Smoking as a Predictor of Cell Surface Receptor Anti PD-1/PD-L1, MUC1, and CTLA-4 as the First Line or Monotherapy and Multiple Therapy Among Them in NSCLC Patients

Background: Smokers have been reported to benefit more than non-smokers when treated with programmed death-1 (PD-1) and programmed death-ligand 1 (PD-1/PD-L1) inhibitors in monotherapy or combined with chemotherapy. Methods: This study is a prospectively planned systematic review and meta-analysis of Hazard ratios (HR) of both progression-free survival (PFS) and overall survival (OS) from the randomized clinical trials treated with cancer drugs in different smoking status. Findings: Among all NSCLC patients, when the data from anti- PD-1/PD-L1, anti-CTLA-4, and anti-MUC1 drugs are combined, the mean HR values of smokers and non-smokers were 0·751 and 1.016, respectively. Meta-analysis with a fixed (FE) effect model indicated that the smokers have an HR value of 0·023 lower than that of the non-smokers. Stratified subgroup meta-analysis indicated that when treated with anti-CTLA-4 drugs, smokers had reduced HR values of 0·152 and 0·165 of reduction on average and FE model meta-analysis, respectively. When treated with an anti-MUC1 drug, smokers had reduced HR values of 1·563 and 0·645 of reduction, on average and FE model meta-analysis, respectively. When treated with a combination between nivolumab and ipilimumab drugs, smokers had reduced HR values of 0·257 and 0·141 of reduction, on average and FE model meta-analysis, respectively. Interpretation: Smoking is an easily available clinical response predictor for anti PD/PD-L1 monotherapy or first-line treatment in lung, urothelial carcinoma, and head and neck cancer. Smokers have a higher chance to benefit from MUC1, and CTLA-4 monotherapy in NSCLC. Smoking potentially is a clinical predictor in the treatment of the combination of these three drugs at least in NSCLC patients.Registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number: CRD42019146402.Funding Statement: This work was partially supported by funding from merit grant I01 BX000671 to WG from the Department of Veterans Affairs and the Veterans Administration Medical Center in Memphis, TN, USA and University of Tennessee Health Science Center, TN, USA. The funding sources have no role in any part of the study as well as the manuscript.Declaration of Interests: Authors have no interest of conflict.Ethics Approval Statement: Ethical approval was not required for this study since it involved no patients.