract

What is known and Objective Smoking has a notable influence on the efficacy of medications for lung cancer. Previous studies illustrated the correlation between smoking and the efficacy of first‐line Epidermal Growth Factor Receptors‐Tyrosine Kinase Inhibitors (EGFR‐TKIs). The benefit of smokers in immunotherapy was still controversial. Here, we investigated the impact of smoking on clinical outcomes of molecularly targeted therapies or immunotherapy in Non‐Small Cell Lung Cancer (NSCLC). Methods We performed meta‐analysis including trials comparing EGFR‐TKIs, Anaplastic Lymphoma Kinase (ALK) inhibitors or Immune Checkpoint Inhibitors (ICIs) against chemotherapy in NSCLC. The Progression‐Free Survival (PFS)‐Hazard Ratios (HRs) of two groups served as the index and we used random effects to pool outcomes. Results and discussion Twenty randomized trials were selected. Compared with chemotherapy, treatment with EGFR‐TKIs had similar benefit in never‐smokers (PFS: HR = 0.46, 95% CI 0.30 to 0.69) and smokers (PFS: HR = 0.68, 95% CI 0.50 to 0.91; p = 0.135) while non‐smokers (PFS: HR = 0.32, 95% CI 0.23 to 0.44) had better benefit from first‐line EGFR‐TKIs than smokers (PFS: HR = 0.54, 95% CI 0.41 to 0.71; p = 0.02). Treatment with ALK inhibitors had similar benefits in never‐smokers (PFS: HR = 0.43, 95% CI 0.35 to 0.53) and smokers (PFS: HR = 0.56, 95% CI 0.44 to 0.71; p = 0.406). The benefit of ICIs in smokers (PFS: HR = 0.79, 95% CI 0.64 to 0.98) was significantly greater than never‐smokers (PFS: HR = 1.81, 95% CI 1.27 to 2.57; p = 0.004). What is new and Conclusion Smoking status is an important clinical predictor of therapy in NSCLC. Never‐smokers and smokers have similar benefit with EGFR‐TKIs therapy compared with chemotherapy, while never‐smokers have greater benefit after first‐line EGFR‐TKIs therapy. There was similar benefit in never‐smokers and smokers when using ALK inhibitors over chemotherapy. Additionally, ICIs treatment over chemotherapy leads to more favourable PFS in smokers both in first‐line and second‐line settings.

Relationship between Patients’ Baseline Characteristics and Survival Benefits in Immunotherapy-Treated Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

“…The results suggest that the using of ICIs significantly prolong survival in smokers with NSCLC compared with control groups, but not in never smokers. This is consistent with the result obtained by Li et al [ 22 ] and El-Osta and Jafri [ 48 ]. Some studies have proved that there is a significant correlation between the clinical benefits of ICIs and TMB in patients with NSCLC.…”

“…In the end, we also evaluated the relationship between patients' smoking status and survival benefits in immunotherapy-treated NSCLC. Although similar researches have been conducted in several previous meta-analyses [ 19 , 22 , 48 ], the results are open to debate due to the small number of trials included and the lack of detailed subgroup analysis. For these reasons, we thoroughly searched the database and included the latest high-quality trials.…”

Impact of Smoking on Response to the First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

“…Tobacco use impairs the treatment efficacy of lung cancer and shortens patients’ survival as smoking tobacco directly influences response to anti-tumor drugs by affecting drugs metabolism ( Gemine and Lewis, 2016 ). On the contrary, immunotherapy performs better in NSCLC patients with a smoking history ( Li et al, 2020 ; Nie et al, 2020 ; Zhao et al, 2021 ). Notably, both studies in the Asian-only subgroup used alectinib, despite dosage differences, which may suggest the excellent efficacy of alectinib in smokers, while the experimental ALK-TKIs in another group dramatically varied in multiracial studies.…”

“…On the one hand, it is well-known that smoking is of great importance in the morbidity and mortality of lung cancer ( Loeb et al, 1984 ; Jung et al, 2016 ). On the other hand, the impact of smoking on treatment decisions is controversial and is recently being widely investigated ( Lin et al, 2018 ; Li et al, 2020 ; Xiao et al, 2020 ; Chen et al, 2021 ; Zhao et al, 2021 ). To our knowledge, the comprehensive and systematic analysis of the relationship between smoking status and first-line treatment efficacy of advanced ALK-positive NSCLC has not been reported yet.…”

“…To date, previous meta-analyses have investigated the correlation between smoking status and the efficacy of advanced NSCLC treatments ( Breadner et al, 2020 ; Li et al, 2020 ). However, conflict occurs in the benefit of never-smoking, as one previous meta-analysis found that never-smokers tended to benefit from ALK-TKIs compared with cytotoxic chemotherapy, whereas another denoted that there were similar benefits regardless of the smoking status.…”