Predictive value of oncogenic driver subtype, programmed death‐1 ligand (PD‐L1) score, and smoking status on the efficacy of PD‐1/PD‐L1 inhibitors in patients with oncogene‐driven non–small cell lung cancer

Abstract

BACKGROUND: This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. METHODS: The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. RESULTS: In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. CONCLUSIONS: Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.

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

“…Rizvi et al [34] found that smoking increased TMB, especially non-synonymous mutations, which further improved the efficacy of anti-PD-1/PD-L1 therapy. The implication is that smoking history is a surrogate marker of tumor mutation and neoantigen burden, and these, in turn, are surrogates for downstream common denominators that ultimately lead to immune recognition of cancer and activation of effective cancer rejection [35]. The relationship between smoking and PD-L1 expression has not been observed in the previous studies [36][37][38].…”

“…Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. Much more clinically, by means of multivariate analysis, Ng et al [35] found that when the level of PD-L1 ≥ 1%, smoking status was the only significant predictor. Thus, they confirmed that smoking status may be the most important and easily available single predictor of efficacy of anti-PD-1/PD-L1 therapy among the relevant clinical characteristics of NSCLC patients with carcinogenic drive.…”

Responses of smoking and nonsmoking cancer patients to drug treatment

“…A most recent publication reported results from a “Systematic Review and Meta-Analysis on the Association Between Smoking and Survival Benefit of Immunotherapy in Advanced Malignancies.” However, the variable of smoking status was not analyzed in this report. [ 21 ] Its result does not agree with that of Ng et al [ 20 ] Together with a few previous publications on this topic, currently no clear answer to the differences and similarities between smokers and non-smokers in response to variety of drug categories.…”

“…We searched PubMed using the key words “smoking” and “cancer treatment” and “PD-1” in the title and abstract fields. We obtained 32 publications including the report by Ng et al [ 20 ] Most of these publications are on the use of PD-1 drugs in lung cancer, in particular on PD-L1 expression as a predictable marker for suitability of treatment by drugs that inhibit PD-1/PD-L1. However, it is not clear whether smokers and non-smokers at the same level of PD-L1 expression differ in response to drug treatment.…”

Cell Block as a Surrogate for Programmed Death-Ligand 1 Staining Testing in Patients of Non-Small Cell Lung Cancer

“…Then sections were embedded in second antibody, an HRP Rabbit/Mouse immunoglobulins (Dako, Carpinteria, CA) for 1 hour. The details were described previously [13,14].…”